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CONTENTS THE AMERICAN JOURNAL OF CARDIOLOGY�

VOL. 99, NO. 11 JUNE 1, 2007

Coronary Artery Disease

Relation of Body Mass Index to Outcome in PatientsWith Known or Suspected Coronary ArteryDisease ........................................................1485Wael Galal, Ron T. van Domburg, Harm H.H. Feringa,Olaf Schouten, Abdou Elhendy, Jeroen J. Bax,Adel M.M. Awara, Jan Klein, and Don Poldermans

Prognostic Implications of Dipyridamole orDobutamine Stress Echocardiography for Evaluationof Patients >65 Years of Age With Known orSuspected Coronary Heart Disease .................1491Lauro Cortigiani, Riccardo Bigi, Rosa Sicari,Patrizia Landi, Francesco Bovenzi, and Eugenio Picano

Patterns of Aspirin Dosing in Non–ST-ElevationAcute Coronary Syndromes in the CRUSADE QualityImprovement Initiative ...................................1496Sumit Tickoo, Matthew T. Roe, Eric D. Peterson,Sarah Milford-Beland, E. Magnus Ohman,W. Brian Gibler, Charles V. Pollack, Jr., andChristopher P. Cannon, for the CRUSADE Investigators

Comparison of Characteristics of Future MyocardialInfarctions in Women With Baseline High VersusBaseline Low Levels of High-Sensitivity C-ReactiveProtein .........................................................1500Sandeep Bansal and Paul M. Ridker

Comparison of Values of Wide-Range C-ReactiveProtein to High-Sensitivity C-Reactive Protein inPatients Undergoing Coronary Angiography ...1504Yaron Arbel, Yoav Eros, Ori Rogowski, Shlomo Berliner,Itzhak Shapira, Gad Keren, Yafa Vered, andShmuel Banai

Coronary Circulation Responses to Binodenoson, aSelective Adenosine A2A Receptor Agonist .......1507John McB. Hodgson, Nabil Dib, Morton J. Kern,Richard G. Bach, and Richard J. Barrett

Effect of Anemia on Hemorrhagic Complicationsand Mortality Following Percutaneous CoronaryIntervention ..................................................1513Michele D. Voeltz, Amar D. Patel, Frederick Feit,Reza Fazel, A. Michael Lincoff, andSteven V. Manoukian

Measuring Aspirin Resistance, ClopidogrelResponsiveness, and Postprocedural Markers ofMyonecrosis in Patients Undergoing PercutaneousCoronary Intervention ....................................1518Ashesh N. Buch, Suman Singh, Probal Roy,Aamir Javaid, Kimberly A. Smith, Christopher E. George,Augusto D. Pichard, Lowell F. Satler, Kenneth M. Kent,William O. Suddath, and Ron Waksman

Effect of Early Statin Treatment at Standard Doseson Long-Term Clinical Outcomes in Patients WithAcute Myocardial Infarction (The Heart Institute ofJapan, Department of Cardiology Statin EvaluationProgram) ......................................................1523Michitaka Nagashima, Ryo Koyanagi, Hiroshi Kasanuki,Nobuhisa Hagiwara, Jun-ichi Yamaguchi,Nobuhiko Atsuchi, Takashi Honda, Kazuo Haze,Tetsuya Sumiyoshi, Mitsuyoshi Urashima, andHiroshi Ogawa, for the Heart Institute of Japan,Department of Cardiology (HIJC) Investigators

Comparison of Multidetector 64-Slice ComputedTomographic Angiography to CoronaryAngiography to Assess the Patency of CoronaryArtery Bypass Grafts .....................................1529Refat Jabara, Nicolas Chronos, Larry Klein,Steven Eisenberg, Rebecca Allen, Shannon Bradford,and Stephen Frohwein

Preventive Cardiology

Relation of Aortic Valve Calcium to MyocardialIschemic Perfusion in Individuals With a LowCoronary Artery Calcium Score ......................1535John Ho, Shannon FitzGerald, John Cannaday,Lisa Stolfus, Dana Weilbacher, Yvette Henderson,Tiffany Newman, Robin Whitehead, and Nina Radford

Comparison of Rosuvastatin Versus Atorvastatin inSouth-Asian Patients at Risk of Coronary HeartDisease (from the IRIS Trial) ...........................1538Prakash C. Deedwania, Milan Gupta, Michael Stein,Joseph Ycas, and Alex Gold, for the IRIS Study Group

Arrhythmias and ConductionDisturbances

Effect of Candesartan and Various InflammatoryMarkers on Maintenance of Sinus Rhythm AfterElectrical Cardioversion for Atrial Fibrillation .....1544Arnljot Tveit, Ingebjørg Seljeflot, Irene Grundvold,Michael Abdelnoor, Pal Smith, and Harald Arnesen

CONTENTS A5

Systemic Hypertension

Factors Influencing Blood Pressure Response toTrandolapril Add-On Therapy in Patients TakingVerapamil SR (from the International Verapamil SR/Trandolapril [INVEST] Study) ..........................1549Martin Brunner, Rhonda M. Cooper-DeHoff, Yan Gong,Jason H. Karnes, Taimour Y. Langaee, Carl J. Pepine,and Julie A. Johnson, for the INVEST Investigators

Heart Failure

Value of Myocardial Viability Estimation UsingDobutamine Stress Echocardiography in AssessingRisk Preoperatively Before Noncardiac VascularSurgery in Patients With Left Ventricular EjectionFraction <35 ................................................1555Stefanos E. Karagiannis, Harm H.H. Feringa,Radosav Vidakovic, Ron van Domburg, Olaf Schouten,Jeroen J. Bax, George Karatasakis, Dennis V. Cokkinos,and Don Poldermans

Roundtable Discussion (CME)

The Editor’s Roundtable: Acute DecompensatedHeart Failure ................................................1560Vincent E. Friedewald, Mihai Gheorghiade,Clyde W. Yancy, James B. Young, andWilliam C. Roberts

Valvular Heart Disease

Effect of Metoprolol on Heart Rate Variability inSymptomatic Patients With Mitral ValveProlapse .......................................................1568Gulten Tacoy, Akif Serhat Balcıoglu, Ugur Arslan,Emre Durakoglugil, Guliz Erdem, Murat Ozdemir, andAtiye Cengel

Comparison of Long-Term Outcome After MitralValve Replacement or Repeated Balloon MitralValvotomy in Patients With Restenosis AfterPrevious Balloon Valvotomy ..........................1571Jin-Bae Kim, Jong-Won Ha, Jung-Sun Kim,Won-Heum Shim, Seok-Min Kang, Young-Guk Ko,Donghoon Choi, Yangsoo Jang, Namsik Chung,Seung-Yun Cho, and Sung-Soon Kim

Cardiomyopathy

Usefulness and Safety of Transcatheter Ablation ofAtrial Fibrillation in Patients With HypertrophicCardiomyopathy ...........................................1575Fiorenzo Gaita, Paolo Di Donna, Iacopo Olivotto,Marco Scaglione, Ivana Ferrero, Antonio Montefusco,Domenico Caponi, Maria Rosa Conte, Stefano Nistri,and Franco Cecchi

Congenital Heart Disease

Effect of Chronic Afterload Increase on LeftVentricular Myocardial Function in Patients WithCongenital Left-Sided Obstructive Lesions ........1582Yat-Yin Lam, Mehmet G. Kaya, Wei Li,Michael A. Gatzoulis, and Michael Y. Henein

Frequency of Development of Aortic CuspalProlapse and Aortic Regurgitation in Patients WithSubaortic Ventricular Septal Defect Diagnosed at<1 Year of Age ...........................................1588Susan F. Saleeb, David E. Solowiejczyk,Julie S. Glickstein, Rosalind Korsin, Welton M. Gersony,and Daphne T. Hsu

Comparison of Echocardiographic and CardiacMagnetic Resonance Imaging for Assessing RightVentricular Function in Adults With RepairedTetralogy of Fallot .........................................1593Markus Schwerzmann, Ahmed M. Samman,Omid Salehian, Johan Holm, Yves Provost,Gary D. Webb, Judith Therrien, Samuel C. Siu, andCandice K. Silversides

Miscellaneous

Association of Multiple Inflammatory Markers withCarotid Intimal Medial Thickness and Stenosis (fromthe Framingham Heart Study) ........................1598Avni H. Thakore, Chao-Yu Guo, Martin G. Larson,Diane Corey, Thomas J. Wang, Ramachandran S. Vasan,Ralph B. D’Agostino, Sr., Izabella Lipinska,John F. Keaney, Jr., Emelia J. Benjamin, andChristopher J. O’Donnell

Changes in Coronary Anatomy and PhysiologyAfter Heart Transplantation ...........................1603Atsushi Hirohata, Mamoo Nakamura,Katsuhisa Waseda, Yasuhiro Honda, David P. Lee,Randall H. Vagelos, Sharon A. Hunt,Hannah A. Valantine, Paul G. Yock, Peter J. Fitzgerald,Alan C. Yeung, and William F. Fearon

Incidental Detection of Cancers and Other Non-Cardiac Abnormalities on Coronary MultisliceComputed Tomography .................................1608Yoshiyuki Kawano, Akira Tamura, Yukie Goto,Kazuhiro Shinozaki, Hirofumi Zaizen, and Junichi Kadota

Relation Between Depressive Symptoms andCommon Carotid Artery Atherosclerosis in AmericanPersons >65 Years of Age ............................1610Mohammed F. Faramawi, Jeanette Gustat,Rachel P. Wildman, Janet Rice, Eric Johnson, andRoger Sherwin

A6 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 99 JUNE 1, 2007

MethodsA Comparison by Medicine Residents of PhysicalExamination Versus Hand-Carried Ultrasound forEstimation of Right Atrial Pressure .................1614J. Matthew Brennan, John E. Blair,Sascha Goonewardena, Adam Ronan, Dipak Shah,Samip Vasaiwala, Erica Brooks, Ari Levy,James N. Kirkpatrick, and Kirk T. Spencer

EditorialsCardioversion for Atrial Fibrillation: DoesInflammation Matter? ....................................1617Timothy Watson, Puneet Kakar, and Gregory Y.H. Lip

A New Generation of Coronary Vasodilators inStress Perfusion Imaging ...............................1619Ami E. Iskandrian

Readers’ CommentsAlcohol-Induced Hypertension—Just How Much of aCardiovascular Risk Factor? ...........................1621

Can Multislice Computed Tomography in anAsymptomatic High-Risk Population Really Impacton Therapeutic Decision-Making? ...................1621

Correction ....................................................1622

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Classifieds on pages A25–A27

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CONTENTS A7

EDITOR IN CHIEF

William C. Roberts, MDBaylor Heart & Vascular InstituteBaylor University Medical CenterWadley Tower No. 4573600 Gaston AvenueDallas, Texas 75246(214)826-8252Fax: (214)826-2855

ASSOCIATE EDITORS

Paul A. GrayburnClyde W. YancyASSISTANT EDITORSVincent E. FriedewaldRobert C. KowalCarlos E. Velasco

EDITORIAL BOARDCARDIOVASCULARMEDICINEIn AdultsJ. Dawn AbbottJonathan AbramsJoseph S. AlpertMartin A. AlpertEzra A. AmsterdamJeffrey L. AndersonRichard W. AsingerGary John BaladyThomas M. BashoreEric BatesJeroen J. BaxGeorge A. BellerWilliam E. BodenMonty M. BodenheimerRobert O. BonowJeffrey S. BorerHarisios BoudoulasMartial G. BourassaEugene BraunwaldJeffrey A. BrinkerDavid L. BrownAlfred E. BuxtonMichael E. CainRichard O. Cannon IIIBernard R. ChaitmanKanu ChatterjeeJohn S. ChildRobert J. CodyLawrence S. CohenMarc CohenC. Richard ContiMichael H. CrawfordGregory J. DehmerEfthymios N. DeliargyrisJames A. de LemosAnthony N. DeMariaPablo DenesGeorge A. DiamondJohn P. DiMarcoMichael J. DomanskiGerald DorrosUri ElkayamKenneth A. EllenbogenMyrvin H. EllestadStephen G. EllisToby R. EngelAndrew E. EpsteinN. A. Mark Estes, IIIMichael Ezekowitz

Rodney H. FalkJohn A. FarmerDavid P. FaxonTed FeldmanJack FerlinzJerome L. FlegGerald F. FletcherJames S. ForresterJoseph A. FranciosaGary S. FrancisW. Bruce FyeWilliam H. GaaschWilliam GanzJulius M. GardinBernard J. GershMihai GheorghiadeRaymond GibbonsD. Luke GlancyStephen P. GlasserMichael R. GoldSamuel Z. GoldhaberRobert E. GoldsteinSidney GoldsteinSteven A. GoldsteinJ. Anthony GomesAntonio M. Gotto, Jr.K. Lance GouldDonald C. HarrisonRichard H. HelfantPhilip D. HenryL. David HillisDavid R. Holmes, Jr.Mun K. HongYuling HongWilliam G. HundleyAmi S. IskandrianAllan S. JaffeJoel S. KarlinerJohn A. KastorSanjiv KaulKenneth M. KentRichard E. KerberDean J. KereiakesMorton J. KernSpencer B. King IIIRobert E. KleigerGeorge J. KleinLloyd W. KleinPaul KligfieldRobert A. KlonerJohn B. KostisCharles LandauRichard L. Lange

Carl J. LavieCarl V. LeierJoseph Lindsay, Jr.Gregory Y.H. LipJoseph LoscalzoG.B. John ManciniFrancis E. MarchlinskiFrank I. MarcusBarry J. MaronRandolph P. MartinAttilo MaseriDean T. MasonCharles MaynardMichael D. McGoonDarren K. McGuireRaymond G. McKayJawahar L. MehtaRichard S. MeltzerFranz H. MesserliEric L. MichelsonRichard V. MilaniAlan B. MillerGary S. MintzFred MoradyArthur J. MossJames E. MullerRobert J. MyerburgGerald B. NaccarelliNavin C. NandaChristopher O’ConnorRobert A. O’RourkeErik Magnus OhmanAntonio PacificoRichard L. PageSebastian T. PalmeriEugene R. PassamaniAlan S. PearlmanCarl J. PepineJoseph K. PerloffBertram PittDon PoldermansPhilip J. PodridArshed A. QuyyumiCharles E. RackleyC. Venkata RamNathaniel ReichekRobert RobertsWilliam J. RogersMaurice E. SaranoMelvin M. ScheinmanDavid J. SchneiderJohn S. SchroederPravin M. Shah

Prediman K. ShahJamshid ShiraniRobert J. SiegelMarc A. SilverMark E. SilvermanRoss J. Simpson, Jr.Steven N. SinghSidney C. Smith, Jr.Burton E. SobelJohn C. SombergDavid H. SpodickLynne W. StevensonJohn R. StrattonJonathan M. TobisEric J. TopolTeresa S. M. TsangByron F. VandenbergHector O. VenturaGeorge W. VetrovecRobert A. VogelRon WaksmanDavid D. WatersNanette K. WengerRobert WilenskyJames T. WillersonBarry L. ZaretDouglas P. ZipesIn Infants and ChildrenHugh D. AllenBruce S. AlpertStanley J. GoldbergWarren G. GuntherothHoward P. GutgesellJohn D. KuglerJames E. LockJohn W. MooreLowell W. PerryDavid J. SahnRichard M. SchiekenCARDIOVASCULAR SURGERYEugene H. BlackstoneLawrence I. BonchekLawrence H. CohnJohn A. ElefteriadesThomas L. SprayRELATED SPECIALISTSL. Maximilian BujaMichael EmmettBarry A. FranklinCharles B. HigginsJeffrey E. SaffitzRenu Virmani

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Relation of Body Mass Index to Outcome in Patients With Knownor Suspected Coronary Artery Disease

Wael Galal, MDa, Ron T. van Domburg, PhDb, Harm H.H. Feringa, MDb, Olaf Schouten, MDc,Abdou Elhendy, MDf, Jeroen J. Bax, MDd, Adel M.M. Awara, MDe, Jan Klein, MDa,

and Don Poldermans, MDa,*

Increased body mass index (BMI), a parameter of total body fat content, is associated withan increased mortality in the general population. However, recent studies have shown aparadoxic relation between BMI and mortality in specific patient populations. This studyinvestigated the association of BMI with long-term mortality in patients with known orsuspected coronary artery disease. In a retrospective cohort study of 5,950 patients (meanage 61 � 13 years; 67% men), BMI, cardiovascular risk markers (age, gender, hypertension,diabetes, current smoking, angina pectoris, old myocardial infarction, heart failure, hyper-cholesterolemia, and previous coronary revascularization), and outcome were noted. Thepatient population was categorized as underweight, normal, overweight, and obese basedon BMI according to the World Health Organization classification. Mean follow-up timewas 6 � 2.6 years. Incidences of long-term mortality in underweight, normal, overweight,and obese were 39%, 35%, 24%, and 20%, respectively. In a multivariate analysis model, thehazard ratio (HR) for mortality in underweight patients was 2.4 (95% confidence interval[CI] 1.7 to 3.7). Overweight and obese patients had a significantly lower mortality thanpatients with a normal BMI (HR 0.65, 95% CI 0.6 to 0.7, for overweight; HR 0.61, 95% CI0.5 to 0.7, for obese patients). In conclusion, BMI is inversely related to long-term mortalityin patients with known or suspected coronary artery disease. A lower BMI was anindependent predictor of long-term mortality, whereas an improved outcome was observedin overweight and obese patients. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol
2007;99:1485–1490)
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n this study, we evaluated the effect of body mass indexBMI) on long-term mortality of patients with known oruspected coronary artery disease (CAD) after controllingor coronary risk factors.

ethods

e retrospectively studied 5,950 adult patients with knownr suspected CAD who were referred to the outpatient clinicsf the Erasmus University Medical Center (Rotterdam, Theetherlands) between January 1993 and January 2005. Our

tudy population consisted of high-risk patients referred tohe vascular clinic for evaluation of systemic atherosclero-is, CAD or peripheral arterial disease, and for managementf underlying risk factors. In these patients, BMI was mea-

Departments of aAnesthesiology, bCardiology, and cVascular Surgery,rasmus MC, Rotterdam, and dDepartment of Cardiology, Leiden Univer-ity MC, Leiden, The Netherlands; eDepartment of Anesthesiology, Tantaaculty of Medicine, Tanta, Egypt; and fDepartment of Cardiology, Marsh-eld Clinics, Marshfield, Wisconsin. Manuscript received October 9, 2006;evised manuscript received and accepted January 10, 2007.

Dr. Galal is supported by an unrestricted educational grant from thegyptian government, Cairo, Egypt. Dr. Feringa is supported by an unre-tricted educational grant from Sanofi-Aventis/BMS, Gouda, The Nether-ands. Dr. Schouten is supported by an unrestricted educational grant fromijf en Leven, Rotterdam, The Netherlands.

*Corresponding author: Tel: 31-10-463-4613; fax: 31-10-463-4957.
oE-mail address: [email protected] (D. Poldermans).
002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2007.01.018

ured at the time of the first visit and cardiac risk factorsere noted. We categorized patients as having known (n �,486; 42%) or suspected (n � 3,464; 58%) CAD. KnownAD was indicated by the presence of angina pectoris,revious myocardial infarction (MI), or previous coronaryevascularization (i.e., previous percutaneous coronary in-ervention and/or coronary artery bypass grafting). Patientsith atypical chest pain, dyspnea, atypical electrocardio-raphic abnormalities (i.e., ST-segment changes without Qaves), or �2 cardiac risk factors (male gender, current

moker, hypertension, renal dysfunction, hypercholesterol-mia, and diabetes) were considered to have suspectedAD.1

The hospital medical ethical committee approved thetudy protocol. Clinical data were obtained by thorougheview of medical records and electronic databases andncluded age, height, weight, previous MI, angina pectoris,oronary artery revascularization, heart failure (HF), diabe-es mellitus (fasting glucose level �7.0 mmol/L or require-ent of hypoglycemic agents), hypertension (blood pressure140/90 mm Hg or intake of antihypertensive medications),

urrent smoker, hypercholesterolemia (plasma cholesterolevel �5.5 mmol/L [213 mg/dl] or intake of lipid-loweringgents), and renal dysfunction (serum creatinine level �2.0g/dl [177 �mol/L] or requirement of dialysis). HF was

onsidered if a patient had a history of shortness of breathn exertion or at rest, decreased physical ability, or swelling
f lower limbs proved clinically or at echocardiography
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1486 The American Journal of Cardiology (www.AJConline.org)

pon medical consultation to be valid for signs of cardiacecompensation.2 Patients were assessed for cardiac medi-ation use. BMI was calculated as body weight (kilograms)ivided by height squared (meters). Accordingly, patientsere grouped according to BMI classifications of the Worldealth Organization3 and the National Institutes of Health4

s underweight (BMI �18.5 kg/m2), normal weight (18.5 to4.9 kg/m2), overweight (25 to 29.9 kg/m2), or obese (�30g/m2).

End points were death from all causes and hard cardiacvents (cardiac death or MI). Cardiac death was defined aseath from any cardiac cause including sudden cardiaceath, MI, congestive HF, cardiac arrhythmias, and death inhich there is evidence of a primary cardiac cause that

ould not be classified as mentioned above. Sudden cardiaceath was defined as unexpected natural death due to car-iac causes within 1 hour of onset of acute symptoms.riteria of MI diagnosis included �2 of the following: highardiac enzyme levels (creatine kinase [CK] level �190/L and CK-MB level �14 U/L, or CK-MB fraction �6%f total CK, or cardiac troponin T level �0.1 ng/ml), de-elopment of typical electrocardiographic changes (new Qaves �1 mm or �30 ms at electrocardiography), and

ypical chest pain. Events were verified by review of hos-ital records or contacting general practitioners, civil regis-ry, or participants’ families (by questionnaires in telephonealls) if needed.

Statistical analysis was performed using the syntax com-ands of SPSS 13.0 for Windows (SPSS, Inc., Chicago,

llinois). Categorical variables are expressed as percentagesnd were compared using Pearson’s chi-square test. Con-inuous variables are presented as mean � SD and wereompared using Student’s t test. Primary end points werell-cause mortality and hard cardiac events (cardiac deathnd/or nonfatal MI). Cox proportional hazards models weresed to determine univariate and multivariate predictors ofortality. Results on all-cause mortality, cardiac death, andI were generated by Kaplan-Meier estimates and differ-

nces in mortality were compared using log-rank test. Haz-rd ratios (HRs) and 95% confidence intervals (CIs) wereerived from a Cox proportional hazard stepwise regressionodel. Assumptions of the proportional hazard model (pro-

ortional hazard, lack of interaction, and linearity of con-inuous variables) were tested and found valid unless oth-rwise indicated. Proportional hazards assumptions wereested by constructing interaction terms between variablesnd time to each end point. Cox regression analyses showedo statistically significant interactions with time (eachvalue �0.05). Model selection is based on the stepwise

rinciple, where the limits for entering and removing vari-bles were 0.05. BMI was divided into its quartiles in alltatistical examinations. The group of normal weight pa-ients served in analyses as the reference group (i.e., HR 1),nd the risk of the other 3 BMI groups compared with thisroup was estimated by HRs from the proportional hazardodels. Multivariate analysis was done by adjusting for all

aseline characteristics including age, gender, and dobut-mine stress echocardiographic results (to eliminate anyignificant interaction with other confounders). For all tests,

p value �0.05 (2-sided) was considered statistically
ignificant. w
esults

istribution of BMI in the population was approximatelyormal, with a mean of 25.4 � 4.0 kg/m2 (Figure 1). Only% of the study population was underweight, 42% wasormal or overweight, and 14% was obese. Clinical char-cteristics of the 4 BMI categories are presented in Table 1.ean age was 60.8 � 13 years and was not different across

ifferent BMI subsets. There were more men in the normalnd overweight groups and more women in the underweightroup. Current smokers were more prevalent in the under-eight group. Diabetes and hypertension were noted more

requently in obese patients. Distribution of coronary riskactors across different groups is presented in Figure 2.

Patients were followed for a mean period of 6 � 2.6ears. Minimum follow-up period was 6 months. In total,,828 of 5,950 patients (64%) were referred for dobutaminetress echocardiography after their initial visit. Stress-nduced myocardial ischemia was assessed in 1,205 of,750 patients (69%) with known CAD and in 651 of 2,078atients (31%) with suspected CAD. In total 1,786 of 5,950atients underwent major vascular noncardiac surgery dur-ng the follow-up period. Of 1,786 patients, 38 (2.1%) diedn the perioperative period. During follow-up, 1,697 pa-ients (29%) died. Of these, 1,235 patients (21%) died fromardiac causes. Univariate associations between risk factorsnd long-term outcome are presented in Table 2. Under-eight patients had a poor long-term outcome for all-cause

nd cardiac mortalities, whereas overweight and obese pa-ients had more favorable long-term outcomes in terms ofll-cause and cardiac deaths (Table 2). In a multivariabletepwise Cox regression model (Table 3), overweight andbese patients remained at significantly lower risk for all-ause mortality and cardiac mortality/MI. Underweight pa-ients represented a high-risk category for all-cause mortal-ty and cardiac death/MI.

Kaplan-Meier survival curves of the 4 BMI categoriesor an average interval of 6 � 2.6 years are presented inigure 3. Incidences of long-term mortality in underweight,ormal, overweight, and obese patients were 39%, 35%,4%, and 20%, respectively. In the same order, incidencesf cardiac death/MI were 33%, 26%, 17%, and 14%. Ashown in Figure 3, mortality hazard was inversely propor-ional to BMI (p �0.001) for either type of mortality.esults were subsequently analyzed separately in patients

Figure 1. Distribution of study population according to BMI values.

ith known CAD and in those with suspected CAD. An

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1487Coronary Artery Disease/Body Mass Index and Outcome

nverse relation between BMI and survival was observed inatients with suspected CAD (all-cause mortality, p0.001; cardiac death, p �0.001) and in patients with

nown CAD (all-cause mortality, p �0.001; cardiac death,�0.001; Figure 4). In patients with suspected CAD, the

nderweight group had 2 short temporary shifts of improvedurvival over the normal weight group (4.5 to 5.5 and 6.5 to.5 years of follow-up), but eventually followed the samenverse relation with BMI at the commencement ofollow-up. Overweight and obese populations showed theame paradoxic trend with BMI over the normal weight andnderweight populations.

iscussion

he main finding of this study is that an inverse relation

igure 2. Categorical distribution of clinical characteristics and identified ceight (dotted bars), overweight (white bars), or obesity (bars with hobstructive pulmonary disease; DM � diabetes mellitus; PCI � percutane

able 1linical characteristics of 5,950 patients according to body mass index

ariable No. of Patients (%)

�18(n � 17

ge, mean � SD 60.8 � 12.6 60.7 �en 4,001 (67%) 98 (55urrent smoker 1,741 (29%) 53 (30ypertension 2,737 (46%) 61 (35ngina pectoris 1,369 (23%) 32 (18revious MI 1,964 (33%) 53 (30enal disease 363 (6%) 32 (18hronic obstructive pulmonary disease 313 (5%) 6 (4%istory of HF 846 (14%) 20 (12iabetes mellitus 883 (15%) 6 (4%ypercholesterolemia 2,093 (35%) 27 (15revious coronary by pass 929 (16%) 12 (7%revious percutaneous coronary

intervention933 (16%) 16 (9%

nown CAD 2,486 (42%) 51 (36uspected CAD 3,464 (58%) 92 (64obutamine stress echocardiographyWall motion abnormalities at rest 2,296 (38%) 98 (55New wall motion abnormalities 1,857 (31%) 68 (38

xists between BMI and incident all-cause and cardiac mor- e

alities during long-term follow-up of patients with knownr suspected CAD. Underweight patients had a greater thanwofold increased risk of mortality compared with normaleight patients, with 40% less mortality and 20% less

ardiac death in the obesity group. This reversed trendersisted after adjustment for coronary risk factors and wasbserved in patients with known CAD and those with sus-ected CAD.

Our population represented a cohort of ambulatory pa-ients with normal distribution of risk factors and clinicaluspicion and/or presentation of CAD. This population wasomposed of a broader spectrum of patients in contrast torevious studies conducted in isolated groups or after acutevent or specific interventions. Previous studies haveointed out the prognostic influence of BMI in moribundatients with very limited functional capacity and/or short

isk factors according to BMI indicating underweight (black bars), normalstripes). CABG � coronary artery bypass grafting; COPD � chronic

ronary intervention.

BMI (kg/m2) p Value

18.5–24.9(n � 2,499, 42%)

25–29.9(n � 2,439, 41%)

�30(n � 834, 14%)

61.7 � 13.3 61.7 � 11.2 59.0 � 11.3 0.71,752 (70%) 1,730 (71%) 421 (50%) �0.01

839 (34%) 673 (28%) 176 (21%) �0.011,050 (42%) 1,173 (48%) 453 (54%) �0.01

545 (22%) 560 (23%) 232 (28%) �0.01819 (33%) 841 (35%) 251 (31%) 0.13172 (7%) 108 (4%) 51 (6%) �0.01163 (7%) 116 (5%) 27 (3%) �0.01372 (15%) 332 (14%) 123 (15%) 0.51267 (11%) 393 (16%) 217 (26%) �0.01800 (32%) 924 (38%) 342 (41%) �0.01359 (14%) 421 (17%) 137 (16%) �0.01361 (14%) 394 (16%) 162 (19%) �0.01

1,023 (41%) 1,085 (44%) 327 (39%) 0.01149 (59%) 1,374 (56%) 507 (61%) 0.01

1,014 (41%) 949 (39%) 235 (25%) �0.01827 (33%) 787 (32%) 175 (21%) �0.01

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able 2nivariate association of clinical data with all-cause mortality and cardiac

ariable Total Mo

No. of Patients H

ge 1en 1,333 2urrent smoker 600 1ypertension 848 1ngina pectoris 335 0revious MI 659 1iabetes mellitus 301 1istory of HF 356 2ypercholesterolemia 451 0Treated with statins 92 0Untreated 359 0hronic obstructive pulmonary disease 166 3enal disease 73 4oronary bypass surgery 254 1�5 yrs 66 0ercutaneous coronary intervention 134 0�5 yrs 72 0obutamine stress echocardiographyWall motion abnormalities at rest 724 1New wall motion abnormalities 608 1MI groupsUnderweight 69 1Overweight 596 0Obese 163 0

able 3ultivariable regression analysis of total (all-cause) mortality and cardiac

atient variables

ariable Total Mo

No. of Patients H

ge 1en 1,333 1urrent smoker 600 1ypertension 848 1revious MI 659 1iabetes mellitus 301 1istory of HF 356 2ypercholesterolemia 451 0Using statins 92 0Untreated 359 0hronic obstructive pulmonary disease 166 2enal disease 73 4oronary bypass surgery 254 1�5 yrs 123 0ercutaneous coronary intervention 134 0�5 yrs 88 0obutamine stress echocardiographyWall motion abnormalities at rest 724 1New wall motion abnormalities 608 1MI groupsUnderweight 69 2Overweight 596 0Obese 163 0

f coronary risk factors and other co-morbidities to the m

azard of death in populations with different weights. In thisegard, old MI remained a significant predictor of all-cause

acute myocardial infarction mortality in univariate regression analysis

Cardiac Death/Acute MI

95% CI No. of Patients HR 95% CI

1.05–1.07 1.03 1.02–1.041.8–2.4 1,234 2.0 1.8–2.31.5–1.9 557 1.6 1.4–1.81.1–1.4 816 1.4 1.2–1.50.7–0.9 338 0.9 0.8–1.01.3–1.6 686 1.9 1.7–2.21.2–1.6 275 1.3 1.1–1.61.8–2.5 312 1.8 1.6–2.20.6–0.7 535 1.2 0.8–1.50.6–1.0 141 1.8 1.4–2.20.5–0.7 394 0.8 0.7–1.02.5–4.0 156 3.0 2.4–3.82.9–7.0 74 2.9 2.0–4.40.9–1.3 252 1.3 1.1–1.60.4–0.7 62 0.7 0.4–0.80.3–0.5 174 0.7 0.6–0.90.4–1.0 92 0.8 0.5–1.4

1.16–1.46 704 1.36 1.21–1.531.21–1.54 604 1.50 1.33–1.69

1.21–2.38 58 1.53 1.08–2.160.55–0.71 422 0.75 0.66–0.850.39–0.57 117 0.58 0.48–0.69

acute myocardial infarction mortality hazard adjusted for all

Cardiac Death/Acute MI

95% CI No. of Patients HR 95% CI

1.04–1.05 1.02 1.02–1.031.7–2.2 1,234 1.7 1.5–2.01.4–1.9 557 1.5 1.3–1.71.2–1.5 816 1.4 1.2–1.61.3–1.7 686 2.0 1.7–2.31.3–1.8 275 1.4 1.2–1.71.7–2.4 312 1.6 1.4–2.00.7–0.9 535 1.2 1.0–1.40.7–1.2 141 1.8 1.5–2.20.7–0.9 394 1.0 0.8–1.21.8–3.2 156 2.3 1.8–3.12.8–7.0 74 4.2 2.6–6.60.8–1.1 252 1.0 0.8–1.10.5–0.8 111 0.8 0.5–0.90.3–0.5 174 0.6 0.5–0.70.5–1.1 91 1.0 0.6–1.6

1.3–1.9 704 1.7 1.4–2.00.9–1.36 604 1.3 1.0–1.6

1.7–3.6 58 2.1 1.5–3.10.6–0.8 422 0.8 0.7–0.90.5–0.8 117 0.8 0.6–0.9

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1489Coronary Artery Disease/Body Mass Index and Outcome

HR 2.0, 95% CI 1.7 to 2.3) after correction for all otheronfounders.

In this population, crude death rate was 29% during aean follow-up of 6 � 3 years. Cardiac deaths were re-

ponsible for 73% of all deaths. Major risk factors (renalisease, diabetes, male gender, and smoking) were associ-ted with increased long-term all-cause and cardiac mortal-ty. As expected, co-morbid conditions (e.g., diabetes andypertension) were more prominent in the obese population,hereas smoking and renal dysfunction were more preva-

ent in the underweight population.As shown by Kaplan-Meier survival curves (Figure 4)

atients with suspected CAD and those with proved CADad similar long-term outcomes. The reason for this similarutcome might be related to the high incidence of asymp-omatic CAD in patients with proved vascular disease.10

The paradoxic relation, a “protective effect,” of obesityn survival had been observed recently in several patientopulations, such as patients with chronic HF or renal dis-ase.5,9,11 Curtis et al11 examined a cohort of 7,767 outpa-ients with an established history of HF controlled underigitalis treatment. Higher BMIs were associated with aower mortality.11 These data confirmed previous survivalata of 4,700 hospitalized patients with congestive HFssociating an increased BMI with lower mortalityp �0.0001).9 Recently, Gruberg et al12 studied patientsho underwent percutaneous coronary intervention or cor-nary artery bypass grafting. The long-term mortality riskas similar across all BMI categories irrespective of type of

evascularization procedure. Thus, overweight or obesityad no effect on crude survival at 3 years.12 Sierra-Johnsont al13 followed 389 patients undergoing cardiac rehabilita-ion and found an inverse relation between BMI and totalnd cardiovascular mortalities, although only the relationith cardiovascular mortality was statistically significant

igure 3. Kaplan-Meier survival curves of studied population showingortality rate according to BMI in terms of all-cause mortality (top) and

ardiac death (bottom).

fter adjustment for age and gender. Kragelund14 examined o

he effect of BMI on survival in 6,676 consecutive patientsith acute MI during 10-year follow-up. Overall obesityas inversely related to mortality from all causes, Thereas no association between obesity assessed as BMI andortality (men, adjusted relative risk 0.90, 95% confidence

nterval 0.85 to 1.14, p � 0.3; women, adjusted relative risk.90, 95% confidence interval 0.74 to 1.10, p � 0.2).14

imilar results were reported by Kennedy et al15 who hadxamined BMI for all-cause mortality and cardiac death in,388 patients with complicated AMI. Comparable resultsere assessed in patients with renal disease.5,16 When a

arge cohort of patients with renal failure requiring dialysisn � 418,021) was examined for survival, overweight andbese patients using dialysis had longer survival than didhose with lower BMI.7

The reason for the paradoxic relation of BMI with mor-ality in the aforementioned patient populations is not un-erstood. Although this pathomodulatory phenomenon isuite obscure, several influences can be suggested in ourtudy. It had been previously demonstrated that peripheraldiposity (i.e., gynoid obesity) poses cardiovascular benefitsue to secretion of adiponectin, which has anti-inflamma-ory, insulin-sensitizing, and antiatherogenic effects in ad-ition to an association with lower total body fat content andhe fact that subcutaneous body fat is relatively “inert” inetabolic and inflammatory/mediation terms.17 Abdominal

besity is associated with higher total body fat content,ore insulin-resistance, more other co-morbid associations,

nd more metabolic activity and inflammatory cascadingnfluences. Thus, an obesity paradox might be reflectedrom a higher prevalence of 1 obesity type (i.e., peripheral)ver another (i.e., central), with its decelerating influencesecoming more manifest as BMI increases to reach higherevels (i.e., �30 kg/m2). It had been suggested that hyper-holesterolemia and high levels of serum low-density li-oproteins associated with obesity serve a scavenging ac-ion against unbound circulating lipopolysaccharides withonsequent anti-inflammatory response and improved long-erm outcomes.18 In the other extreme, it can be inferredrom our population characteristics that active smokers wereostly in the normal BMI and underweight groups, an

nsurprising finding knowing that those were the 2 groupsith lowest survival. Loss of weight in geriatric patients,hich might be related to malnutrition, multiorgan dysfunc-

ion, or unidentified occult malignancies (especially in themoking population), had been identified as a significantredictor of mortality.19,20 In this instance, those patientsho presented at the time of evaluation with a BMI �18.5g/m2 at �60 years of age represented a subcohort ofatients at a higher risk of mortality. Most offending coro-ary risk factors were associated with a BMI �25 kg/m2.hose patients with symptomatic co-morbidities were ex-ected to have had consulted medical care, with a high prob-bility that they were maintained on drugs proved to improveurvival in a CAD population such as � blockers, statins, �2gonists and angiotensin-converting enzyme inhibitors.

One limitation of the study is its retrospective design.ue to time limits, we could not extend our follow-upeyond the date of conclusion. Data regarding waist cir-umference and waist/hip ratio that measures abdominal
besity were not routinely available. A more precise differ-

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ntiation between peripheral adiposity and central compart-ent adiposity would have served to support the suggested

ypothetical explanation about the role of a high BMI inrolonging survival in our patient population. Regarding theetection of our end points, a number of nonfatal asymp-omatic MIs might have not been reported, especially ifhese occurred outside the hospital. Unfortunately, we haveo data regarding a particular cause of cardiac death.

1. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative repro-ducibility and validity of systems for assessing cardiovascular func-tional class: advantages of a new specific activity scale. Circulation1981;64:1227–1234.

2. Remme WJ, Swedberg K. European Society of Cardiology Compre-hensive guidelines for the diagnosis and treatment of chronic heartfailure. Task force for the diagnosis and treatment of chronic heartfailure of the European Society of Cardiology. Eur J Heart Fail2002;4:11–22.

3. Energy and protein requirements: report of a joint FAO/WHO/UNUExpert Consultation. World Health Organ Tech Rep Ser 1985;724:1–206.

4. National Institutes of Health. Evidence-Based Guidelines: ClinicalGuidelines on the Identification, Evaluation, and Treatment of Over-weight and Obesity in Adults: Executive Summary. Bethesda, MD:National Heart, Lung, and Blood Institute, 2002.

5. Kalantar-Zadeh K, Abbott KC, Salahudeen AK, Kilpatrick RD, Hor-wich TB. Survival advantages of obesity in dialysis patients. Am J ClinNutr 2005;81:543–554.

6. Davos CH, Doehner W, Rauchhaus M, Cicoira M, Francis DP, CoatsAJ, Clark AL, Anker SD. Body mass and survival in patients withchronic heart failure without cachexia: the importance of obesity.J Card Fail 2003;9:29–35.

7. Snyder JJ, Foley RN, Gilbertson DT, Vonesh EF, Collins AJ. Bodysize and outcomes on peritoneal dialysis in the United States. KidneyInt 2003;64:1838–1844.

8. Halabi S, Small EJ, Vogelzang NJ. Elevated body mass index predictsfor longer overall survival duration in men with metastatic hormone-refractory prostate cancer. J Clin Oncol 2005;23:2434–2435.

9. Gustafsson F, Kragelund CB, Torp-Pedersen C, Seibaek M, BurchardtH, Akkan D, Thune JJ, Kober L for the DIAMOND Study Group.

Figure 4. Examination of patients with known versus su

Effect of obesity and being overweight on long-term mortality in

congestive heart failure: influence of left ventricular systolic function.Eur Heart J 2005;26:58–64.

0. Hertzer NR, Beven EG, Young JR, O’Hara PJ, Ruschhaupt WF III, GraorRA, Dewolfe VG, Maljovec LC. Coronary artery disease in peripheralvascular patients. A classification of 1000 coronary angiograms and re-sults of surgical management. Ann Surg 1984;199:223–233.

1. Curtis JP, Selter JG, Wang Y, Rathore SS, Jovin IS, Jadbabaie F,Kosiborod M, Portnay EL, Sokol SI, Bader F, Krumholz HM. Theobesity paradox: body mass index and outcomes in patients with heartfailure. Arch Intern Med 2005;165:55–61.

2. Gruberg L, Mercado N, Milo S, Boersma E, Disco C, van Es GA,Lemos PA, Ben Tzvi M, Wijns W, Unger F, Beyar R, Serruys PW, forthe Arterial Revascularization Therapies Study Investigators. ArterialRevascularization Therapies Study Investigators. Impact of body massindex on the outcome of patients with multivessel disease randomizedto either coronary artery bypass grafting or stenting in the ARTS trial:the obesity paradox II? Am J Cardiol 2005;95:439–444.

3. Sierra-Johnson J, Wright SR, Lopez-Jimenez F, Allison TG. Relationof body mass index to fatal and nonfatal cardiovascular events aftercardiac rehabilitation. Am J Cardiol 2005;96:211–214.

4. Kragelund C, Hassager C, Hildebrandt P, Torp-Pedersen C, Kober L.Impact of obesity on long-term prognosis following acute myocardialinfarction. Int J Cardiol 2005;98:123–131.

5. Kennedy LM, Dickstein K, Anker SD, Kristianson K, Willenheimer R.OPTIMAAL Study Group. The prognostic importance of body massindex after complicated myocardial infarction. J Am Coll Cardiol2005;45:156–158.

6. Kalantar-Zadeh K. Causes and consequences of the reverse epidemiologyof body mass index in dialysis patients. J Ren Nutr 2005;15:142–147.

7. McCarty MF. A paradox resolved: the postprandial model of insulinresistance explains why gynoid adiposity appears to be protective. MedHypotheses 2003;61:173–176.

8. Rauchhaus M, Clark AL, Doehner W, Davos C, Bolger A, Sharma R,Coats AJ, Anker SD. The relationship between cholesterol and sur-vival in patients with chronic heart failure. J Am Coll Cardiol 2003;42:1933–1940.

9. Knudtson MD, Klein BE, Klein R, Shankar A. Associations with weightloss and subsequent mortality risk. Ann Epidemiol 2005;15:483–491.

0. Su D. Body mass index and old-age survival: a comparative studybetween the Union Army Records and the NHANES-I Epidemiolog-

CAD for (A) total death and (B) cardiac mortality/MI.

ical Follow-Up Sample. Am J Hum Biol. 2005;17:341–354.

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Prognostic Implications of Dipyridamole or Dobutamine StressEchocardiography for Evaluation of Patients >65 Years of

Age With Known or Suspected Coronary Heart Disease

Lauro Cortigiani, MDa,*, Riccardo Bigi, MDb, Rosa Sicari, MD, PhDc, Patrizia Landi, BScc,Francesco Bovenzi, MDa, and Eugenio Picano, MD, PhDc

This study investigated the value of pharmacologic stress echocardiography for risk strat-ification of patients >65 years of age. The study cohort consisted of 2,160 patients >65years of age (1,257 men, mean � SD 71 � 5 years of age) undergoing dipyridamole (n �1,521) or dobutamine (n � 639) stress echocardiography for evaluation of known (n � 913)or suspected (n � 1,247) coronary artery disease. Of 2,160 patients, 753 (35%) had a normaltest result, whereas 772 (36%) showed a myocardial ischemic pattern and 635 (29%) a scarpattern. During a median follow-up of 26 months, 241 deaths and 87 nonfatal myocardialinfarctions occurred. Patients (n � 568) undergoing revascularization were censored. Of 16analyzed variables, age (hazard ratio [HR] 1.07 per unit increment), wall motion scoreindex at rest (HR 2.63 per unit increment), ischemia at stress echocardiography (HR 1.81),and diabetes (HR 1.57) were multivariable predictors of death, whereas age (HR 1.06 perunit increment), ischemia at stress echocardiography (HR 2.60), wall motion score index atrest (HR 1.98 per unit increment), scar pattern (HR 1.99), and diabetes (HR 1.48) weremultivariable predictors of death or myocardial infarction. Using an interactive stepwiseprocedure, stress echocardiography showed incremental prognostic value over clinical andechocardiographic data at rest, which decreased with increasing age. In addition, theannual hard event rate associated with a normal test result progressively increased withage. In conclusion, pharmacologic stress echocardiography provides useful prognosticinformation in patients >65 years of age. However, its prognostic value decreases withincreasing age. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:
1491–1495)
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oronary artery disease (CAD) is the most common causef morbidity and mortality in patients �65 years of age,1ccounting for �66% of deaths in men and 50% of deathsn women.2 Exercise electrocardiography shows limited fea-ibility in these patients, mainly due to neuromusculareakness, physical deconditioning, or neurologic, orthope-ic, peripheral vascular, or respiratory limitations. In addi-ion, test interpretation is frequently difficult because ofepolarization abnormalities or conduction defects onlectrocardiogram at rest.3 Stress echocardiography pro-ides effective prognostic information in unselected4

opulations with advanced age and in subgroups of pa-ients with preserved5 or impaired6 exercise capacity andhose with uncomplicated myocardial infarction.7,8 How-ver, whether the prognostic value of the test is preservedith increasing age has not been definitely established.e analyzed data in a large, unselected population of

atients �65 years of age who were referred to pharma-

aDivision of Cardiology, Lucca Hospital, Lucca; bCardiology, Depart-ent of Medicine and Surgery, University School of Medicine, Milan; and

Institute of Clinical Physiology, CNR, Pisa, Italy. Manuscript receivedovember 23, 2006; revised manuscript received and accepted January 10,007.

*Corresponding author: Tel: 39-583-970450; fax: 39-583-970445.
dE-mail address: [email protected] (L. Cortigiani).

ologic stress echocardiography for evaluation of knownr suspected CAD.

ethods

he initial population consisted of 2,205 patients �65ears of age who underwent pharmacologic stress echo-ardiography between 1986 and 2001 at the Clinicalhysiology Institute (Pisa, Italy) and the Division ofardiology, Campo di Marte Hospital (Lucca, Italy).atients with significant valvular or congenital heart dis-ase, prognostically relevant noncardiac disease (cancer,nd-stage renal disease, or severe obstructive pulmonaryisease), and inadequate acoustic window were excluded.orty-five patients (2%) were lost to follow-up. Thus, thenalysis refers to 2,160 patients (1,257 men, 903 women;ean � SD 71 � 5 years of age). Indications for stress

chocardiography were diagnosis of suspected CAD in,247 subjects (58%) and prognostic stratification ofnown CAD (as defined by history of myocardial infarc-ion, coronary revascularization, and/or angiographicallyocumented coronary artery stenosis �50%) in the re-aining 913 (42%). Pharmacologic stress was used be-

ause of inability to exercise maximally in 46%, 50%,5%, and 77% of patients 65 to 69, 70 to 74, 75 to 79, and80 years of age, respectively; other causes were non-

iagnostic or doubtful exercise electrocardiographic re-

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ults. Stressor (dipyridamole in 1,521 patients and dobut-mine in 639) choice was guided by the underlyinglinical condition and presence of contraindications tohe use of each drug.

Stress echocardiography was performed on and off anti-nginal therapy in 697 patients (32%; � blockers in 291,alcium antagonists in 253, or nitrates in 491) and 1,463atients (68%), respectively.

Hypertension,9 diabetes,10 and hypercholesterolemia11

ere defined according to standard definitions.Dipyridamole and dobutamine/atropine stress echocardi-

graphy was done according to established protocols.12,13

tarting in 1992, the dipyridamole stress protocol was mod-fied to include coadministration of atropine.14

Echocardiographic images were semiquantitatively as-essed using a 16-segment, 4-point scale model of the leftentricle.15 A wall motion score index (WMSI) was de-ived by dividing the sum of individual segment scoresy the number of interpretable segments. Ischemia wasefined as stress-induced new and/or worsening of are-existing wall motion abnormality or biphasic re-ponse (i.e., low-dose improvement followed by high-ose deterioration). Scar was defined as akinetic or dys-inetic myocardium with no thickening during stress. Aest result was normal in case of no rest and stress wallotion abnormality.Electrocardiographic analysis was done according to

tandard criteria.12,13 Electrocardiography was consideredninterpretable in the presence of left bundle branch blockr paced rhythm.

Outcome was determined from patient interviews at the

able 1haracteristics of patients according to age

65–69 yrs(n � 922)

70(n

linical findingsAge (yrs) 67 � 1 7Men 557 (60%) 40Previous myocardial infarction 328 (36%) 29Previous revascularization 67 (7%) 6Previous angioplasty 26 (3%) 3Previous surgery 41 (4%) 3Known CAD 355 (39%) 31Diabetes mellitus 155 (17%) 13Hypertension 435 (47%) 35Hypercholesterolemia 348 (38%) 28Smoking habit 340 (37%) 20Left bundle branch block 54 (6%) 2chocardiographic findingsWall motion abnormalities at rest 451 (49%) 38WMSI at rest 1.25 � 0.35 1.2Dipyridamole 661 (72%) 49Dobutamine 261 (28%) 22Ischemic result 326 (35%) 27Scar 247 (27%) 22Peak WMSI 1.34 � 0.38 1.3ECG changes during test 242 (26%) 17Angina during test 208 (23%) 12

Data presented are mean � SD or number of patients (percentage).ECG � electrocardiographic.

utpatient clinic, hospital chart reviews, and telephone in- q

erviews with the patient, a close relative, or referring phy-ician. Death and nonfatal myocardial infarction wereegistered as clinical events. Coronary revascularizationsurgery or angioplasty) was also recorded. To avoid mis-lassification of cause of death,16 overall mortality wasonsidered. Myocardial infarction was defined by typicalymptoms, electrocardiographic changes, and cardiac en-yme changes. Follow-up data were separately analyzed forrediction of all-cause mortality and hard events (death,yocardial infarction).Continuous variables are expressed as mean � SD.

ifferences in continuous variables were assessed with-way analysis of variance or unpaired t test; chi-squareest was used for categorical variables. Survival ratesere estimated with Kaplan-Meier curves and comparedy log-rank test. Patients undergoing coronary revascu-arization were censored at the time of the procedure.nly the first event was taken into account. Annual event

ates were obtained from Kaplan-Meier estimates to takeensoring of data into account. Association of selectedariables with outcome was assessed with Cox propor-ional hazard model using univariate and stepwise mul-ivariate procedures. A significance of 0.05 was requiredor a variable to be included into the multivariate model,nd 0.1 was the cut-off value for exclusion. Hazard ratiosHRs) with corresponding 95% confidence intervals (CIs)ere estimated. Statistical significance was set at a palue �0.05. To verify whether the prognostic value ofhe test was affected by age, the analysis was conductedfter grouping patients according to age. Clinical rest-nd stress-induced wall motion abnormalities were se-

)75–79 yrs(n � 367)

�80 yrs(n � 154)

p Value

77 � 1 82 � 2 �0.0001) 205 (56%) 86 (56%) 0.98) 157 (43%) 71 (46%) 0.01

28 (8%) 8 (5%) 0.2916 (4%) 5 (3%) 0.3412 (4%) 3 (2%) 0.46

) 172 (47%) 73 (47%) 0.01) 66 (18%) 27 (18%) 0.83) 202 (55%) 76 (49%) 0.006) 128 (35%) 50 (32%) 0.30) 82 (22%) 19 (12%) �0.0001

21 (6%) 6 (4%) 0.26

) 198 (54%) 88 (57%) 0.086 1.31 � 0.41 1.35 � 0.40 0.002) 253 (69%) 112 (73%) 0.42) 114 (31%) 42 (27%) 0.42) 123 (34%) 53 (34%) 0.21) 118 (32%) 50 (32%) 0.0098 1.39 � 0.43 1.42 � 0.42 0.02) 85 (23%) 33 (21%) 0.79) 65 (18%) 25 (16%) 0.02

–74 yrs� 717

2 � 19 (57%5 (41%6 (9%)1 (4%)5 (5%)3 (44%3 (19%7 (50%1 (39%6 (29%8 (4%)

6 (54%8 � 0.35 (69%2 (31%0 (38%0 (31%7 � 0.38 (25%1 (17%

uentially included into the model. Global chi-square

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1493Coronary Artery Disease/Risk Stratification in Patients �65 Years

alue of the model was calculated from the log-likelihoodatio. SPSS 11.0 (SPSS, Inc., Chicago, Illinois) was usedor analysis.

esults

normal test result was found in 753 patients (35%).tress-induced ischemia was ascertained in 772 patients36%): 488 of 1,123 with and 284 of 1,037 without wallotion abnormalities at rest (43% vs 27%, p �0.0001). In

hese patients, WMSI increased from 1.30 � 0.34 to 1.57 �.35 during stress. A scar pattern was found in 635 patients29%) whose WMSI was 1.54 � 0.36. Main clinical andchocardiographic characteristics by age are presented in

igure 1. Kaplan-Meier survival curves for study population describingroups with ischemia, scar, and normal test findings. Number of patientsxamined each year is shown.

able 2nivariate and multivariate indicators of mortality and hard events (death

Mortality

Univariate Analysis Multivar

HR (95% CI) p Value HR (95% C

ge (yrs) 1.07 (1.05–1.10) �0.0001 1.07 (1.04–1en 1.44 (1.10–1.89) 0.008

revious infarction 1.84 (1.43–2.37) �0.0001revious revascularization 0.62 (0.34–1.14) 0.13nown CAD 1.74 (1.36–2.25) �0.0001iabetes mellitus 1.78 (1.32–2.41) �0.0001 1.57 (1.16–2ypertension 0.91 (0.70–1.17) 0.46ypercholesterolemia 0.95 (0.72–1.25) 0.70moking habit 1.08 (0.82–1.42) 0.59eft bundle branch block 1.38 (0.82–2.32) 0.23MSI at rest 3.53 (2.68–4.64) �0.0001 2.63 (1.85–3

car 1.70 (1.31–2.20) �0.0001schemia at stress

echocardiography1.60 (1.23–2.09) �0.0001 1.81 (1.24–2

eak WMSI 3.88 (2.95–5.11) �0.0001CG changes during test 0.96 (0.70–1.31) 0.80ngina during test 0.90 (0.64–1.27) 0.54

Abbreviation as in Table 1.

able 1. 7

During a median follow-up of 26 months (first quartile 6,hird quartile 52), a total of 328 (15%) events occurred: 241eaths and 87 myocardial infarctions. There were 12917%) events in patients with ischemia, 134 (21%) in thoseith scar pattern, and 65 (9%) in those with normal test

esult.According to the physician’s judgment, 568 patients

26%) underwent coronary intervention (surgery in 225 andngioplasty in 343), 396 (70%) within and 172 (30%) aftermonths from index stress echocardiography. Revascular-

zation was more frequent (p �0.0001) in patients withschemia (382 of 772, 49%) than in those with scar (102 of35, 16%) or a normal test result (84 of 753, 11%). Inddition, revascularized patients were younger (70 � 4 vs

igure 2. Kaplan-Meier hard event-free survival curves for study popula-ion describing groups with ischemia, scar, and normal test findings. Num-er of patients examined each year is shown.

rdial infarction)

Hard Events

alysis Univariate Analysis Multivariate Analysis

p Value HR (95% CI) p Value HR (95% CI) p Value

�0.0001 1.07 (1.05–1.09) �0.0001 1.06 (1.04–1.08) �0.00011.27 (1.01–1.60) 0.041.97 (1.59–2.45) �0.00010.95 (0.61–1.46) 0.811.89 (1.52–2.35) �0.0001

0.004 1.71 (1.32–2.22) �0.0001 1.48 (1.14–1.92) 0.0041.03 (0.83–1.29) 0.761.04 (0.83–1.32) 0.711.06 (0.84–1.34) 0.641.35 (0.86–2.12) 0.19

�0.0001 3.10 (2.44–3.94) �0.0001 1.98 (1.45–2.71) �0.00011.69 (1.35–2.10) �0.0001 1.99 (1.39–2.84) �0.0001

0.002 1.84 (1.47–2.29) �0.0001 2.60 (1.87–3.60) �0.0001

3.46 (2.73–4.39) �0.00011.16 (0.89–1.50) 0.271.07 (0.81–1.43) 0.62

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68, 54%, p �0.0001) and smokers (234, 41%, vs 413,6%, p �0.0001), and had higher rates of knownAD (311, 55%, vs 602, 38%, p �0.0001), hypercholes-

erolemia (268, 47%, vs 539, 34%, p �0.0001), and diabe-es mellitus (124, 22%, vs 257, 16%, p � 0.002) comparedith medically treated patients.Annual hard event rates were 4.3%, 5.4%, 7.8%, and

0.8% in patients 65 to 69, 70 to 74, 75 to 79, and �80ears of age, respectively.

Univariate and multivariate predictors of mortality areisted in Table 2. Age (HR 1.07 per unit increment, 95% CI.04 to 1.09, p �0.0001), WMSI at rest (HR 2.63 per unitncrement, 95% CI 1.85 to 3.75, p �0.0001), ischemia attress echocardiography (HR 1.81, 95% CI 1.24 to 2.63, p �.002), and diabetes mellitus (HR 1.57, 95% CI 1.16 to.12, p � 0.004) were independently associated with prog-osis. The 5-year survival was significantly higher in pa-ients with normal test results than in those with ischemicnd scar patterns (p �0.0001; Figure 1).

Univariate and multivariate predictors of hard eventsre listed in Table 2. Age (HR 1.06 per unit increment,5% CI 1.04 to 1.08, p �0.0001), ischemia at stresschocardiography (HR 2.60, 95% CI 1.87 to 3.60,

igure 3. Annual hard event rate per year of a normal test result in differentge groups. yy � years.

igure 4. Incremental prognostic value of ischemia at stress echocardiog-aphy (black bars) over clinical and echocardiographic findings at restwhite bars) in different age groups Abbreviation as in Figure 3.

�0.0001), WMSI at rest (HR 1.98 per unit increment, a

5% CI 1.45 to 2.71, p �0.0001), scar (HR 1.99, 95% CI.39 to 2.84, p �0.0001), and diabetes mellitus (HR 1.48,5% CI 1.14 to 1.92, p � 0.004) were independentrognostic indicators. Compared with ischemia and scarattern, a normal test result predicted a significantlyigher 5-year hard event-free survival (p �0.0001; Fig-re 2). Nevertheless, the annual hard event rate associ-ted with a normal test result progressively increasedith age (Figure 3). In particular, it was �4.5 times asreat in patients �80 years old than in those 65 to 69ears of age (Figure 3). Hard event rates associated withnormal test result were 1.5%, 2.0%, 1.8%, and 6.0% at-year follow-up and 2.8%, 5.0%, 5.4%, and 15.6% at-year follow-up in patients 65 to 69, 70 to 74, 75 to 77,nd �80 years of age, respectively.

Ischemia at stress echocardiography provided incremen-al prognostic value over clinical and echocardiographicariables at rest; however, it progressively decreased withdvancing age (Figure 4). In particular, ischemia failed todd prognostic information in subjects �80 years of ageFigure 4). The prognostic value of the combined clinicalnd echocardiographic model at rest also decreased withncreasing age, as shown by 77% lower global chi-square11.7 vs 50.4) in patients �80 years of age compared withhose 65 to 69 years of age (Figure 4).

iscussion

revious studies have reported on the value of stress echo-ardiography in prognostic stratification of patients �65ears of age.4–8 Exercise stress echocardiography providedncremental value over clinical and echocardiographic find-ngs at rest for predicting cardiac death and cardiac events inlarge, unselected cohort of patients �65 years fo age.5 In

ddition, pharmacologic stress echocardiography showednducible ischemia to be independently associated withrognosis in a consecutive series of patients �65 years ofge4 and in patients evaluated before major noncardiacascular surgery6 or after an uncomplicated myocardial in-arction.7,8 The present results reinforce this body of knowl-dge, showing that in a general population of patients �65ears of age an effective risk stratification can be obtainedn the basis of clinical and echocardiographic findings. Inarticular, ischemia at stress echocardiography, age, WMSIt rest, and diabetes mellitus were multivariable predictorsf mortality, whereas the same variables and scar patternndependently predicted hard events. Nevertheless, the pre-ictive value of a normal test result and the incrementalrognostic information provided by inducible ischemia pro-ressively decreased with advancing age. In octogenarians,he yearly hard event rate associated with a normal testesult was �4.5-fold as great as that observed in patients 65o 69 years old. Moreover, ischemia failed to convey addi-ional prognostic information to clinical and echocardio-raphic information at rest in this age subgroup. Althoughlder people had a higher risk profile, as demonstrated byore frequent CAD, and higher WMSI values at rest and

eak, the prognostic contribution of clinical and echocar-iographic findings at rest progressively decreased withncreasing age. This is consistent with the hypothesis that
ge per se rather than age-related differences in clinical

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1495Coronary Artery Disease/Risk Stratification in Patients �65 Years

rofile could have affected our results. This study demon-trated not only the prognostic value of stress echocardiog-aphy but also that of clinical and echocardiographic infor-ation at rest to be age dependent. A normal test result was

ssociated with a relatively low 1-year event rate in patients80 years of age. However, no “warranty period” could be

dentified, likely due to the large number of subjects withoor exercise capacity representing per se a strong markerf risk.17 Percentage of abnormal test results was high in ourtudy population. A possible explanation could be the rel-vant prevalence of CAD (42%) and wall motion abnormal-ties on echocardiography at rest (52%).

Pooled results of dipyridamole and dobutamine stresschocardiography are presented. Although the 2 drugs cannduce ischemia by different mechanisms, their prognosticalue18–22 are comparable when state-of-the-art protocolsre used. Due the long period of recruitment the outcomeased on stress test results may have been potentially influ-nced by an evolution of methods, technology, experience,nd advances in medical therapy.

1. Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T,Zheng ZJ, Flegal K, O’Donnell C, Kittner S, et al. American HeartAssociation Statistics Committee and Stroke Statistics Subcommittee.Heart disease and stroke statistics—2006 update: a report from theAmerican Heart Association Statistics Committee and Stroke StatisticsSubcommittee. Circulation 2006;113:e85–e151.

2. National Center for Health Statistics. Vital Statistics of the UnitedStates, 1993. Washington, DC: US Government Printing Office, PublicHealth Service. 1993:II(pt A).

3. Mihalick MJ, Fisch C. Electrocardiographic findings in the aged. AmHeart J 1974;87:117–119.

4. Biagini E, Elhendy A, Schinkel AF, Rizzello V, Bax JJ, Sozzi FB,Kertai MD, van Domburg RT, Krenning BJ, Branzi A, et al. Long-term prediction of mortality in elderly persons by dobutamine stressechocardiography. J Gerontol A Biol Sci Med Sci 2005;60:1333–1338.

5. Arruda AM, Das MK, Roger VL, Klarich KW, Mahoney DW, PellikkaPA. Prognostic value of exercise echocardiography in 2,632 patients�65 years of age. J Am Coll Cardiol 2001;37:1036–1041.

6. Poldermans D, Fioretti PM, Boersma E, Thomson IR, Cornel JH, tenCate FJ, Arnese M, van Urk H, Roelandt JR. Dobutamine-atropinestress echocardiography in elderly patients unable to perform an ex-ercise test. Arch Intern Med 1994;154:2681–2686.

7. Camerieri A, Picano E, Landi P, Nichelassi C, Pingitore A, Minardi G,Gandolfo N, Severo G, Chiarella F, Bolognese L. Prognostic value ofdipyridamole echocardiography early after myocardial infarction inelderly patients. J Am Coll Cardiol 1993;22:1809–1815.

8. Smart S, Sagar K, Tresch D. Age-related determinants of outcomeafter acute myocardial infarction: a dobutamine-atropine stress echo-cardiography study. J Am Geriatr Soc 2002;50:1176–1185.

9. The sixth report on the Joint National Committee on prevention,detection, evaluation, and treatment of high blood pressure. Arch
Intern Med 1997;157:2413–2446.
0. World Health Organization. Diabetes Mellitus. Report of a WHOStudy Group. Technical Report Series Number 727. Geneva: WorldHealth Organization, 1985.

1. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, ColeTG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braun-wald E. The effect of pravastatin on coronary events after myocardialinfarction in patients with average cholesterol levels. N Engl J Med1996;335:1001–1009.

2. Picano E, Lattanzi F, Masini M, Distante A, L’Abbate A. High dosedipyridamole echocardiography test in effort angina pectoris. J AmColl Cardiol 1986;8:846–854.

3. McNeill AJ, Fioretti PM, El-Said ESM, Salustri A, Forster T, RoelandtJRTC. Enhanced sensitivity for detection of coronary artery disease byaddition of atropine to dobutamine stress echocardiography. Am JCardiol 1992;70:41–46.

4. Picano E, Pingitore A, Conti U, Kozakova M, Boem A, Cubani E,Ciuti M, Distnate A, L’Abbate A. Enhanced sensitivity for detection ofcoronary artery disease by addition of atropine to dipyridamole echo-cardiography. Eur Heart J 1993;14:1216–1222.

5. Lang RM, Bierig M, Devereaux RB, Flachskampf FA, Foster E,Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, et al.Chamber Quantification Writing Group, American Society of Echo-cardiography’s Guidelines and Standards Committee, European Asso-ciation of Echocardiography. Recommendations for chamber quanti-fication: a report from the American Society of Echocardiography’sGuidelines and Standards Committee and the Chamber QuantificationWriting Group, developed in conjunction with the European Associ-ation of Echocardiography, a branch of the European Society ofCardiology. J Am Soc Echocardiogr 2005;18:1440–1463.

6. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death inclinical research: time for a reassessment? J Am Coll Cardiol 1999;34:618–620.

7. Christensen NJ, Schultz-Larsen K. Resting venous plasma adrenalin in70-year-old men correlated positively to survival in a population study:the significance of the physical working capacity. J Intern Med 1994;235:229–232.

8. Pingitore A, Picano E, Varga A, Gigli G, Cortigiani L, Previstali M,Minardi G, Colosso MO, Lowenstein J, Mathias W Jr, Landi P.Prognostic value of pharmacological stress echocardiography inpatients with known or suspected coronary artery disease: a prospec-tive, large-scale, multicenter, head-to-head comparison between dipy-ridamole and dobutamine test. J Am Coll Cardiol 1999;34:1769–1777.

9. Schroeder K, Wieckhorst A, Voller H. Comparison of the prognosticvalue of dipyridamole and dobutamine stress echocardiography inpatients with known or suspected coronary artery disease. Am J Car-diol 1997;79:1516–1517.

0. Minardi G, Disegni M, Manzara C, Pulignano G, Chiantera A, DeSantis F, Amiento G, Vajola FS, Giovannini E. Diagnostic and prog-nostic value of dipyridamole and dobutamine stress echocardiographyin patients with acute myocardial infarction. Am J Cardiol 1997;80:847–851.

1. Cortigiani L, Bigi R, Sicari R, Landi P, Bovenzi F, Picano E. Prog-nostic value of pharmacological stress echocardiography in diabeticand nondiabetic patients with known or suspected coronary arterydisease. J Am Coll Cardiol 2006;47:605–610.

2. Sicari R. Anti-ischemic therapy and stress testing: pathophysiologic,diagnostic, and prognostic implications. Cardiovasc Ultrasound 2004;
2:14.

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Patterns of Aspirin Dosing in Non–ST-Elevation Acute Coronary Syndromes inthe CRUSADE Quality Improvement Initiative

Sumit Tickoo, MDa, Matthew T. Roe, MD, MHSb, Eric D. Peterson, MD, MPHb,Sarah Milford-Beland, MSb, E. Magnus Ohman, MDb, W. Brian Gibler, MDc,

Charles V. Pollack, Jr., MD, MAd, and Christopher P. Cannon, MDe,*,for the CRUSADE Investigators

Recent studies have suggested that low-dose aspirin has preserved benefit with less bleedingcompared with standard-dose aspirin when given with or without clopidogrel in patients withhigh-risk non–ST-segment elevation acute coronary syndromes (NSTE ACSs). We evaluated22,618 patients with NSTE ACSs and high-risk features (ischemic ST-segment changes and/orpositive cardiac markers) from 369 hospitals included in the CRUSADE initiative from May 4,2003 to September 30, 2004. We analyzed acute (<24 hours of admission) and discharge aspirindoses in relation to concomitant clopidogrel use and other clinical predictors. Dosing of aspirinin the first 24 hours was as follows: 17.3% of patients (n � 3,911) received 81 mg, 13.5% (n �3,062) received 162 mg, 67.4% (n � 15,247) received 325 mg, and 1.8% (n � 398) received >325mg. Use of lower dose aspirin increased at discharge: 40.2% (n � 7,524) received 81 mg, 3.1%(n � 579) received 162 mg, and 55.7% (n � 10,423) received 325 mg. In patients who receivedconcomitant clopidogrel at discharge (n � 12,635), 37.6% received aspirin 81 mg and 58.5%received 325 mg. Compared with patients who did not receive concomitant discharge clopi-dogrel (n � 4,772), 44.0% received aspirin 81 mg and 51.2% received 325 mg. Use of aspirin 81mg was significantly lower in patients undergoing percutaneous coronary intervention (31.5%vs 46.2%, p <0.0001). In conclusion, most patients with high-risk NSTE ACSs in the UnitedStates continue to be treated with aspirin 325 mg at discharge with and without concomitantclopidogrel, despite recent studies that have shown a better safety profile with low-dose
aspirin. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1496–1499)
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ecent guidelines have recommended the use of aspirin,lopidogrel, and glycoprotein IIb/IIIa inhibitors for high-isk patients with non–ST-segment elevation acute coronaryyndromes (NSTE ACSs).1 When these drugs are used inombination, the risk of major bleeding increases.2 Therere limited data available on specifically how antiplateletrugs are being used in clinical practice. Therefore, wexamined the current use of aspirin on admission and dis-harge in relation to clopidogrel and other clinical predic-ors.

ethods and Results

sing the Can Rapid Risk Stratification of Unstable Anginaatients Suppress ADverse Outcomes with Early Imple-

aBridgeport Hospital, Bridgeport, Connecticut; bDivision of Cardiologynd Duke Clinical Research Institute, Durham, North Carolina; cUniversityf Cincinnati College of Medicine, Cincinnati, Ohio; dPennsylvania Hos-ital, University of Pennsylvania School of Medicine, Philadelphia,ennsylvania; and eTIMI Study Group, Brigham and Women’s Hospital,oston, Massachusetts. Manuscript received August 17, 2006; revisedanuscript received and accepted January 10, 2007.

CRUSADE is funded by Schering-Plough Corporation, Kenilworth,ew Jersey. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership,ew York, New York, provides additional funding support. Millenniumharmaceuticals, Inc., Cambridge, Massachusetts, also provided fundingor this work.

sE-mail address: [email protected] (C.P. Cannon).

entation of the American College of Cardiology/Americaneart Association Guidelines (CRUSADE) initiative data-ase, we analyzed acute (�24 hours) and discharge aspirinoses in relation to concomitant clopidogrel use and otherlinical predictors. Acute aspirin use was recorded as “yes”f administered in the first 24 hours of care, regardless ofocation (e.g., transferring facility or emergency medicalervice). Aspirin taken at home before hospital arrival, andherefore not readministered until the next day of the hos-italization, was recorded as yes. The date and time thenitial dose was given and the amount of the initial dosesere recorded. Discharge use was defined as aspirin con-

inued or prescribed at hospital discharge.The CRUSADE is an ongoing, voluntary, observa-

ional data collection and quality improvement Initiative.RUSADE was initiated in November 2001, with retro-

pective data collection beginning from January 2001, andata collection remains ongoing. The CRUSADE Initiatives designed to track guideline adherence, provide feedbackbout performance, and develop quality improvement toolso improve adherence to guideline recommendations.

All patients in the CRUSADE Initiative must presentt a participating hospital with acute ischemic symptomslasting �10 minutes) at rest within 24 hours of hospitalrrival and have �1 of the following diagnostic featuresecommended in the American College of Cardiology/merican Heart Association guidelines to distinguish pa-

ients with an increased risk of adverse outcomes: ST-
egment depression �0.5 mm, transient ST-segment ele-
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1497Coronary Artery Disease/Aspirin Dosing Acute Coronary Syndromes

ation 0.5 to 1.0 mm (lasting �10 minutes), and/or positiveardiac markers (increased troponin I or T and/or creatineinase-MB levels above the upper limit of normal for theocal laboratory assay used at each institution). Patients are in-ligible for CRUSADE if they transfer into a participatingospital �24 hours after the last episode of ischemic symp-oms.

We evaluated 22,618 patients with NSTE ACSs from69 hospitals for acute aspirin analyses and 18,698 patientsrom 359 hospitals for discharge aspirin analyses. The studyeriod included patients enrolled in CRUSADE from May, 2003 to September 30, 2004.

In September 2002, CRUSADE formally assessed the re-iability of data abstraction. Sites and records were randomlyelected. Study co-ordinators from 25% of CRUSADE hospi-als were contacted and asked to send the CRUSADE Coor-inating Center copies of medical records without patient iden-ifiers. Records were audited by trained site managementersonnel who were knowledgeable about CRUSADE vari-ble definitions and who had had previous monitoring experi-nce. In addition to selected clinical characteristics, auditedariables included all medical therapies, procedures, and in-ospital clinical events. Overall accuracy of audited recordsas 94.8%.Overall degree of missing data was quite low for a

egistry, averaging �5% across all collected data elements.

able 1aseline characteristics and hospital features of acute aspirin dosing

haracteristics (n � 22,618)

81 (n � 3,911) 162 (n

ge (yrs)* 72 (59, 81) 67 (5omen 43.0% 39

ody mass index (kg/m2)* 27.3 (23.9, 31.7) 27.8 (2hite 82.1% 74ypertension 72.5% 70iabetes mellitus 34.9% 31urrent/recent smoker 22.9% 28yslipidemia† 50.2% 51revious myocardial infarction 33.5% 27revious percutaneous coronary

infarction23.1% 18

revious coronary artery bypassgrafting

22.7% 17

revious congestive heartfailure

23.3% 16

revious stroke 11.7% 9enal insufficiency‡ 16.5% 13resenting characteristicsST depression 33.6% 36Signs of congestive heart

failure29.2% 20

Heart rate (beats/min)* 84 (70, 100) 82 (7Systolic blood pressure

(mm Hg)*141 (121, 164) 146 (1

ther featuresPrimary care by cardiologist 51.6% 53Academic teaching hospital 25.1% 26

* Medians (25th, 75th percentiles).† Known total cholesterol level �200 mg/dl (5.2 mmol/L) or long-term‡ Creatinine level 2.0 mg/dl, calculated creatinine clearance �30 ml/mi

otably, variables such as age and gender were missing in q

0.5% of all cases. Various routine procedures have beenstablished to maintain and monitor the data quality of theRUSADE database. At data entry and during quarterlyuality control procedures, values that exceed expectedanges are flagged and excluded from analyses. In addition,very quarter sites receive a report summarizing any datauality problems observed in their submitted data. Issues arepecified on a per-record level. Sites are encouraged toake corrections and thus may iteratively improve the over-

ll quality of the database.Patients were also categorized as cardiology or noncar-

iology patients based on the specialty of the attendinghysician who primarily cared for the patient according tohe most frequent and consistent notations in the medicalecord.

Baseline characteristics, treatment patterns (medicationse within 24 hours of presentation, use and timing oforonary angiography and revascularization procedures),nd hospital features were compared in patients receivingspirin 81, 162, 325, and �325 mg within 24 hours ofdmission. In addition, discharge aspirin dose, similarlyategorized, was compared in patients according to theiraseline characteristics and treatment patterns. Continuousariables are presented as medians with 25th and 75thercentiles, and categorical variables are presented as fre-

spirin Dose (mg) p Value

2) 325 (n � 15,247) � 325 (n � 398)

66 (55, 77) 66 (55, 76) �0.00137.2% 33.7% �0.001

7) 28.1 (24.6, 32.2) 28.1 (25.1, 31.9) �0.00180.1% 84.2% �0.00169.4% 64.3% �0.00132.3% 30.9% 0.01529.8% 27.9% �0.00151.7% 44.5% 0.0328.3% 22.9% �0.00121.3% 14.6% �0.001

18.8% 16.8% �0.001

14.6% 10.3% �0.001

8.9% 8.5% �0.00111.5% 7.8% �0.001

34.7% 36.4% 0.0220.9% 19.6% �0.001

82 (70, 97) 82 (68, 98) �0.001) 145 (126, 166) 149 (128, 171) �0.001

60.7% 62.8% �0.00132.7% 28.4% �0.001

ent with a lipid-lowering agent.ed for long-term renal dialysis.

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ruskal-Wallis rank-sum tests, and categorical variables areompared using chi-square tests.

In the study period from May 4, 2003 to September 30,004 there were 42,156 patients enrolled into theRUSADE Initiative. Of these, 4,424 patients were ex-luded because they received no aspirin within 24 hours ofdmission. Also, there were 15,114 patients excluded due toissing or out-of-range dose information. Therefore we

nalyzed 22,618 patients who received an acute aspirinose. For discharge aspirin analysis, of the initial 42,156atients, 10,174 received no aspirin at discharge, 12,382 hadissing data or were given another dose, 888 were trans-

erred out, and there were 14 deaths, resulting in an analysisopulation for discharge aspirin of 18,698.

Dosing of aspirin in the first 24 hours was as follows:7.3% of patients (n � 3,911) received aspirin 81 mg,3.5% (n � 3,062) received 162 mg, 67.4% (n � 15,247)eceived 325 mg, and 1.8% (n � 398) received �325 mgTable 1). Use of lower dose aspirin increased at discharge:0.2% (n � 7,524) received 81 mg, 3.1% (n � 579) re-eived 162 mg, 55.7% (n � 10,423) received 325 mg, and1% (n � 172) received �325 mg (Table 2). Higher-dose

spirin use in the first 24 hours was associated with signif-cantly shorter time to catheterization and percutaneous cor-nary intervention.

Baseline characteristics were recorded for all patientsTable 1). Lower doses of aspirin were associated with moredvanced age and increased rates of co-morbidities such asrevious percutaneous coronary intervention, previous cor-nary artery bypass graft surgery, previous heart failure,revious stroke, and renal insufficiency. In contrast, patientsdministered higher doses of aspirin were generally healthiernd more likely to receive in-hospital procedures includingiagnostic catheterization, percutaneous coronary interven-ion, and coronary artery bypass graft surgery.

In patients who received concomitant clopidogrel at dis-harge (n � 12,635), 37.6% (n � 4,745) received aspirin 81

able 2ischarge aspirin dose

haracteristics (n � 18,698)

81(n � 7,524)

en 37.4%omen 44.9%ge (yrs)�65 34.1%�65 45.9%iabetes mellitus 41.1%ardiology inpatient service 37.5%ercutaneous coronary intervention 31.5%oronary artery bypass grafting 40.8%revious aspirin therapy 41.6%spirin within 24 h 39.6%lopidogrel at discharge 37.6%ercutaneous coronary intervention �24 h of arrival 29.1%ongestive heart failure in hospital 48.3%ed blood cell transfusion* 49.1%

* Unrelated to coronary artery bypass grafting.

g and 58.5% (n � 7,397) received 325 mg. In patients f

ho did not receive concomitant discharge clopidogrel (n �,772), 44.03% (n � 2,101) received aspirin 81 mg and1.24% (n � 2,445) received 325 mg (Table 2). Therefore,lthough there is a greater tendency to receive low-dosespirin when no concomitant discharge clopidogrel isdministered, most patients still receive higher-dose dis-harge aspirin. In patients who were discharged from aardiology inpatient service (n � 11,587), 37.5% (n �,350) received aspirin 81 mg and 58.5% (n � 6,780)eceived 325 mg, whereas 44.6% of patients (n � 3,083)ho were not cardiology inpatients (n � 6,914) received

spirin 81 mg and 51.4% (n � 3,553) received 325 mgTable 2). Thus, cardiology inpatients are less likely thanoncardiology inpatients to receive aspirin 81 versus 325 mg.

iscussion

lthough aspirin is the most important antithrombotic agentor the treatment of ACSs, we observed that, of the initial2,156 patients enrolled in CRUSADE during the studyeriod, 4,424 patients (10.5%) received no aspirin within 24ours and 10,174 (24.1%) did not receive aspirin at the timef hospital discharge. Although the CRUSADE Initiativeoes not include reasons for not administering acute andischarge aspirin to patients enrolled in the study, these datauggest that aspirin is still being underutilized in the initialreatment and discharge of patients with NSTE ACSs.

Of patients who do receive aspirin, we found that mostatients are still being treated with aspirin 325 mg at dis-harge with and without concomitant clopidogrel, despiteecent studies that have demonstrated a better safety profileith low-dose aspirin.3–6

Patients undergoing percutaneous coronary interventionere more likely to be discharged home with aspirin 325g than were those who did not undergo percutaneous

oronary intervention. The 2004 American Heart Associa-ion’s guidelines for ST-segment elevation myocardial in-

Aspirin Dose (mg) p Value

162(n � 579)

325(n � 10,423)

� 325(n � 172)

3.1% 58.6% 1.0% �0.0013.1% 51.2% 0.8%

2.9% 61.9% 1.1% �0.0013.3% 50.1% 0.8%2.6% 55.2% 1.1% 0.0163.1% 58.5% 0.9% �0.0013.0% 64.6% 0.9% �0.0012.0% 56.6% 0.6% 0.0023.1% 54.3% 1.0% 0.0013.1% 56.4% 0.9% �0.0012.9% 58.5% 1.0% �0.0013.1% 67.0% 0.8% �0.0013.3% 47.6% 0.7% �0.0013.3% 46.6% 1.1% �0.001

arction recommended an initial dose of aspirin 162 to 325

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1499Coronary Artery Disease/Aspirin Dosing Acute Coronary Syndromes

g and a maintenance dose of aspirin 75 to 162 mg to allatients thereafter.7 Recent guidelines published by themerican Heart Association for percutaneous coronary in-

ervention have recommended aspirin 325 mg at discharge,8hereas the 2004 guidelines for ST-elevation myocardial

nfarction have recommended a lower maintenance dose ofspirin 75 to 162 mg. These recommendations contrast withhe guidelines for NSTE ACSs, which provide a dosingange of aspirin 75 to 325 mg at discharge, hence theariability seen in the CRUSADE results.

Patients who developed in-hospital clinical events suchs heart failure and bleeding were significantly more likelyo be discharged with lower doses of discharge aspirin thanere those who did not have these adverse events. There isgreater tendency for discharge clopidogrel users to have

igher doses of discharge aspirin than for nonclopidogrelsers.

. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD,Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, et al, forthe American College of Cardiology/American Heart Association TaskForce on Practice Guidelines (Committee on the Management of Pa-tients With Unstable Angina). ACC/AHA guideline update for themanagement of patients with unstable angina and non–ST-segmentelevation myocardial infarction—2002: summary article: a report of theAmerican College of Cardiology/American Heart Association TaskForce on Practice Guidelines (Committee on the Management of Pa-tients With Unstable Angina). Circulation 2002;106:1893–1900.

. Boersma E, Harrington RA, Moliterno DJ, White H, Theroux P, Van deWerf F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, et al.Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes:a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189–198.

. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, forthe Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial
Investigators. Effects of clopidogrel in addition to aspirin in patients
with acute coronary syndromes without ST-segment elevation. N EnglJ Med 2001;345:494–502.

. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis ofrandomized trials of antiplatelet therapy for prevention of death, myo-cardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86.

. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, Diaz R,Commerford PJ, Valentin V, Yusuf S, for the Clopidogrel in UnstableAngina to Prevent Recurrent Events (CURE) Trial Investigators. Effectsof aspirin dose when used alone or in combination with clopidogrel inpatients with acute coronary syndromes: observations from the Clopi-dogrel in Unstable angina to prevent Recurrent Events (CURE) study.Circulation 2003;108:1682–1687.

. Topol EJ, Easton D, Harrington RA, Amarenco P, Califf RM, Graf-fagnino C, Davis S, Diener HC, Ferguson J, Fitzgerald D, et al. Ran-domized, double-blind, placebo-controlled, international trial of the oralIIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease.Circulation 2003;108:399–406.

. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M,Hochman JS, Krumholz HM, Kushner FG, Lamas GA, et al, for theAmerican College of Cardiology/American Heart Association TaskForce on Practice Guidelines (Writing Committee to Revise the 1999Guidelines for the Management of Patients With Acute MyocardialInfarction). ACC/AHA guidelines for the management of patients withST-elevation myocardial infarction—executive summary: a report ofthe American College of Cardiology/American Heart Association TaskForce on Practice Guidelines (Writing Committee to Revise the 1999Guidelines for the Management of Patients With Acute MyocardialInfarction). Circulation 2004;110:588–636.

. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, KingSB III, Morrison DA, O’Neill WW, Schaff HV, Whitlow PL, et al, forthe American College of Cardiology/American Heart Association TaskForce on Practice Guidelines; American College of Cardiology/AmericanHeart Association/Society for Cardiovascular Angiography and Inter-ventions Writting Committee to Update the 2001 Guidelines for Per-cutaneous Coronary Intervention. ACC/AHA/SCAI 2005 guideline up-date for percutaneous coronary intervention—summary article: a reportof the American College of Cardiology/American Heart AssociationTask Force on Practice Guidelines (ACC/AHA/SCAI Writing Commit-tee to Update the 2001 Guidelines for Percutaneous Coronary Interven-
tion). Circulation 2006;113:156–175.

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Comparison of Characteristics of Future Myocardial Infarctionsin Women With Baseline High Versus Baseline Low Levels

of High-Sensitivity C-Reactive Protein

Sandeep Bansal, MD*, and Paul M. Ridker, MD, MPH†

High-sensitivity C-reactive protein (hs-CRP) has previously been shown to be an indepen-dent predictor for the development of cardiovascular disease. However, little is knownabout the association between hs-CRP and the severity of cardiovascular events that occur.This study compared characteristics of incident myocardial infarctions (MIs) in 40 initiallyhealthy women with very high baseline hs-CRP levels (>7.5 mg/L) with infarctions in 40women with very low hs-CRP levels (<1 mg/L). At baseline, very high hs-CRP wasassociated with a clinical diagnosis of hypertension, higher body mass index, lower high-density lipoprotein, and higher triglycerides. Our analysis found that the 2 study groupshad similar proportions of ST-segment elevations on electrocardiograms, peak cardiacenzyme levels, postinfarct left ventricular function, and burden of coronary atherosclerosisseen on angiography. However, subjects with very high hs-CRP levels developed infarctionssignificantly sooner than those with very low hs-CRP levels (median time to event 4.45 vs6.64 years, respectively, p <0.0001). In addition, higher baseline levels of hs-CRP wereassociated with significantly more fatal MIs (0% vs 4.6% vs 9.6% in subjects with hs-CRPlevels <1, 1 to <3, and >3 mg/L, respectively, p for trend � 0.02). In conclusion, this studydemonstrates that in initially healthy women high levels of hs-CRP predict earlier occur-rence of MIs and a greater likelihood that infarctions will be fatal. © 2007 Elsevier Inc.
All rights reserved. (Am J Cardiol 2007;99:1500–1503)
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umerous large-scale studies have demonstrated that high-ensitivity C-reactive protein (hs-CRP) is an independentisk factor for the development of myocardial infarctionMI), stroke, and cardiovascular death.1–6 However, little isnown about the association between initial hs-CRP levelsnd the clinical characteristics of MIs that later occur. Lows-CRP levels have been associated with slower progressionf atherosclerosis7,8 and thus may be associated with de-ayed onset of clinical events and less extensive vascularisease at the time of infarction. In addition, lower markersf systemic inflammation have been associated with lowerropensity for coronary artery plaque rupture.9,10 Theseascular characteristics corresponding to low hs-CRP levelight therefore be associated with milder infarctions. In

ontrast, high levels of hs-CRP may be associated withreater burden of disease, more extensive vulnerablelaque, and more severe infarctions. To address this

Center for Cardiovascular Disease Prevention, Division of Preventiveedicine, Brigham and Women’s Hospital, Harvard Medical School,oston, Massachusetts. Manuscript received September 21, 2006; revisedanuscript received January 10, 2007.

This study was supported by grants from the Donald W. Reynoldsoundation, Las Vegas, Nevada and Grant T32 HL007575-21 from theational Heart, Lung, and Blood Institute, Bethesda, Maryland.

*Corresponding author: Tel: 617-278-0748; fax: 617-731-3843.E-mail address: [email protected] (S. Bansal).

† Conflicts of interest: Dr. Ridker is listed as a co-inventor on patentseld by Brigham and Women’s Hospital that relate to the use of inflam-

eatory biomarkers in cardiovascular disease and diabetes mellitus.


uestion, we compared clinical characteristics of initiallyealthy women with very high baseline levels of hs-CRP�7.5 mg/L) with those of women with very low baselineevels of hs-CRP (�1 mg/L), all of whom went on to havefirst ever MI during a median 10-year follow-up period.

ethods

ll study participants were enrolled in the Women’s Healthtudy, a prospective cohort of 39,876 initially healthy Amer-

can women �45 years of age. Details of the study design andrimary outcomes have been reported previously.11–13 Withinhis cohort, 27,939 participants provided baseline demo-raphic data, health history, and blood samples that could bessayed for lipid levels and hs-CRP. Study participants wereollowed for a median of 10 years for incident cardiovas-ular events, and all reported end points were confirmed byblinded end-points committee. MI was defined by Worldealth Organization criteria of ischemic symptoms accom-anied by increased cardiac enzymes or diagnostic electro-ardiograms.

For the purpose of this analysis, we identified allomen participating in the Women’s Health Study whoent on to have a confirmed incident MI during follow-p. We then selected the 40 subjects with the highestaseline hs-CRP levels (�7.5 mg/L) and for comparisonhe 40 subjects with the lowest baseline hs-CRP levels�1 mg/L). We reviewed physician reports, hospital dis-harge summaries, cardiac catheterization reports, echo-ardiographic reports, electrocardiograms, and laboratoryata to ascertain clinical characteristics of infarctions in
ach subject.
www.AJConline.org

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1501Coronary Artery Disease/hs-CRP and Characteristics of MI

Severity of MI was determined by 30-day mortality,resence of ST-segment elevations on electrocardiogram,eak cardiac enzyme levels (creatine kinase, creatine ki-ase-MB isoenzyme, and cardiac troponin), and postinfarcteft ventricular ejection fraction as determined by echocar-iography or left ventriculography at cardiac catheteriza-ion. Burden of coronary artery disease was evaluated fromardiac catheterization reports. Stenoses were consideredlinically significant if �70% obstructed in an epicardialrtery or �50% in the left main coronary artery. Time tovent was defined as time from randomization until MI. Allecords were reviewed by a researcher (S.B.) blinded toaseline values of hs-CRP.

Subjects with very low baseline hs-CRP levels wereompared with subjects with very high hs-CRP levels inerms of baseline characteristics and infarction characteris-ics. Differences in mean values were analyzed for signifi-

able 1aseline characteristics of subjects according to high-sensitivity-reactive protein levels at randomization

ariable hs-CRP p Value

�1.0 mg/L(n � 40)

�7.5 mg/L(n � 40)

s-CRP (mg/L) 0.69 (0.22–0.98) 14.01 (7.53–92.0)ge (yrs) 60.0 � 9.4 61.2 � 8.1 0.6hite race 40 (100%) 36 (90%) 0.12ypertension 15 (38%) 26 (65%) 0.01ypertension therapy 5 (13%) 19 (48%) 0.001ipids (mg/dl)Total cholesterol 217 � 36 230 � 41 0.14LDL cholesterol 129 � 33 137 � 33 0.3HDL cholesterol 53.1 � 19.6 41.8 � 10.5 0.002Triglycerides 151 � 103 236 � 150 0.004holesterol-lowering

therapy4 (10%) 5 (13%) �0.9

mokingCurrent 7 (18%) 11 (28%) 0.5Previous 17 (43%) 13 (33%)Never 16 (40%) 16 (40%)iabetes mellitus 4 (10%) 10 (25%) 0.08ody mass index

(kg/m2)25.1 � 3.3 29.8 � 6.1 �0.0001

�25 19 (50%) 11 (28%)25–30 17 (45%) 12 (31%) 0.001 (trend)�30 2 (5%) 16 (41%)reatinine (mg/dl) 0.76 � 0.13 0.74 � 0.16 0.6xercise (times/wk)Rarely/never 21 (53%) 22 (55%) 0.5�1 6 (15%) 7 (18%)1–3 9 (23%) 10 (25%)�4 4 (10%) 1 (3%)ormone therapy useNever 21 (53%) 14 (35%) 0.11Previous 9 (23%) 7 (18%)Current 10 (25%) 19 (48%)andomized to

aspirin17 (43%) 23 (58%) 0.18

Values are medians (ranges), numbers of subjects (percentages), orean � SD.HDL � high-density lipoprotein; LDL � low-density lipoprotein.

ance using Student’s t test if the distributions approximated s

ormality and the Wilcoxon rank-sum test if non-normallyistributed. Differences in proportions were analyzed forignificance using chi-square analysis for nominal measure-ents and Cochran-Armitage test for trend for ordinal mea-

igure 1. Probability of MI according to quintile (Q) of baseline hs-RP.

able 2haracteristics of incident myocardial infarctions according to baselineigh-sensitivity C-reactive protein

ariable hs-CRP p Value

�1.0 mg/L(n � 40)

�7.5 mg/L(n � 40)

edian time to event(yrs)

6.64 4.45 �0.0001

atal within 30 d 0 (0%) 5 (12.5%) 0.055T-segment elevations 24 (62%) 21 (58%) 0.8eak cardiac enzymesCreatine kinase (IU) 393 (279–854) 747 (428–1381) 0.04Creatine kinase-MB

(IU)43.9 (23.2–113) 52.0 (19.9–169) 0.9

Troponin (ng/ml) 8.9 (6.6–32.0) 17.8 (4.2–38.3) 0.7eft ventricular

ejection fraction(%)

55 (40–60) 57 (50–60) 0.3

oronary arterynarrowed

Left main �50% 1 (3%) 2 (5%) �0.9Left anterior

descending �70%18 (50%) 18 (47%) �0.9

Left circumflex�70%

13 (36%) 13 (34%) �0.9

Right coronary�70%

14 (39%) 18 (47%) 0.5

No. of coronaryarteries narrowed�70%

0 6 (17%) 3 (8%) 0.6 (trend)1 19 (53%) 24 (63%)2 7 (19%) 5 (13%)3 4 (11%) 6 (16%)

Values are numbers of subjects (percentages) or medians (interquartileanges).

ures. Differences in event rates were analyzed for signifi-

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ance with log-rank test, and hazard ratios were calculatedsing Cox proportional hazards model. All p values are-tailed, and a p value �0.05 was considered statisticallyignificant. All statistical analyses were run using SAS 9.0SAS Institute, Cary, North Carolina) and S-Plus 6.2 (In-ightful Corp., Seattle, Washington).

esults

aseline characteristics of the 2 study groups at the time ofnrollment are listed in Table 1. No significant differencesere noted in age, race, total and low-density lipoprotein

holesterol, smoking status, presence of diabetes mellitus,erum creatinine, family history of premature atherosclero-is, exercise frequency, hormone replacement therapy use,nd random treatment assignment to aspirin between the 2roups at study entry. As might be expected given knownodest correlations in this cohort between components of

he metabolic syndrome and hs-CRP,14 those with very highevels of hs-CRP had somewhat lower levels of high-densityipoprotein cholesterol, higher levels of triglycerides, andreater mean body mass index compared with those withery low hs-CRP levels at study entry. In addition, the studyroup with very high hs-CRP levels was more likely toarry a diagnosis of hypertension and be treated for hyper-ension at study entry.

Table 2 presents data comparing clinical characteris-ics of incident MIs in the 2 study groups. No significantifferences were found between those with very low andhose with very high baseline hs-CRP levels in terms ofhe proportion of MIs with ST elevations or postinfarcteft ventricular function. We also observed no differencesn location of coronary stenoses or number of vesselsith significant stenoses. With respect to peak cardiac

nzyme levels, there was a higher peak creatine kinaseevel in subjects with very high hs-CRP levels (median47 vs 393 IU in high vs low hs-CRP group, respectively,� 0.04). However, because creatine kinase-MB isoen-

yme and cardiac troponin levels were not significantlyifferent, this may represent a false-positive finding dueo multiple testing rather than a true difference in myo-ardial necrosis.

There appeared to be a trend toward increased fatalitiesithin 30 days of MI in the high hs-CRP group (12.5% vs

able 3ox hazard ratio for incident myocardial infarction by quintile of high-se

Quinti

1 2�0.49 0.50–1.08

o. of events 11 36vent rate (per 1,000 person-years

of follow-up)0.26 0.76

rude model 1.0 (ref) 2.9 (1.5–5.8)ge-adjusted model 1.0 (ref) 2.5 (1.3–5.0)isk-factor-adjusted model* 1.0 (ref) 2.1 (1.1–4.2)

Values are hazard ratios (95% confidence intervals).* Adjusted for age, smoking, diabetes mellitus, blood pressure, low-den

herapy.

% in high vs low hs-CRP group, respectively, p � 0.055).

o further explore this result, we retrospectively analyzedhe full cohort of participants in the Women’s Health Studyith baseline blood samples who developed incident MIsuring follow-up (257 subjects) and compared 30-day mor-ality based on initial hs-CRP levels. In this analysis, thereere 0 fatal events in 45 women with an hs-CRP level �1g/L, 3 fatal events in 66 women (4.6%) with hs-CRP

evels �1.0 and �3.0 mg/L, and 14 fatal events in 146omen (9.6%) with an hs-CRP level � 3.0 mg/L (p for

rend � 0.02). Other characteristics of women who went ono have fatal MIs, including hypertension, lipid levels, andody mass index, were not significantly different from thoseho had nonfatal MIs.Subjects with very high hs-CRP levels at study entry also

eveloped MIs significantly sooner than did those with veryow hs-CRP levels (median time to event 4.45 vs 6.64 years,espectively, p �0.0001). To further pursue this observa-ion, we divided the full cohort of subjects in the Women’sealth Study who provided baseline blood samples intouintiles of baseline hs-CRP level based on its distributionn women not taking hormone therapy, according to guide-ines from the Department of Health and Human Servicesor lipid standardization.15 Kaplan-Meier event curves wereonstructed according to quintiles of hs-CRP (Figure 1).igher quintiles of hs-CRP were associated with earlier

nfarctions across the full 10-year period of exposure (p0.0001). In Cox proportional hazards models, unadjusted

azard ratios for MI were higher for increasing quintiles ofs-CRP (p for trend �0.0001; Table 3). As expected, basedn previously published results,16 these effects were atten-ated but persisted after adjustment for traditional cardiacisk factors.

iscussion

n this prospective evaluation of initially healthy womenho subsequently had an MI, we observed that women with

he highest baseline level of hs-CRP had earlier MIs andere more likely to have fatal events than were women withery low baseline hs-CRP levels. No other differences in MIharacteristics were found, including proportion of infarc-ions with ST-segment elevations, peak cardiac enzymeevels, residual cardiac function, and burden of coronarytherosclerosis on angiography.

C-reactive protein

s-CRP (range, mg/L) p Value for Trend

3 4 5–2.09 2.10–4.19 �4.19

70 108.60 1.12 1.49

.2–4.5) 4.3 (2.3–8.1) 5.7 (3.1–10.6) �0.0001

.9–3.7) 3.3 (1.8–6.3) 4.5 (2.4–8.4) �0.0001

.7–2.9) 2.2 (1.2–4.3) 2.3 (1.2–4.5) 0.04

oprotein cholesterol, body mass index, and use of hormone replacement

nsitivity

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sity lip

One hypothesis of this study was that higher hs-CRP

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1503Coronary Artery Disease/hs-CRP and Characteristics of MI

evels would be associated with a propensity for plaquenstability and atherothrombosis. Although transmural in-arcts and extent of myocardial damage appeared to beimilar in the 2 study groups, the finding of increasedropensity for fatal MIs with increasing hs-CRP was in-riguing. Although CRP may play a biologic role in leadingo fatal infarctions, causality cannot be assumed from theata in this study. As a marker of systemic inflammation,s-CRP may simply represent a downstream summation ofisk factors that predispose a patient to infarctions that areatal. Alternatively, hs-CRP may represent a subclinicalealth state that portends poor tolerance of myocardial dam-ge. Although this association was based on a small totalumber of fatal MIs, the trend achieved statistical signifi-ance and warrants exploration in future studies.

A second hypothesis of this study was that high circu-ating levels of hs-CRP, signifying systemic inflammation,ould lead to more extensive atherosclerosis in the coro-ary tree. In our data, hs-CRP did not have any apparentssociation with extent of plaque burden seen on coronaryngiography in subjects at the time of their infarctions, anding consistent with previous studies.17–22 However,irroring what has been demonstrated in previous studies

f hs-CRP and cardiovascular events, this study foundhat baseline hs-CRP values are associated with earlier

Is, even after adjusting for traditional cardiac riskactors.1,3–5,16,23 Despite earlier MIs (and therefore earlierngiography) in the high hs-CRP group, these subjects hadhe same atherosclerotic plaque build-up and myocardial dam-ge as subjects in the low hs-CRP group. Thus, a high hs-CRPevel may be associated with an acceleration of the atheroscle-otic process, a finding consistent with previous studies.7,8

Limitations of this study merit consideration. All hs-CRPamples were drawn at study enrollment, and levels wereot remeasured at the time of MI. Although we cannot ruleut changes in hs-CRP immediately preceding infarction,s-CRP has been shown to be stable over time in asymp-omatic patients.5,24 Further, this study was designed spe-ifically to ascertain the predictive ability of baselines-CRP level on characteristics of future infarctions. Inddition, our conclusions are derived from data on incidentIs in women; similar studies would be needed to extend

hese results to men, recurrent infarctions, and other cardio-ascular events.

1. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH.Inflammation, aspirin, and the risk of cardiovascular disease in appar-ently healthy men. N Engl J Med 1997;336:973–979.

2. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein andother markers of inflammation in the prediction of cardiovasculardisease in women. N Engl J Med 2000;342:836–843.

3. Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M,Meilahn EN, Kuller LH. Relationship of C-reactive protein to risk ofcardiovascular disease in the elderly. Results from the CardiovascularHealth Study and the Rural Health Promotion Project. ArteriosclerThromb Vasc Biol 1997;17:1121–1127.

4. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A,Hutchinson WL, Pepys MB. C-reactive protein, a sensitive marker ofinflammation, predicts future risk of coronary heart disease in initiallyhealthy middle-aged men: results from the MONICA (MonitoringTrends and Determinants in Cardiovascular Disease) Augsburg CohortStudy, 1984 to 1992. Circulation 1999;99:237–242.

5. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P,
Gallimore JR, Pepys MB. Low grade inflammation and coronary heart
disease: prospective study and updated meta-analyses. BMJ 2000;321:199–204.

6. Cushman M, Arnold AM, Psaty BM, Manolio TA, Kuller LH, Burke GL,Polak JF, Tracy RP. C-reactive protein and the 10-year incidence ofcoronary heart disease in older men and women: the cardiovascular healthstudy. Circulation 2005;112:25–31.

7. van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A,Koudstaal PJ, Breteler MM. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 2005;112:900–905.

8. Schillinger M, Exner M, Mlekusch W, Sabeti S, Amighi J, NikowitschR, Timmel E, Kickinger B, Minar C, Pones M, et al. Inflammation andCarotid Artery—Risk for Atherosclerosis Study (ICARAS). Circula-tion 2005;111:2203–2209.

9. Ishikawa T, Hatakeyama K, Imamura T, Date H, Shibata Y, Hikichi Y,Asada Y, Eto T. Involvement of C-reactive protein obtained by direc-tional coronary atherectomy in plaque instability and developing re-stenosis in patients with stable or unstable angina pectoris. Am JCardiol 2003;91:287–292.

0. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive proteinin “active” coronary artery disease. Am J Cardiol 1990;65:168–172.

1. Buring JE, Hennekens CH. The Women’s Health Study: summary ofthe study design. J Myocardial Ischemia 1992;4:27–29.

2. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE,Hennekens CH, Buring JE. A randomized trial of low-dose aspirin inthe primary prevention of cardiovascular disease in women. N EnglJ Med 2005;352:1293–1304.

3. Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE,Hennekens CH, Buring JE. Vitamin E in the primary prevention ofcardiovascular disease and cancer: the Women’s Health Study: arandomized controlled trial. JAMA 2005;294:56–65.

4. Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean ME,Haffner SM. Prospective study of C-reactive protein in relation to thedevelopment of diabetes and metabolic syndrome in the Mexico CityDiabetes Study. Diabetes Care 2002;25:2016–2021.

5. Hainline A, Karon J, Lippel K. Manual of Laboratory Operations:Lipid Research Clinics Program and Lipid and Lipoprotein Analysis.Bethesda, MD: Department of Health and Human Services, 1982.

6. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison ofC-reactive protein and low-density lipoprotein cholesterol levels in theprediction of first cardiovascular events. N Engl J Med 2002;347:1557–1565.

7. Redberg RF, Rifai N, Gee L, Ridker PM. Lack of association ofC-reactive protein and coronary calcium by electron beam computedtomography in postmenopausal women: implications for coronaryartery disease screening. J Am Coll Cardiol 2000;36:39–43.

8. Hunt ME, O’Malley PG, Vernalis MN, Feuerstein IM, Taylor AJ.C-reactive protein is not associated with the presence or extent ofcalcified subclinical atherosclerosis. Am Heart J 2001;141:206–210.

9. Wang TJ, Larson MG, Levy D, Benjamin EJ, Kupka MJ, Manning WJ,Clouse ME, D’Agostino RB, Wilson PW, O’Donnell CJ. C-reactiveprotein is associated with subclinical epicardial coronary calcificationin men and women: the Framingham Heart Study. Circulation 2002;106:1189–1191.

0. Wang TJ, Nam BH, Wilson PW, Wolf PA, Levy D, Polak JF,D’Agostino RB, O’Donnell CJ. Association of C-reactive protein withcarotid atherosclerosis in men and women: the Framingham HeartStudy. Arterioscler Thromb Vasc Biol 2002;22:1662–1667.

1. Park R, Detrano R, Xiang M, Fu P, Ibrahim Y, LaBree L, Azen S.Combined use of computed tomography coronary calcium scores andC-reactive protein levels in predicting cardiovascular events in nondi-abetic individuals. Circulation 2002;106:2073–2077.

2. Khera A, de Lemos JA, Peshock RM, Lo HS, Stanek HG, Murphy SA,Wians FH Jr, Grundy SM, McGuire DK. Relationship between C-re-active protein and subclinical atherosclerosis: the Dallas Heart Study.Circulation 2006;113:38–43.

3. Mendall MA, Strachan DP, Butland BK, Ballam L, Morris J, Sweet-nam PM, Elwood PC. C-reactive protein: relation to total mortality,cardiovascular mortality and cardiovascular risk factors in men. EurHeart J 2000;21:1584–1590.

4. Ockene IS, Matthews CE, Rifai N, Ridker PM, Reed G, Stanek E.Variability and classification accuracy of serial high-sensitivity C-re-active protein measurements in healthy adults. Clin Chem 2001;47:
444–450.

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Comparison of Values of Wide-Range C-Reactive Protein to High-SensitivityC-Reactive Protein in Patients Undergoing Coronary Angiography

Yaron Arbel, MDa, Yoav Eros, MDa, Ori Rogowski, MDb, Shlomo Berliner, MD, PhDb,Itzhak Shapira, MDb, Gad Keren, MDa, Yafa Vered, PhDc, and Shmuel Banai, MDa,*

This study compared the recently introduced cheaper and more accessible wide-rangeC-reactive protein (wr-CRP) with the commonly used high-sensitivity C-reactive protein(hs-CRP) in patients undergoing coronary angiography. One hundred fifty-two consecutivepatients who were admitted to a tertiary medical center and underwent angiography wereincluded in the study. Arterial blood was obtained for the 2 assays at the beginning ofangiography. A highly significant correlation (r � 0.983, p <0.001) was found between the2 methods. This correlation was observed in different clinical scenarios and in differentranges of CRP. In conclusion, the real-time, online, and low-cost wr-CRP assay is areasonable alternative to the Behring Dade hs-CRP method in the setting of stable andunstable coronary artery disease. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol
2007;99:1504–1506)
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e recently introduced the Bayer wide-range C-reactiverotein (wr-CRP) measurement.1,2 The low-cost, online, andeal-time availability of this assay might be relevant forlinicians and for interventional cardiologists.3–6 In theresent study we compared results of the Bayer wr-CRPith those of the commonly used Dade Behring high-sen-

itivity CRP (hs-CRP) in patients undergoing coronary an-iography.

ethods and Results

ne hundred fifty-two consecutive patients who were ad-itted for coronary angiography were included in this

tudy. Patients with a history of malignancy or chronicnflammatory diseases (inflammatory bowel disease, arthri-is, and so forth) were excluded. All participants signed aritten informed consent that was approved by the local

thics committee.Arterial blood was obtained from all participants from

rterial access puncture as part of the angiographic proce-ure. The hs-CRP was determined by using the Behring BNI Nephelometer (Dade Behring, Marburg, Germany) ac-ording to the method of Rifai et al.7 The wr-CRP wasetermined by the Bayer wr-CRP assay (Bayer, Leverkusen,ermany). The wr-CRP in human serum was analyzed by

n immunoturbidimetric assay on an ADVIA 1650 chemis-ry system using a Bayer ADVIA kit for wr-CRP. It has aarticularly wide sensitivity range (lower limit of detection.12 mg/L). The wr-CRP reagent is a suspension of uniformolystyrene latex particles coated with anti-CRP antibody.hen serum-containing CRP is mixed with the latex re-

gent, agglutination takes place, resulting in an increase in

aInterventional Cardiology, Department of Cardiology, bDepartment ofedicine “D”, and cCentral Laboratory, Tel Aviv Sourasky Medical Cen-

er, Tel Aviv, affiliated to the Sackler Faculty of Medicine, Tel Avivniversity, Tel Aviv, Israel. Manuscript received November 9, 2006;

evised manuscript received and accepted January 10, 2007.*Corresponding author: Tel: 972-3-697-3395; fax: 972-3-696-2334.

pE-mail address: [email protected] (S. Banai).


urbidity. This turbidity was measured at 571 nm. CRPoncentration in serum was determined from a calibrationurve that is generated with the calibrators.

Diabetes mellitus was defined as known diabetes melli-us or use of insulin or oral hypoglycemic medications.ypertension was defined as a blood pressure �140/90 mmg in 2 separate measurements or use of antihypertensiveedications. Hyperlipidemia was defined as low-density li-

oprotein cholesterol concentrations or non–high-density li-

able 1edical conditions in the study population

ypertension 109 (72%)iabetes mellitus 47 (31%)yperlipidemia 112 (74%)revious myocardial infarction 47 (31%)revious stroke 14 (9%)revious coronary artery bypass surgery 32 (27%)urrent smokers 33 (21%)revious smokers 58 (38.2%)

Values are numbers of patients (percentages).

able 2sage of medications in the study population

spirin 102 (67%)tatins 100 (66%)Blockers 68 (45%)

alcium channel blockers 37 (24%)lopidogrel 21 (14%)ibrates 9 (6%)ngiotensin-converting enzyme inhibitors 68 (45%)ngiotensin II receptor blockers 14 (9%)hiazide diuretics 21 (14%)Blockers 23 (15%)itrates 28 (18%)urosemide 15 (10%)ral hypoglycemics 34 (22%)

Values are numbers of patients (percentages).

oprotein cholesterol concentrations above the recommended

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1505Coronary Artery Disease/Wide-Range C-Reactive Protein in the Catheterization Laboratory

evels according to the risk profile defined by the updatedational Cholesterol Education Program recommendations8 orse of lipid-lowering medications. Smokers were defined asubjects who smoked �5 cigarettes/day, and previous smokersad quit smoking �30 days before examination.

All continuous data were summarized and presented asean � SD. Chi-square test was used to evaluate categor-

cal variables (i.e., gender). To compare the 2 methods ofeasurement, we used Pearson correlation coefficient in

ddition to Deming regression to evaluate the slope andntercept of the regression line best fitted between the meth-ds. In addition, Bland-Altman analysis was used to eval-ate the mean difference between methods. A p value

Stable Angina

0.0

10.0

20.0

30.0

40.0

0.00 10.00 20.00 30.00 40.00

wr-CRP

hs-

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P

igure 1. Correlation between wr-CRP and hs-CRP (milligrams per liter)atients combined.

able 3orrelation of wide-range C-reactive protein to high-sensitivity C-reactive

Stable Angina(n � 30)

p Value Unstable(n �

s-CRP 0.994 �0.001 0.lope 0.971 �0.001 1.ntercept �0.11 �0.001 �0.

Slope and intercept are from the Deming regression.

0.05 was considered statistically significant. SPSS 13.0 a

or Windows (SPSS, Inc., Chicago, Illinois) was used toarry out all statistical analyses.

In total 152 patients were included in the study; 10569.1%) were men and 47 (30.9%) were women (mean �D 65.2 � 12.34 years of age, range 44 to 82). Of these 152atients, 30 (19.7%) had stable angina, 90 (59.2%) hadnstable angina, and 32 (21.1%) had acute myocardial in-arction. Tables 1 and 2 list clinical characteristics andedications used by patients.To assess the efficacy of the test, the level of correlation

etween the 2 tests was also examined in subgroups ofatients according to different clinical conditions. The co-ort was divided into 3 groups: stable angina, unstable

Unstable Angina

0.0

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nts with stable angina, unstable angina, or myocardial infarction and all

n in three different clinical settings

a p Value Myocardial Infarction(n � 32)

p Value

�0.001 0.990 �0.001�0.001 0.982 �0.001�0.001 �0.06 �0.001

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elation was extremely high (Table 3). Deming regressionnalysis showed that the slope was near 1 in all and that thentercept was small (Figure 1).

We examined whether the high correlation between the 2ethods existed in the low and high ranges of CRP. There-

ore, we divided our cohort into groups with CRP levelsbove and below the median (3.76 mg/L). The correlation ofr-CRP and Deming regression parameters in these 2roups is presented in Table 4.

To assess whether there was a constant difference and theattern of difference between the 2 methods, along thehole range of results, Bland-Altman analysis was con-ucted. As presented in Table 5, there was no significantifference between the 2 methods.

iscussion

arious techniques have been used to determine serumRP concentrations. The Dade Behring method is 1 of

able 4orrelation of wide-range C-reactive protein high-sensitivity C-reactiverotein in patients with C-reactive protein levels above and below theedian

Below MedianCRP (3.76 mg/L)

(n � 76)

p Value Above MedianCRP (3.76 mg/L)

(n � 76)

p Value

s-CRP 0.986 �0.001 0.964 �0.001lope 0.8684 �0.001 1.030 �0.001ntercept 0.3758 �0.001 �1.141 �0.001

Slope and intercept are from the Deming regression.

able 5esults from Bland-Altman analysis comparing the two methods inarious clinical scenarios and for patients with relative high (aboveedian) and relatively low (below median) C-reactive protein

oncentrations

Mean Bias 95% Confidence Interval

ll patients (n � 152) �0.21 �3.72 to 3.3table angina (n � 30) �0.3 �1.78 to 1.18nstable angina (n � 90) �0.16 �3.16 to 2.84yocardial infarction (n � 32) �0.39 �5.39 to 4.61elow median CRP (n � 76) 0.17 �0.43 to 0.77bove median CRP (n � 76) 0.06 �5.42 to 4.24

he most commonly used in the field of acute cardiac

are, enabling detection of CRP concentrations at theicro-inflammatory range. However, due to budget and

ogistic constraints, results are not always available ateal time at the point of care. With the recently intro-uced wr-CRP, using the Bayer kit system, we are able tobtain CRP results at a wide range of concentrationsncluding the microinflammatory concentrations.1,4 Theseesults are obtained from the primary tube, drawn foroutine chemistry, and are available within a short period,round the clock, and during weekends. The method isully automated and the physician receives data directlyo a personal computer within 40 minutes.

In our study we found that the correlation between the 2ethods was high (r � 0.984). The good correlation was

een in different clinical conditions and in a wide range ofRP values. The Bayer wr-CRP assay could be a usefullternative to the Dade Behring hs-CRP assay for acuteardiac care and invasive cardiologists.

. Rogowski O, Vered Y, Shapira I, Hirsh M, Zakut V, Berliner S.Introducing the wide range C-reactive protein (wr-CRP) into clinicaluse for the detection of microinflammation. Clin Chim Acta 2005;358:151–158.

. Shenhar-Tsarfaty S, Ben Asayag E, Bova I, Vered Y, Berliner S,Rogowski O, Shapira I, Bornstein NM. Wide-range C-reactive proteinefficacy in acute ischemic stroke patients. Acta Neurol Scand 2006;114:29–32.

. Cushman M, Arnold AM, Psaty BM, Manolio TA, Kuller LH, BurkeGL, Polak JF, Tracy RP. C-reactive protein and the 10-year incidence ofcoronary heart disease in older men and women: the cardiovascularhealth study. Circulation 2005;112:25–31.

. Laaksonen DE, Niskanen L, Nyyssonen K, Punnonen K, TuomainenTP, Salonen JT. C-reactive protein in the prediction of cardiovascularand overall mortality in middle-aged men: a population-based cohortstudy. Eur Heart J 2005;26:1783–1789.

. Labarrere CA, Zaloga GP. C-reactive protein: from innocent by-stander to pivotal mediator of atherosclerosis. Am J Med 2004;117:499 –507.

. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC,Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, et al.Targeting C-reactive protein for the treatment of cardiovasculardisease. Nature 2006;440:1217–1221.

. Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automatedhigh-sensitivity C-reactive protein assay. Clin Chem 1999;45:2136–2141.

. Executive summary of the Third Report of the National CholesterolEducation Program (NCEP) expert panel on detection, evaluation, andtreatment of high blood cholesterol in adults (Adult Treatment Panel
III). JAMA 2001;285:2486–2497.

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Coronary Circulation Responses to Binodenoson, a SelectiveAdenosine A2A Receptor Agonist

John McB. Hodgson, MDa,*, Nabil Dib, MDb, Morton J. Kern, MDc,Richard G. Bach, MDd, and Richard J. Barrett, PhDe

The purpose of this study was to define binodenoson dosing regimens that producecoronary hyperemia comparable to those of adenosine and that are tolerated wellby patients. An open-label, randomized, parallel-group, multicenter study enrolledadult patients who had completed diagnostic cardiac catheterization. Coronary bloodflow velocity (CBFV) was measured with a Doppler flow wire, and CBFV reservewas determined before binodenoson administration. Patients (n � 133) received a3-minute infusion of 0.3, 0.5, or 1 �g/kg/min or a bolus intravenous injection of 1.5 or3 �g/kg. Coronary hyperemic responses were evident within seconds of administeringbinodenoson, and the magnitudes and durations of coronary hyperemic responseswere dose related. The 1.5- and 3-�g/kg doses, by infusion or bolus, produced maximalcoronary hyperemia equivalent to CBFV reserve. All doses transiently decrease bloodpressure and increased heart rate and rate-pressure product. In conclusion, the1.5-�g/kg binodenoson bolus dose produced nearly maximal coronary hyperemia by4.5 � 3.7 minutes that was sustained for 7.4 � 6.86 minutes, was accompanied bymodest changes in blood pressure, heart rate, and rate-pressure product, and producedno adverse changes on electrocardiogram, including no second- or third-degree atrio-ventricular block. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:
1507–1512)
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yperemic responses to adenosine and dipyridamole, whendministered during pharmacologic stress myocardial per-usion imaging procedures, result from activation of aden-sine A2A receptors located in the smooth muscle of theoronary vessels. Some associated adverse events (e.g.,hest pain, dyspnea, flushing, atrioventricular block, andronchoconstriction)1–3 may result from unnecessary acti-ation of the A1, A2B, and A3 receptors. Binodenoson (2-(cyclohexylmethylene)hydrazino]adenosine) is an investi-ational, highly selective adenosine A2A receptor agonisthat has weaker affinity for the other adenosine receptorubtypes.4 Binodenoson has an elimination 1/2-life of �10inutes5 and produced fewer and less severe adverse events

han adenosine in a crossover study.6 This report describeshe results of an invasive study conducted to define pre-erred doses and dosing regimens for binodenoson use as aharmacologic stress agent.

ethods

n open-label, randomized, parallel-group study wasonducted at 18 centers in the United States in accor-

aSt. Joseph’s Hospital and Medical Center, Phoenix, and bArizonaeart Institute, Phoenix, Arizona; cSt. Louis University, and dWashingtonniversity in St. Louis, St. Louis, Missouri; and eKing Pharmaceuticalsesearch and Development, Inc., Cary, North Carolina. Manuscript re-eived March 31, 2006; revised manuscript received and accepted Decem-er 28, 2006.

(E-mail address: [email protected] (J.McB. Hodgson).

ance with good clinical practices and principles of theeclaration of Helsinki and after approval by institu-

ional review boards. Patients enrolled from June 2000 toebruary 2001.

Patients presenting for cardiac catheterization werecreened for eligibility and provided informed consent be-ore sedation. Final eligibility was determined during diag-ostic catheterization. Eligible patients included men oronpregnant women �18 years of age and weighing 40 to25 kg who had �1 unobstructed (�40% diameter ste-osis by visual inspection) and accessible coronary arteryor measurement of coronary blood flow velocity (CBFV)ith a Doppler guidewire (FloWire, Volcano Corpora-

ion, Rancho Cordova, California). Key exclusions werengestion of caffeine within 12 hours, active asthma,cute myocardial infarction within 30 days, and uncon-rolled or severe heart disease. All vessels except thoseubject to an intervention during the same catheterizationrocedure were allowed.

All usual catheterization procedural medications includ-ng intracoronary nitroglycerin, anxiolytics, analgesics, andeparin were allowed. Within 15 minutes before adminis-ration of binodenoson, 2 to 3 escalating intracoronary aden-sine doses were injected rapidly into the target coronaryrtery to define CBFV reserve. Patients were randomlyssigned to receive 1 of 5 intravenous binodenoson dosingegimens: 3-minute infusions of 0.3, 0.5, or 1.0 �g/kg/mintotal doses 0.9, 1.5, and 3 �g/kg) or bolus injections (over0 seconds) of 1.5 or 3 �g/kg.

CBFV was measured as continuous pulsatile velocity
centimeters per second); mean values were used in calcu-
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ations. Systolic and diastolic blood pressures were recordedrom the catheter tip, and heart rate was derived fromlectrocardiographic signal. Each patient’s maximal CBFVeserve was used as a benchmark against which CBFVesponses to binodenoson were compared. Rate-pressureroduct and coronary vascular resistance were derived atach time point.

Data were analyzed using an intent-to-treat populationi.e., all patients who received binodenoson). A paired t testssessed the significance of within-treatment differencespeak vs baseline), and repeated comparisons were cor-ected using the Bonferroni-Holm method. Differencescross treatment groups were assessed with analysis ofariance. Enrollment of 120 patients (24 patients per dose)rovided 90% power to conclude that the lower boundary ofhe 95% confidence interval on the population success rateas 65%. To allow for dropouts, enrollment of 138 patients

able 1aseline patient demographics

ariable Binodenoson Infusion (�g/kg

0.3(n � 26)

0.5(n � 28)

en 14 (54%) 13 (46%)omen 12 (46%) 15 (54%)hite 21 (81%) 25 (89%)

lack 2 (8%) 1 (4%)ther 3 (12%) 2 (7%)ge (yrs)Mean � SD 57 � 12 56 � 14Range 33–76 33–81eight (lb)

Mean � SD 189 � 29 187 � 45Range 129–242 106–272eight (inches)Mean � SD 68 � 4 66 � 4Range 58–73 60–73

able 2oronary blood flow velocity and coronary blood flow velocity reserve af

ariable B

(

aseline CBFV† (cm/s)Mean � SD 20Rangeeak CBFV‡ (cm/s)Mean � SDRangeBFV reserve§ to intracoronary adenosineMean � SD 3Range 1ose of intracoronary adenosine resulting in CBFV reserve (�g)Mean � SDRange

* p �0.05 for overall treatment effect for each outcome variable (ANO† Preintracoronary adenosine.‡ Postintracoronary adenosine; p �0.001 for each within-treatment diffe§ Peak CBFV after intracoronary adenosine/baseline CBFV.

as planned. n

esults

n all, 138 patients were enrolled and 133 received a singleose of binodenoson. Five randomized patients did noteceive binodenoson because of pretreatment adversevents, technical difficulties, or withdrawal of consent.BFV was measured from the left anterior descendingoronary artery (n � 77), left circumflex coronary arteryn � 42), or right coronary artery (n � 14). Demographicharacteristics (Table 1), baseline mean CBFV values, meandenosine CBFV reserve values (range 1.7 to 6.2), andean intracoronary adenosine doses administered (range 10

o 60 �g; Table 2) were similar across the 5 dose groups.denosine CBFV reserve was achieved with the highest

denosine dose in 43 patients, a lower dose in 42 patients,nd 49 patients received only 1 adenosine dose.

Baseline mean CBFV, heart rate, blood pressure, coro-

3 min) Binodenoson Bolus (�g/kg)

1(n � 26)

1.5(n � 28)

3(n � 25)

13 (50%) 16 (57%) 13 (52%)13 (50%) 12 (43%) 12 (48%)21 (81%) 19 (68%) 20 (80%)4 (15%) 5 (18%) 3 (12%)1 (4%) 4 (14%) 2 (8%)

55 � 13 55 � 12 54 � 1037–85 29–75 34–78

193 � 38 199 � 41 192 � 34115–270 99–264 135–249

67 � 4 68 � 4 67 � 461–77 60–78 60–74

acoronary adenosine*

oson Infusion (�g/kg/min � 3 min) Binodenoson Bolus (�g/kg)

)0.5

(n � 28)1

(n � 26)1.5

(n � 28)3

(n � 25)

3 16.8 � 6.3 17.3 � 7.2 20.5 � 10.6 16.7 � 4.37–30 4–31 6–53 10–29

51 � 20 501 � 18 56 � 19 52 � 1430–136 21–92 21–93 30–92

0 3.2 � 0.9 3.1 � 0.9 3.0 � 0.8 3.2 � 0.61.8–5.7 1.7–5.4 1.7–4.8 2.1–4.1

29 � 9 29 � 9 34 � 10 29 � 1010–48 15–48 18–60 12–48

etween peak and baseline (paired t test).

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1509Coronary Artery Disease/Coronary Circulation Responses to Binodenoson

efore binodenoson dosing were similar across treatmentroups (Tables 2 and 3). Coronary hyperemic responses toinodenoson were evident within seconds of drug adminis-ration (Figure 1). CBFV achieved nearly maximal levelsithin 3 minutes, and similar peak responses occurredithin the first 6 minutes in all treatment groups (p �0.001,aired t test, each group; p � 0.76, analysis of varianceANOVA]; Table 3 and Figure 2). Binodenoson decreasedoronary vascular resistance in all patients in all doseroups and by �50% in 114 of 129 patients (89%).aximal numerical decreases in coronary vascular resis-

ance were recorded 1 to 8 minutes after binodenosondministration in 92% of all patients (Table 3). The 1.5-

able 3ital signs and hemodynamic parameters after binodenoson dosing*

ariable Binodenoson Infusion (

0.3(n � 26)

0.5(n �

eart rate (beats/min)†

Baseline 75 � 18 70 �Maximum‡ 95 � 18 95 �ystolic BP (mm Hg)†

Baseline 135 � 26 133 �Minimum 109 � 25 108 �iastolic BP (mm Hg)†

Baseline 75 � 12 74 �Minimum 60 � 13 58 �oronary vascular resistance†�

Baseline 5.3 � 2.2 6.2 �Minimum 1.7 � 0.6 1.9 �ate–pressure product†#

Baseline 9,913 � 3,051 9,096 �Maximum 12,035 � 2,686 11,995 �

* Data are presented as mean � SD. Maximum/minimum values reflebservation period. For each variable, the p value was �0.001 for each w

† p �0.05; ‡ p � 0.003; § p � 0.010 for overall treatment effect (ANO� Coronary vascular resistance (centimeters times millimeters of merc# Rate-pressure product (beats times millimeters of mercury per minuteBP � blood pressure.

igure 1. Doppler signal showing determination of CBFV reserve (peak Cnd CBFV response to 1.5-�g/kg bolus dose of binodenoson.

nd 3-�g/kg doses, whether infused over 3 minutes or p

njected as boluses, produced coronary hyperemia equiv-lent to adenosine, and the hyperemic response to the.3-�g/kg/min 3-minute infusion was only slightly lessffective (Table 4 and Figure 2). Frequencies of patientsn all dose groups who achieved peak hyperemia at eachinute 1 to 8 minutes after starting binodenoson were

.5%, 14.3%, 22.2%, 11.9%, 17.5%, 5.6%, 6.4%, and

.8%. Duration of mean maximal hyperemia (CBFV time85% of CBFV reserve) was dose related (p � 0.006,NOVA; Table 4). It was not possible to determine

ccurately when CBFV and coronary vascular resistanceeturned fully to baseline because catheters were re-oved from most patients �15 minutes after dosing. All

min � 3 min) Binodenoson Bolus (�g/kg)

1(n � 26)

1.5(n � 28)

3(n � 25)

72 � 12 75 � 14 75 � 15103 � 17 97 � 15 108 � 11

128 � 24 133 � 23 126 � 21105 � 24 103 � 20 103 � 17

72 � 11 72 � 8 74 � 1156 � 11 55 � 10 59 � 10

5.8 � 2.7 5.1 � 2.6 5.2 � 1.21.7 � 0.6 1.7 � 0.8 1.6 � 0.4

9,111 � 1,859 9,975 � 2,784 9,344 � 2,00912,839 � 3,355 12,101 � 2,974 13,152 � 2,573

bles at their greatest change from baseline during the in-catheterizationeatment difference between maximum and baseline (paired t test).

r second) � ([systolic BP � diastolic BP]/3 � diastolic BP)/CBFV.tolic BP � heart rate.

ter intracoronary adenosine/baseline CBFV) with intracoronary adenosine

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ng CBFV responses suggests CBFV would return fullyo baseline within 30 minutes (Figure 3).

Coronary hyperemic responses were accompanied byose-related increases in heart rate (p � 0.003, ANOVA)nd rate-pressure product (p � 0.010, ANOVA; Table 3).aximal decreases in blood pressure were similar

cross doses (Table 3). Binodenoson-induced changes inlood pressure and heart rate returned to nearly baselineevels within �15 minutes (Figure 3). No patient whoeceived binodenoson in this study (n � 133) and inreviously reported trials (n � 24 and 240)5,6 developedecond- or third-degree atrioventricular block, thus con-rming the weak affinity of binodenoson at the adenosine1 receptor.

iscussion

he magnitude of the coronary hyperemic responses tontracoronary adenosine and intravenous binodenosonere heterogenous in this population. Variability in the

denosine coronary flow reserve determined by bolusntracoronary adenosine injections confirms previous re-orts, and similar variability in individual patient re-ponses to intravenous adenosine and dipyridamole haseen reported previously.7–11

Onset of binodenoson-induced hyperemia is immediate.aximal coronary vasodilatory responses tended to be dose

elated, although only the 0.9-�g/kg infusion dose producedess than maximal hyperemia. Because doubling the dose ofnfusions and bolus injections from 1.5 to 3 �g/kg did notroduce significantly greater maximal coronary hyperemia,he 1.5-�g/kg intravenous bolus dose appears to representhe upper asymptote of the hyperemic dose-effect curve.

aximal hyperemia persisted longer after the 3-�g/kg bolus12.3 � 9.59 minutes) than after the 1.5-�g/kg dose (7.4 �.86 minutes) but at the expense of higher heart rate andate-pressure product and more subjective adverse events.inodenoson-induced changes in vital signs were consistentith those reported for binodenoson and adenosine in unse-ated patients undergoing single-photon emission computedomographic (SPECT) procedures.6 In many patients, heartate increased sooner and remained higher longer than did

igure 2. Time course of mean CBFV responses, expressed as percentdenosine CBFV reserve (peak CBFV after intracoronary adenosine/aseline CBFV), of 5 binodenoson doses.

ecreases in blood pressure, suggesting that increases in i

eart rate are not simply reflexive. A study in rats suggestedhat adenosine A2A agonists may increase heart rate byromoting catecholamine release from preganglionic sym-athetic nerve terminals,12 but this has not been confirmedn humans. It is likely that increased oxygen consumptionecondary to increased rate-pressure product contributeso the direct coronary vasodilatory responses to binode-oson, but the relative contribution of direct and indirectffects on CBFV could not be determined in these pa-ients.

Similar hyperemic and hemodynamic responses wereroduced by bolus injections and by 3-minute infusionsf the same binodenoson doses, indicating that total doses more important than dosing regimen and confirminghe appropriateness of weight-based dosing to achieveaximal coronary hyperemia while producing the fewest

nd least severe adverse events.5 In contrast, use of aingle fixed dose would be expected to produce submaxi-al hyperemia in larger patients and more frequent andore intense adverse events in smaller patients.Diagnostic and prognostic utilities of adenosine were

stablished with continuous 6-minute infusions, but adeno-ine is currently commonly infused for 3 to 4 minutes, withnd without concomitant exercise. Magnitudes and dura-ions of coronary hyperemic responses to the approved-minute infusion or to 3- to 4-minute infusions of adeno-ine have not been reported. Only 1 study in 9 patientsocumented the time course (over 11 minutes) of hyperemicesponses to dipyridamole.8 It is presumed optimal to in-ect radiopharmaceuticals during peak coronary hyper-mia, but there are no data supporting the magnitude oruration of hyperemia required for extraction of radio-racers needed to detect myocardial perfusion mis-atches during noninvasive imaging. Occurrence or per-

istence of subjective side effects (e.g., dyspnea, chestain, nausea) and not myocardial ischemia is nearly al-ays the reason for terminating an adenosine infusion or

eversing responses to dipyridamole. Because vasodilatortressors very rarely induce ischemia even at peak re-ponse, it is likely that a gradual return of CBFV afterinodenoson administration (as is assumed to occur withipyridamole) will be tolerated well by patients. Thus, its unlikely that reversal of a binodenoson effect withminophylline will be necessary.

Three factors contributed to a decision to inject radio-harmaceutical 3 minutes after binodenoson: the highestrequency of patients achieved maximal coronary hyper-mia at �3 minutes (22%), the mean duration of thiseak hyperemic response included times to peak re-ponses of the highest proportions of patients, and thegreement of these objective results with the subjectiveudgments of 5 experienced nuclear cardiologists whondicated optimal injection times on blinded tracingsrom every study patient (presented as in Figure 3).uitability of this dose and time of radiopharmaceutical

njection were confirmed in a study of 240 patients whoompleted 2 SPECT studies at rest and during stress, 1ith adenosine and the other with 1 of 4 doses of bino-enoson (0.5-, 1-, or 1.5-�g/kg bolus or a 3-minute
nfusion of 1.5 �g/kg). SPECT images acquired with the

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1511Coronary Artery Disease/Coronary Circulation Responses to Binodenoson

.5-�g/kg bolus binodenoson dose were most concordantith the adenosine images in the same patients.6Intracoronary doses of adenosine are consistent with

hose known to define coronary flow reserve,7–11 butany patients did not receive 3 increasing intracoronary

njections of adenosine, so true maximal CBFV reserveay not have been defined. In such cases, calculation of

esponses to binodenoson as percent CBFV reserveould overestimate the vasodilatory potency of the ago-ist. Doppler wires were removed in most patients beforeBFV returned to within 25% of baseline, thus prevent-

ng observation of time for CBFV to return fully toaseline.

Conclusions: The 1.5-�g/kg intravenous bolus dose of

igure 3. Effect over time of binodenoson 1.5-�g/kg bolus on CBFVcentimeters per second), systolic blood pressure (BP; millimeters of mer-ury), diastolic BP (millimeters of mercury), heart rate (beats per minute),nd coronary vascular resistance.

able 4oronary blood flow velocity and percent coronary blood flow velocity re

ariable Binode

0.3(n � 26)

aseline CBFV* (cm/s)Mean � SD 21.3 � 8.4Range 8–38eak CBFV*† (cm/s)Mean � SD 55.2 � 21.Range 17–122ime of peak* CBFV (min)Mean � SD 4.3 � 2.8Range 1–12ercent CBFV reserve at peak*Mean � SD 83.5 � 19.Range 40.0–124.5uration (min) of hyperemia �85% of CBFV reserve‡

Mean � SD 3.1 � 2.0Range 1–8

* p �0.05 for overall treatment effect for each outcome variable (ANO† After binodenoson. Highest CBFV after binodenoson during the in-ca

etween peak and baseline (paired t test).‡ p � 0.006 treatment effect (ANOVA).

inodenoson produced nearly maximal coronary hyper-

mia that was sustained for 7 minutes, was accompaniedy modest changes in blood pressure, heart rate, andate-pressure product, and produced no adverse changesn electrocardiogram, including no second- or third-de-ree atrioventricular block. This dose was selected fordditional testing to determine its safety and efficacy as aharmacologic stress agent for use with myocardial per-usion imaging.

ppendix

articipating investigators: P. Alagona, Tampa, Florida;. Bailey, San Antonio, Texas; D.L. Brown, Bronx, Nework; L. Christie, Portland, Oregon; T. Fischell, Kalama-

oo, Michigan; L.I. Heller, Atlanta, Georgia; S. Kazziha,t. Clemens, Michigan; N. Kleiman, Houston, Texas; B.lugherz, Philadelphia, Pennsylvania; M. Leesar, Louis-ille, Kentucky; A.O. Mehra, Los Angeles, California; A.ichaels, San Francisco, California; J.D. Rossen, Iowaity, Iowa; and R.F. Wilson, Minneapolis, Minnesota.

1. Johnston DL, Daley JR, Hodge DO, Hopfenspirger MR, Gibbons RJ.Hemodynamic responses and adverse effects associated with adeno-sine and dipyridamole pharmacologic stress testing: a comparison in2,000 patients. Mayo Clin Proc 1995;70:331–336.

2. Cerqueira MD, Verani MS, Schwaiger M, Heo J, Iskandrian AS.Safety profile of adenosine stress perfusion imaging: results from theAdenoscan Multicenter Trial Registry. J Am Coll Cardiol 1994;23:384–389.

3. Ranhosky A, Kempthorne-Rawson J. The safety of intravenous dipyrid-amole thallium myocardial perfusion imaging. Intravenous DipyridamoleThallium Imaging Study Group. Circulation 1990;81:1205–1209.

4. Martin PL, Barrett RJ, Sykes A, Droppleman DA, Wright KF, MossemD. Pharmacology and toxicology of the A2A adenosine receptor ago-nist 2-[(cyclohexylmethylene)hydrazine]adenosine (MRE0470) in therat. Drug Dev Res 1997;42:76–85.

5. Barrett RJ, Lamson MJ, Johnson J, Smith WB. Pharmacokinetics and

chieved after binodenoson dosing

nfusion (�g/kg/min � 3 min) Binodenoson Bolus (�g/kg)

0.5(n � 28)

1(n � 26)

1.5(n � 28)

3(n � 25)

18.9 � 11.0 18.5 � 7.5 22.2 � 10.8 18.3 � 4.47–57 8–35 6–55 13–31

49.6 � 20.4 53.1 � 14.8 54.0 � 19.9 55.8 � 14.626–135 29–81 21–96 35–94

5.4 � 5.9 5.8 � 3.8 4.5 � 3.7 6.0 � 3.81–30 1–13 1–15 1–14

95.0 � 40.4 100.9 � 22.1 90.6 � 23.7 99.9 � 22.152.2–288.1 66.5–144.5 45.8–156.6 44.4–130.5

5.3 � 4.5 10.9 � 8.5 7.4 � 6.9 12.3 � 9.61–14 1–24 1–21 2–39

ation observation period; p �0.001 for each within-treatment difference

serve a

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0

4

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safety of binodenoson after intravenous dose escalation in healthyvolunteers. J Nucl Cardiol 2005;12:166–171.

1

1

1


6. Udelson JE, Heller GV, Wackers FJ, Chai A, Hinchman D, ColemanPS, Dilsizian V, DiCarli M, Hachamovitch R, Johnson JR, Barrett RJ,Gibbons RJ. Randomized, controlled dose-ranging study of the selec-tive adenosine A2A receptor agonist binodenoson for pharmacologicalstress as an adjunct to myocardial perfusion imaging. Circulation2004;19:457–464.

7. DiSegni E, Higano ST, Rihal C, Holmes DR, Lennon R, Lerman A.Incremental doses of intracoronary adenosine for the assessment ofcoronary velocity reserve for clinical decision making. Catheter Car-diovasc Intervent 2001;54:34–40.

8. Wilson RF, Laughlin DE, Ackell PH, Chilian WM, Holida MD,Hartley CJ, Armstrong ML, Marcus ML, White CW. Transluminal,subselective measurement of coronary artery blood flow velocity and
vasodilator reserve in man. Circulation 1985;72:82–92.
9. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effectsof adenosine on human coronary arterial circulation. Circulation 1990;82:1595–1606.

0. Rossen JD, Quillen JE, Lopez AG, Stenberg RG, Talman CL,Winniford MD. Comparison of coronary vasodilation with intrave-nous dipyridamole and adenosine. J Am Coll Cardiol 1991;18:485– 491.

1. Rossen JD, Simonetti I, Marcus ML, Winniford MD. Coronary dila-tion with standard dose dipyridamole and dipyridamole combined withhandgrip. Circulation 1989;79:566–572.

2. Dhalla AK, Wong MY, Wang WQ, Biaggioni, I, Belardinelli L.Tachycardia caused by adenosine A2A receptor agonists is mediated bydirect sympathoexcitation in awake rats. J Pharmacol Exp Ther 2006;
316:695–7002.

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Effect of Anemia on Hemorrhagic Complications and MortalityFollowing Percutaneous Coronary Intervention

Michele D. Voeltz, MDa, Amar D. Patel, MDa, Frederick Feit, MDb, Reza Fazel, MDa,A. Michael Lincoff, MDc, and Steven V. Manoukian, MDa,*

The relation across anemia, hemorrhagic complications, and mortality associated withpercutaneous coronary intervention (PCI) is unclear. We reviewed the Randomized Eval-uation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 Trial, whichcompared bivalirudin plus provisional glycoprotein IIb/IIIa blockade with heparin plusplanned glycoprotein IIb/IIIa blockade in patients undergoing urgent or elective PCI. Ofthe 6,010 patients randomized in REPLACE-2, 1,371 (23%) were anemic. Major bleedingwas more common in anemic than in nonanemic patients (4.9% vs 2.8%, p � 0.0001). Inanemic patients, treatment with bivalirudin (n � 678) resulted in a lower risk of majorbleeding versus heparin plus glycoprotein IIb/IIIa blockade (n � 693, 3.5% vs 6.2%, p �0.0221). Mortality was higher in anemic patients than in nonanemic patients at 30 days(0.9% vs 0.2%, p <0.0001), 6 months (2.6% vs 0.7%, p <0.0001), and 1 year (4.3% vs 1.5%,p <0.0001). There were no differences between anemic and nonanemic patients with regardto ischemic complications at 30 days. Although anemic patients had higher mortality rates,proportions of cardiovascular and noncardiovascular mortalities were equal in anemic andnonanemic patients. In conclusion, anemic patients undergoing PCI have an increased riskof mortality and major bleeding, but not of ischemic events, and the use of bivalirudin withprovisional glycoprotein IIb/IIIa blockade decreases the risk of hemorrhagic complicationscompared with heparin plus planned glycoprotein IIb/IIIa blockade. © 2007 Elsevier Inc.
All rights reserved. (Am J Cardiol 2007;99:1513–1517)
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nemia may increase the risk of major hemorrhagic com-lications during percutaneous coronary intervention (PCI),nd the link between bleeding and mortality is becomingncreasingly recognized.1–3 In aggregate, current data ap-ear to define anemia as a high-risk marker for mortalitynd hemorrhagic complications in patients undergoingCI.4–7 However, it remains unclear whether the higherortality in anemic patients is driven by an increase in the

umber of ischemic events, hemorrhagic complications, orther causes. In addition, the effect of newer and potentiallyafer antithrombotic agents, such as bivalirudin, on hemor-hagic and myocardial ischemic complications in anemicatients has not been evaluated. The Randomized Evaluationn PCI Linking Angiomax to Reduced Clinical EventsREPLACE)-2 Trial demonstrated that treatment with bivaliru-in with provisional glycoprotein IIb/IIIa blockade resulted inimilar ischemic event rates and fewer hemorrhagic complica-ions compared with heparin with planned glycoprotein IIb/IIIalockade during urgent or elective PCI.8,9 The present analysisought to further define the relation between anemia and risk of

aDepartment of Medicine, Division of Cardiology, Emory Universitychool of Medicine, Atlanta, Georgia; bDepartment of Medicine, Divisionf Cardiology, New York University School of Medicine, New York, Nework; and cDepartment of Cardiovascular Medicine, The Cleveland Clinicoundation, Cleveland, Ohio. Manuscript received October 4, 2006; re-ised manuscript received and accepted January 10, 2007.

This study was funded by a research grant from The Medicines Com-any, Parsippany, New Jersey.

wE-mail address: [email protected] (S.V. Manoukian).

ortality, ischemic events, and hemorrhagic complications. Inddition, we evaluated the influence of antithrombotic therapyn the magnitude of these risks in anemic patients undergoingCI in REPLACE-2.

ethodsStudy population: The methods and results of

EPLACE-2 have been previously published.8,9 Briefly,EPLACE-2 randomized 6,010 patients in a multicenter,ouble-blind comparison of bivalirudin with provisionallycoprotein IIb/IIIa blockers (bivalirudin group) with hep-rin plus planned glycoprotein IIb/IIIa blockers (heparinlus glycoprotein IIb/IIIa blockade group) in patients un-ergoing urgent or elective PCI. Patients with primary PCIor acute ST-elevation myocardial infarction (MI), poorlyontrolled hypertension, significant unprotected left maintenosis, pregnancy, PCI within the previous 30 days orlanned staged PCI within the following month, activenternal bleeding, surgery, trauma, or gastrointestinal orenitourinary bleeding within the preceding 6 weeks, his-ory of intracranial bleeding or structural abnormality,hrombocytopenia (platelets �100,000), chronic kidney dis-ase (serum creatinine level �4.0 mg/dl), and using hemo-ialysis were excluded. Only patients for whom completeata existed were included in the analysis.

Study protocol: All patients received aspirin. Pretreat-ent with clopidogrel 300 mg was at the discretion of the

reating physician, followed by daily dosing of 75 mg for30 days. Before randomization, physicians specified
hether abciximab (0.25-mg/kg bolus and then 0.125 �g/
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g/min [maximum 10 �g/min] infusion for 12 hours) orptifibatide (2 180-�g/kg boluses 10 minutes apart and then-�g/kg/min infusion for 18 hours) would be used as thelanned glycoprotein IIb/IIIa blockade in the heparin pluslycoprotein IIb/IIIa blockade group or as the provisionallycoprotein IIb/IIIa blockade in the bivalirudin group. Pa-ients were then randomized in a 1:1 double-blind manner toeceive bivalirudin (0.75-mg/kg bolus and then 1.75 mg/kg/our for the duration of the procedure) or heparin (65 U/kgmaximum 7,000 U] before PCI) with planned glycoproteinIb/IIIa blockade according to the aforementioned dosingegimens. Provisional glycoprotein IIb/IIIa blockade wasuggested for those in the bivalirudin group in the event ofbrupt or side branch closure, new or suspected thrombus,bstructive dissection, impaired or slow flow, distal embo-ization, persistent residual stenosis, unplanned stent place-ent, prolonged ischemia, or other clinical instability andas used in 7.2% of patients.

Study end points: The REPLACE-2 primary end pointas a quadruple composite of death, MI, urgent surgical orercutaneous revascularization, or in-hospital major bleed-ng at 30 days. A secondary triple composite end point ofeath, MI, and urgent revascularization at 30 days was alsoefined. MI was defined as new significant Q waves in �2ontiguous electrocardiographic leads or increased creati-ine kinase (CK) levels or CK-MB levels to �3 times thepper limit of normal within 2 days of revascularization or2 times the upper limit of normal outside the setting of

ecent revascularization. Major bleeding was defined as in-racranial, intraocular, or retroperitoneal bleeding, clinicallyvert blood loss with a decrease �3 g/dl in hemoglobin, anyecrease �4 g/dl in hemoglobin, or transfusion of �2 U ofacked red blood cells or whole blood. Minor bleeding wasefined as clinically overt blood loss that did not meet majorleeding criteria. Thrombolysis In Myocardial InfarctionTIMI)–defined major bleeding has been previously defined asntracranial hemorrhage or bleeding with a hemoglobin de-rease �5 g/dl or hematocrit decrease �15%.10 TIMI minorleeding has been defined as a hemoglobin decrease �3 g/dl orhematocrit decrease �10% with a source or a hemoglobin

ecrease �4 g/dl or a hematocrit decrease �12% without aource.10 End-point classifications were made by a blindedlinical events committee.

Anemia: Anemia was defined for the purpose of thistudy according to the World Health Organization (hemo-lobin levels �12.0 g/dl in women and �13.0 g/dl in men)nd baseline hemoglobin values.11

Causes of mortality: Three of the present authorsblinded to treatment allocation) adjudicated mortality intoardiovascular and noncardiovascular causes. Cardiovascu-ar causes were categorized as those directly related to theeart and aorta. Unknown causes of death were classified asoncardiovascular.

Acute coronary syndrome: Acute coronary syndromeas defined as a procedural indication of unstable angina

including new onset angina, accelerating angina, and an-ina at rest) and non–ST-elevation MI or ST-elevation MI
ithin 7 days before enrollment. s
Statistical analysis: Baseline and procedural character-stics and unadjusted rates of the primary and secondary endoints were compared between anemic and nonanemic pa-ients using the chi-square test for categorical variables andtest for continuous variables. Categorical variables are

xpressed as frequencies and percentages, and continuousariables are expressed as medians and means. Predictors of-year mortality were identified using a multiple logisticegression analysis that was based on stepwise model se-ection technique, where factors were entered in the modelith a p value �0.20 and retained with a p value �0.05.ariables are expressed as odds ratios (ORs) with corre-

ponding 2-sided 95% confidence intervals (CIs). In addi-ion, Cox analysis was performed to identify independentredictors of mortality. Kaplan-Meier curve was used tollustrate the cumulative percentage of events for anemicersus nonanemic patients. Additional curves were plottedo compare outcomes of anemic and nonanemic patients

able 1aseline patient and procedural characteristics

ariable Anemic(n � 1,371)

Nonanemic(n � 4,499)

p Value

aseline patient characteristicsMedian age (yrs) 67 61 �0.0001Age �75 yrs 330 (24.1%) 461 (10.2%) �0.0001Mean hemoglobin (g/dl) 11.7 14.3 �0.0001Women 444 (32.4%) 1,062 (23.6%) �0.0001Men 927 (67.6%) 3,437 (76.4%) �0.0001Caucasian 1231 (89.8%) 4,206 (93.5%) �0.0001Median weight (kg) 83 86 �0.0001Median body mass index

(kg/m2)28.4 28.85 0.0001

Creatinine clearance (ml/min)

83.5 97.9 �0.0001

Previous MI 563 (42.0%) 1,587 (35.9%) �0.0001Previous PCI 508 (37.2%) 1,528 (34.1%) 0.0373Previous Coronary artery

bypass grafting295 (21.5%) 782 (17.4%) 0.0006

Angina pectoris 1,018 (75.5%) 3,426 (76.9%) NSCerebrovascular accident 42 (3.1%) 97 (2.2%) NSHypertension 978 (71.6%) 2,937 (65.5%) �0.0001Heart failure 152 (11.2%) 257 (5.7%) �0.0001Tobacco use (previous

1 yr)293 (21.9%) 28.1 (28.1%) �0.0001

Diabetes mellitus 491 (35.9%) 1,098 (24.4%) �0.0001rocedural characteristicsProcedure indication

Acute coronarysyndrome

644 (47.6%) 1,881 (42.4%) 0.0007

Stable angina pectoris 299 (22.1%) 1,164 (26.3%) 0.0022Positive stress test

result309 (22.6%) 1,114 (25.1%) NS

Target coronary arteryintervention

Left anteriordescending

590 (43.0%) 2,008 (44.7%) NS

Left circumflex 420 (30.6%) 1,406 (31.3%) NSLeft main 19 (1.4%) 56 (1.2%) NSRight 542 (39.5%) 1,707 (38.0%) NSBalloon only 130 (9.6%) 333 (7.5%) 0.012

tratified by treatment regimen.

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1515Coronary Artery Disease/Effect of Anemia on Bleeding and Mortality in PCI

esults

f the 6,010 patients randomized in REPLACE-2, 1,37123%) were anemic based on baseline hemoglobin values.aseline patient and procedural characteristics are listed inable 1. Anemic patients were older, more likely to be women,nd more likely to be non-Caucasian (p �0.0001 for all). Theyad lower body weight and lower creatinine clearance levelsompared with nonanemic patients (p �0.0001 for 2 compar-sons). Further, anemic patients were more likely to have co-orbid conditions such as previous MI, PCI (p � 0.04),

oronary artery bypass grafting (p � 0.0006), hypertension,ongestive heart failure, and diabetes mellitus and were lessikely to have used tobacco within the previous yearp �0.0001 for all unless specified). Mean baseline hemo-lobin values in anemic and nonanemic patients were 11.7nd 14.3 g/dl, respectively (p �0.0001). Anemic patientsere more likely to present with acute coronary syndrome

p � 0.0007). With regard to procedural characteristics,nemic patients were more likely to have balloon angio-lasty only (p � 0.01). There were no differences in targetessel or need for urgent coronary artery bypass grafting.

Bleeding outcomes: Protocol-defined major bleedingas more common in anemic than in nonanemic patients

4.9% vs 2.8%, p � 0.0001; Table 2), whereas minor bleed-ng rates were similar (20.9% vs 19.2%, p � NS). Whenndividual components of bleeding were evaluated, anemicatients had a higher incidence of gastrointestinal bleeding1.1% vs 0.2%, p �0.0001) and transfusion of �2 U ofhole blood or packed red blood cells (3.6% vs 0.7%,�0.0001; Table 3). There was no difference in TIMI-

able 2rotocol-defined and TIMI bleeding in anemic patients



pValue

ajor bleeding (protocol defined) 67 (4.9%) 126 (2.8%) 0.0001ajor bleeding (TIMI defined) 15 (1.1%) 30 (0.7%) NSinor bleeding (protocol defined) 286 (20.9%) 865 (19.2%) NSinor bleeding (TIMI defined) 31 (2.3%) 98 (2.2%) NS

TIMI � Thrombolysis In Myocardial Infarction.

able 3emorrhagic complications in anemic patients



p Value

ntracranial bleed 1 (0.1%) 2 (0.04%) NSetroperitoneal bleed 6 (0.4%) 17 (0.4%) NSheath puncture site bleed 30 (2.2%) 69 (1.5%) NSastrointestinal bleed 15 (1.1%) 7 (0.2%) �0.0001enitourinary bleed 0 (0%) 7 (0.2%) NSurgical bleed 1 (0.1%) 3 (0.1%) NSny transfusion 73 (5.3%) 52 (1.2%) �0.0001ransfusion �2 U 49 (3.6%) 31 (0.7%) �0.0001latelet transfusion 9 (0.7%) 19 (0.4%) NSadir platelets �100,000 22 (1.6%) 69 (1.6%) NSadir platelets �50,000 6 (0.4%) 20 (0.5%) NS

efined major or minor bleeding in anemic versus nonane- r

ic patients (1.1% vs 0.7%, p � NS, and 2.3% vs 2.2%,� NS, respectively).When anemic patients were evaluated by treatment group,

ajor bleeding was less frequent in the bivalirudin group thann the heparin plus glycoprotein IIb/IIIa blockade group (3.5%s 6.2%, p � 0.0221; Figure 1). Minor bleeding was lessrequent in anemic patients in the bivalirudin group than inhose in the heparin plus glycoprotein IIb/IIIa blockade group13.4% vs 25.1%, p �0.0001; Figure 2). Anemic patients inhe bivalirudin group had a similar risk of major bleeding asonanemic patients in the heparin plus glycoprotein IIb/IIIalockade group (3.5% vs 3.6%, p � NS).

Ischemic events: The incidence of the triple ischemicvent composite, including death, MI, and urgent revascu-arization at 30 days, did not differ between anemic andonanemic patients (7.6% vs 7.3%, p � NS). Similarly, noignificant differences were observed in individual ischemicomponents of MI (6.9% vs 6.5%, p � NS) and urgent

Figure 1. Protocol-defined major bleeding by treatment strategy.

Figure 2. Protocol-defined minor bleeding by treatment strategy.

Figure 3. Ischemic events for anemic versus nonanemic patients.

evascularization (1.2% vs 1.3%, p � NS; Figure 3).

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When anemic patients in the bivalirudin group were com-ared with those in the heparin plus glycoprotein IIb/IIIalockade group, there were no significant differences in theriple ischemic event composite at 30 days (7.6% vs 7.6%, p �S) or individual components of MI (6.7% vs 7.1%, p � NS)

nd urgent revascularization (1.2% vs 1.3%, p � NS).

Mortality: Unadjusted mortality was significantlyigher in anemic than in nonanemic patients at 30 days0.9% vs 0.2%, p �0.0001), 6 months (2.6% vs 0.7%,�0.0001), and 1 year (4.3% vs 1.5%, p �0.0001). Mor-

ality is illustrated using Kaplan-Meier curves for all anemicersus nonanemic patients (Figure 4) and anemic versusonanemic patients by treatment strategy (Figure 5).

Multivariate analysis: After adjustment for differencesn baseline characteristics, risk of protocol-defined majorleeding was significantly higher in anemic patients than inheir nonanemic counterparts (OR 1.44, 95% CI 1.01 to

igure 4. Kaplan-Meier curve of mortality for anemic versus nonanemicatients.

igure 5. Kaplan-Meier curve of mortality for anemic versus nonanemicatients by treatment strategy.

.04, p � 0.0443). However, anemia did not independently 4

redict TIMI-defined major plus minor bleeding (OR 0.918,5% CI 0.594 to 1.419, p � NS).

Anemia was a significant predictor of mortality at 1 yearhazard ratio 1.97, 95% CI 1.32 to 2.95, p � 0.0009) by Coxnalysis. Inclusion of the anemic interaction term in the modelp � 0.0003) further illustrated the significant relation betweennemia and mortality. After adjusting for transfusion, anemiaemained an independent predictor of mortality (hazard ratio.84, 95% CI 1.22 to 2.78, p � 0.0035; Table 4).

Causes of mortality in anemic patients: When causesf death were examined in anemic and nonanemic patients,nemic patients had a higher rate of cardiovascular andoncardiovascular mortalities at all time points including 30ays (OR 5.99, 95% CI 1.75 to 20.52, p �0.0001), 6 monthsOR 3.64, 95% CI 1.9 to 6.95, p �0.0001), and 1 year (OR.18, 95% CI 1.97 to 5.12, p �0.0001). Interestingly,reslow-Day testing showed a proportionate increase inardiovascular and noncardiovascular mortalities in anemicnd nonanemic patients.

iscussion

he present analysis of �6,000 patients from a single,ontemporary, prospective, randomized study populationemonstrates the following major findings in anemic pa-ients undergoing urgent or elective PCI: (1) short- andong-term mortalities are higher despite the lack of an in-rease in ischemic events such as MI or urgent revascular-zation; (2) major hemorrhagic complications are signifi-antly more frequent; (3) bivalirudin significantly decreasesemorrhagic complications and maintains efficacy with re-ard to ischemic outcomes; and (4) proportions of cardio-ascular and noncardiovascular deaths in anemic and non-nemic patients are similar.

Several recent studies have defined anemia as a commonigh-risk clinical finding and discussed its effect on mortal-ty and hemorrhagic complications in patients undergoingCI, although no single-study population treated with aontrolled antithrombotic regimen, such as that in RE-LACE-2, has been previously analyzed.1,4–7 A databasenalysis of 6,929 patients after PCI by Nikolsky et al7 demon-trated a prevalence of 24.6% for anemia.7 Similarly,

cKechnie et al6 reported, in a large, multicenter database of

able 4ultivariate predictors of one-year mortality by Cox analysis after

djusting for transfusion

ariable Hazard Ratio (95% CI) p Value

0-Day MI 2.36 (1.37–4.07) 0.00210-Day revascularization 4.88 (1.98–12.0) 0.0006ge �75 yrs 1.69 (1.02–2.80) 0.0427ransfusion 2.81 (1.45–5.43) 0.0022aseline anemia 1.84 (1.22–2.78) 0.0035eart failure 2.92 (1.83–4.64) �0.0001eparin or low-molecular weightheparin within 48 h

1.58 (1.01–2.48) 0.0452

reprocedure left ventricularejection fraction �50%

2.12 (1.39–3.23) 0.0004

revious angina 1.92 (1.08–3.42) 0.0273

8,851 patients undergoing PCI, prevalences of anemia of

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1517Coronary Artery Disease/Effect of Anemia on Bleeding and Mortality in PCI

1.7% in men and 30.4% in women and a mean hemoglobinalue of 11.3 g/dl. These findings are corroborated by theresent analysis, which showed a prevalence approaching 25%nd a mean hemoglobin value of 11.7 g/dl in anemic patients.

With regard to ischemic outcomes and mortality,cKechnie et al6 found that anemic patients had a greater

ikelihood of in-hospital death (OR 2.29, p �0.0001) andomposite major adverse cardiac events (OR 1.2, p �0.01),hich included death, MI, and cerebrovascular events, as-

ociated with PCI. Similarly, in a database of �6,000 pa-ients undergoing PCI, Lee et al5 described higher postpro-edure levels of CK-MB (p � 0.04) and troponin I (p �.0003) and 30-day composite major adverse cardiac eventsdeath, MI, urgent revascularization) in anemic patients.5 Inontrast, the present study demonstrates significantly in-reased mortality rates in anemic patients, despite the lackf an increase in ischemic events, including MI and urgentevascularization. Demonstration of similar ischemic eventates in anemic and nonanemic patients in this analysis maye due to standardization of the antithrombotic regimensed. It is possible that anemic patients are frequently in-ppropriately dosed with intraprocedural antithromboticherapy because of the increased frequency of coexistentenal disease or concern for bleeding complications. Theresent trial indicates that, with a standardized approach tonticoagulation, ischemic complications can be minimizedn the anemic population.

The mechanism for the dramatic increase in risk ofortality in anemic patients is likely multifactorial and, we

ypothesize, mediated by the interaction across hemody-amics, inflammation, and overall health. The normal he-odynamic response to anemia involves increasing heart

ate and cardiac output to maintain tissue oxygen delivery,esulting in increased myocardial contractility.12 However,he ability to sufficiently increase cardiac output to maintaindequate oxygenation in a low hemoglobin state may belunted in patients with coronary atherosclerosis. Levy etl13 evaluated the role of normovolemic hemodilution in aog model of critical coronary stenosis and found thatignificant coronary atherosclerosis results in a blunted he-odynamic response to low hemoglobin with failure to

ncrease cardiac output and systemic oxygen delivery. Ex-rapolating these findings to anemic patients with coronaryrtery disease, in the face of fixed myocardial contractility,n increase in heart rate is required to improve systemicissue oxygenation. However, this response results in short-ning of diastole, potentially decreasing myocardial oxygenelivery. These hemodynamic changes, including tachycar-ia and failure to appropriately increase cardiac output, inombination with significant obstructive coronary disease,ay result in worsening myocardial ischemia, heart failure,

nd malignant arrhythmias in anemic patients. In addition, aong-term inflammatory state and high levels of inflamma-ory modulators and cytokines associated with many typesf anemia may contribute to the increased severity of car-iac disease and mortality rates in these patients.14 More-
ver, anemic patients may simply represent a sicker cohort
1

ith a larger number of co-morbidities for which multivar-ate analysis may not entirely account.

The present analysis is limited because it was not pre-pecified in the original study design. In addition, causes ofnemia were not identified in the study population, andreatment of anemia, such as transfusion and use of eryth-opoietic agents, was not specified by study protocol. Givenhe findings of the present analysis, we believe that baselinenemia in patients undergoing PCI represents a significantisk factor for hemorrhagic complications and mortality.

1. Nikolsky E, Aymong ED, Halkin A, Grines CL, Cox DA, Garcia E,Mehran R, Tcheng JE, Griffin JJ, Guagliumi G, et al. Impact of anemiain patients with acute myocardial infarction undergoing primary per-cutaneous coronary intervention: analysis from the Controlled Abcix-imab and Device Investigation to Lower Late Angioplasty Complica-tions (CADILLAC) Trial. J Am Coll Cardiol 2004;44:547–553.

2. Moscucci M, Fox KA, Cannon CP, Klein W, Lopez-Sendon J, Mon-talescot G, White K, Goldberg RJ. Predictors of major bleeding inacute coronary syndromes: the Global Registry of Acute CoronaryEvents (GRACE). Eur Heart J 2003;24:1815–1823.

3. Kinnaird TD, Stabile E, Mintz GS, Lee CW, Canos DA, Gevorkian N,Pinnow EE, Kent KM, Pichard AD, Satler LF, et al. Incidence, pre-dictors, and prognostic implications of bleeding and blood transfusionfollowing percutaneous coronary interventions. Am J Cardiol 2003;92:930–935.

4. Gurm HS, Lincoff AM, Kleiman NS, Kereiakes DJ, Tcheng JE,Aronow HD, Askari AT, Brennan DM, Topol EJ. Double jeopardy ofrenal insufficiency and anemia in patients undergoing percutaneouscoronary interventions. Am J Cardiol 2004;94:30–34.

5. Lee PC, Kini AS, Ahsan C, Fisher E, Sharma SK. Anemia is anindependent predictor of mortality after percutaneous coronary inter-vention. J Am Coll Cardiol 2004;44:541–546.

6. McKechnie RS, Smith D, Montoye C, Kline-Rogers E, O’Donnell MJ,DeFranco AC, Meengs WL, McNamara R, McGinnity JG, et al.Prognostic implication of anemia on in-hospital outcomes after per-cutaneous coronary intervention. Circulation 2004;110:271–277.

7. Nikolsky E, Mehran R, Aymong ED, Mintz GS, Lansky AJ, Lasic Z,Negoita M, Fahy M, Pocock SJ, Na Y, et al. Impact of anemia onoutcomes of patients undergoing percutaneous coronary interventions.Am J Cardiol 2004;94:1023–1027.

8. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD,Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, et al. Bivalirudin andprovisional glycoprotein IIb/IIIa blockade compared with heparin andplanned glycoprotein IIb/IIIa blockade during percutaneous coronary in-tervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863.

9. Lincoff AM, Kleiman NS, Kereiakes DJ, Feit F, Bittl JA, Jackman JD,Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, et al. Long-termefficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockadevs heparin and planned glycoprotein IIb/IIIa blockade during percuta-neous coronary revascularization: REPLACE-2 randomized trial.JAMA 2004;292:696–703.

0. Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, Bell WR,Knatterud G, Robertson TL, Terrin ML. Thrombolysis In MyocardialInfarction (TIMI) Trial—phase I: hemorrhagic manifestations andchanges in plasma fibrinogen and the fibrinolytic system in patientstreated with recombinant tissue plasminogen activator and streptoki-nase. J Am Coll Cardiol 1988;11:1–11.

1. World Health Organization. Nutritional Anemias: Report of a WHOScientific Group. Geneva: World Health Organization, 1968.

2. Hebert PC, Van der Linden P, Biro G, Hu LQ. Physiologic aspects ofanemia. Crit Care Clin 2004;20:187–212.

3. Levy PS, Quigley RL, Gould SA. Acute dilutional anemia and criticalleft anterior descending coronary artery stenosis impairs end organoxygen delivery. J Trauma 1996;41:416–423.

4. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med2005;352:1011–1023.

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Measuring Aspirin Resistance, Clopidogrel Responsiveness, andPostprocedural Markers of Myonecrosis in Patients

Undergoing Percutaneous Coronary Intervention

Ashesh N. Buch, MBChB, Suman Singh, MBBS, MPH, Probal Roy, MBBS, Aamir Javaid, MBBS,Kimberly A. Smith, BS, Christopher E. George, BSc, Augusto D. Pichard, MD,

Lowell F. Satler, MD, Kenneth M. Kent, MD, PhD, William O. Suddath, MD, andRon Waksman, MD*

Aspirin and clopidogrel are proven to prevent thromboembolic events during percutaneouscoronary intervention (PCI). Enzyme release of creatine kinase-MB (CK-MB) enzymeduring PCI has been associated with an increased risk of future adverse cardiac events.This study examined the correlation between measurements of aspirin resistance and thelevel of inhibition of the thienopyridine-specific P2Y12 platelet receptor and CK-MBrelease after PCI. We prospectively studied 330 patients with elective PCI treated withdrug-eluting stents. Patients were pretreated with aspirin and clopidogrel. Patients withpositive CK-MB or acute coronary syndrome and those on glycoprotein IIb/IIIa inhibitorswere excluded. Serum assays of aspirin resistance (Ultegra Rapid Platelet Function Assay-ASA, Accumetrics) and clopidogrel resistance (Rapid Platelet Function Assay P2Y12,Accumetrics) were performed before PCI. Serum troponinI and CK-MB levels were mea-sured at 8, 16, and 24 hours after PCI. Aspirin resistance unit (ARU) measurement >550was detected in 12 patients (3.7%). Mean platelet reactivity unit (PRU; measurement ofinhibition of P2Y12 activity) was 192.2 � 95.4 (lower PRU, more inhibition of P2Y12receptor). There was no correlation between level of ARU or PRU and troponin I orCK-MB release after PCI at any time point. Only multivessel coronary disease was foundto be a predictor of any increase in CK-MB in a multivariate analysis (odds ratio 2.2, 95%confidence interval 1.4 to 3.3, p � 0.0003). A positive correlation was found between levelsof ARU and PRU. Target vessel revascularization/major adverse cardiac event rate at 6months was 8.2% with no correlation between ARU or PRU and release of cardiac enzymesor occurrence of adverse cardiac events. In conclusion, this study does not support routinemeasurements of aspirin and clopidogrel resistance in stable patients undergoing
PCI. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1518–1522)
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ntiplatelet therapy decreases the risk of ischemic compli-ations during percutaneous coronary interventions (PCIs),ith the combination of aspirin and clopidogrel being theost effective.1–3 However, there is significant interpatient

ariability in response to these 2 drugs.4–7 Previously pub-ished work has demonstrated suboptimal antiplatelet ef-ects in 5% to 45% of aspirin-treated patients and 4% to0% of those on clopidogrel.4,5,7–9 Some studies have dem-nstrated an association between aspirin resistance (usingarious assays) and adverse cardiac events,7,10 with 1 studyhowing its association with an increase in markers ofyonecrosis after PCI.11 Most,12–16 but not all, studies have

hown that increases in creatine kinase-MK (CK-MB) afterCI are associated with higher rates of death, myocardial

nfarction, and repeat revascularization. This study thereforeested the hypothesis that a lower level of responsiveness to

Department of Medicine, Division of Cardiology, Washington Hospitalenter, Washington, DC. Manuscript received August 8, 2006; revisedanuscript received and accepted January 10, 2007.

DE-mail address: [email protected] (R. Waksman).

ntiplatelet drugs, as measured by point-of-care assays, isssociated with higher levels of CK-MB and troponin I afterCI, which are surrogate markers of ischemic damage.

ethods

e prospectively recruited 330 patients undergoing electiveCI. All were taking aspirin for �1 week and had been onlopidogrel for �6 hours (300- or 600-mg loading dose, alln 75 g/day after PCI). Exclusion criteria included all pa-ients with acute coronary syndromes with positive cardiacarkers or acute ST-segment elevation myocardial infarc-

ion, patients on glycoprotein IIb/IIIa inhibition, nonsteroi-al anti-inflammatory use within the 2 weeks before PCI,nd any patient with a co-morbidity that was judged to limitife expectancy to �6 months. The study was carried outccording to the Declaration of Helsinki and approved byhe local research ethics committee, and written consent wasbtained from all patients. After obtaining full written con-ent and before PCI, 6 ml of whole blood was taken.

Aspirin resistance was measured using the Ultegra Rapidlatelet Function Assay–ASA (RPFA-ASA; Accumetrics, San
iego, California). Citrate-anticoagulated blood (2 ml) was
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1519Coronary Artery Disease/Correlates of Antiplatelet Drugs and Post-PCI CK-MB Release

dded to RPFA-ASA cartridges, which contain fibrinogen-oated beads and platelet agonists. The greater the antiplateletffect of aspirin, the less the fibrinogen-coated beads will

able 1aseline clinical characteristics for the entire cohort

ariable Aspirin Resista(n � 12)

ge (yrs) 67.5 � 8.9en 8 (66.7%)ody mass index (kg/m2) 28.1 � 4.8ypertension 10 (83.3%)iabetes mellitus 7 (58.3%)

nsulin-treated diabetes 2 (16.7%)ypercholesterolemia 11 (91.7%)urrent smoker 4 (33.3%)revious myocardial infarction 3 (25.0%)revious coronary artery bypass surgery 4 (33.3%)revious percutaneous coronary intervention 5 (55.6%)hronic renal failure 5 (41.7%)ialysis dependant 0jection fraction 0.4 � 0.14aseline medicationsAspirin 80 mg 0Aspirin �80–160 mg 6 (50%)Aspirin 300 mg 6 (50%)Statin 9 (75%)� blocker 9 (75%)ACE inhibitor 7 (58.3%)

ACE � angiotensin-converting enzyme.

able 2ngiographic and procedural characteristics (lesion based)

ariable Aspirin Resistant(n � 20)

o. of narrowed coronary vessels 1.8 � 0.8reated vesselLeft main stem 2 (10.0%)Left anterior descending 11 (55.0%)Left circumflex 3 (15.0%)Right 1 (5.0%)Saphenous vein graft 3 (15.0%)Internal mammary artery 0esion locationOstial 1 (5.3%)Proximal 3 (15.8%)Mid 13 (68.4%)Distal 2 (10.5%)Restenosis 3 (15.0%)CC/AHA classificationType A 1 (5.3%)Type B1/B2 11 (57.9%)Type C 7 (36.8%)evice usageBalloon predilatation 12 (60.0%)Debulking devicestent detailsDiameter (mm) 2.91 � 0.41Length (mm) 18.9 � 6.2No. per patient 1.82 � 1.25

ACC/AHA � American College of Cardiology/American Heart Associ

gglutinate and lower the transmission of light. The result is U

xpressed as aspirin reaction unit (ARU), with an ARU �550eing the accepted cutoff for the definition of aspirin resistance.

Response to clopidogrel was tested using the version of the

Aspirin Sensitive(n � 309)

p Value Overall

63.9 � 18.2 0.21 64.1 � 17.8224 (72.5%) 0.74 239 (72.4%)29.7 � 5.5 0.31 29.6 � 5.5245 (80.3%) 1.0 263 (80.7%)116 (38.0%) 0.23 124 (38.0%)

39 (12.8%) 0.67 41 (12.6%)267 (87.3%) 1.0 285 (87.2%)49 (15.9%) 0.12 55 (16.7%)

109 (38.4%) 0.55 116 (38.3%)164 (58.6%) 1.0 119 (36.3%)164 (58.6%) 1.0 170 (57.4%)38 (12.5%) 0.01 43 (13.2%)6 (2.0%) 1.0 6 (1.8%)

0.5 � 0.12 0.05 0.49 � 0.13

0 — —152 (49.2%) 0.96 —156 (50.5%) 0.97 —223 (72.2%) 1.0 —204 (66.0%) 0.76 —135 (43.4%) 0.32 —

Aspirin Sensitive(n � 559)

p Value Overall

1.9 � 0.8 0.65 1.9 � 0.84

10 (1.8%) 0.06 12 (2.1%)172 (30.9%) 0.02 183 (31.8%)144 (25.9%) 0.27 147 (25.5%)177 (31.8%) 0.01 178 (30.9%)50 (9.0%) 0.42 53 (9.2%)

0 — —

47 (8.5%) 1.0 48 (8.4%)162 (29.2%) 0.20 165 (28.7%)261 (47.0%) 0.07 274 (47.7%)83 (15.0%) 1.0 85 (14.8%)45 (10.0%) 0.45 59 (10.2%)

39 (7.7%) 1.0 40 (7.6%)342 (67.5%) 0.38 353 (67.1%)126 (24.9%) 0.28 133 (25.3%)

337 (60.3%) 0.98 349 (60.3%)0 — 0

3.01 � 0.32 0.36 3.01 � 0.3220.9 � 6.8 0.38 20.82 � 6.771.52 � 1.01 0.35 1.53 � 1.02

nt

ltegra Rapid Platelet Function Assay-P2Y12 (RPFA-P2Y12)

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efore Food and Drug Administration approval. This specifi-ally measures the degree of inhibition of the thienopyridine-pecific P2Y12 platelet receptor by clopidogrel. Whole bloodas taken into 1.8-ml plastic Vacuette tubes (Gernier, Monroe,orth Carolina) containing 3.2% sodium citrate. After discard-

ng the first tube, a second citrated tube was collected. To avoidross contamination, all tubes containing noncitrate anticoag-lant (for full blood counts) were filled after the citrated tubesere drawn. Tubes were gently inverted to mix the contents

nd incubated at room temperature for 10 minutes. The assayevice consisted of 2 whole blood assay channels. One con-ained fibrinogen-coated polystyrene beads and the plateletgonist adenosine diphosphate (ADP) at a concentration equiv-lent to that observed with 5 �M in studies performed usinglatelet-rich plasma in an optical aggregometer. This channellso contained prostaglandin E1 to decrease the nonspecificontribution of the P2Y1 receptor. The second channel con-ained fibrinogen-coated polystyrene beads and the plateletgonist thrombin receptor-activating protein, which essentiallyctivated all platelet aggregatory pathways. The beads in eitherhannel will agglutinate in whole blood in direct proportion tohe number of uninhibited platelets present. Clopidogrel me-abolite inhibits aggregation in the ADP-containing channel,ut not in the channel containing thrombin receptor-activatingrotein. In the 2 channels, aggregation is measured as thencrease in light transmittance reported as platelet responsenits (PRUs) for the 2 channels. In the version of the machinepproved by the Food and Drug Administration, where thehrombin receptor activating protein channel has been cali-rated, inhibition percentage of the P2Y12 receptor is calcu-ated by dividing the PRU value of the ADP channel by theRU value of the thrombin receptor activating protein channelnd converting this into a percentage. In this study, the P2Y12RU alone is quoted. The lower the PRU value, the greater theegree of inhibition of the P2Y12 receptor by clopidogrel.

A dedicated data coordinating center (Data Center, MedStaresearch Institute, Washington, DC) performed all data man-gement and analyses. Clinical follow-up at 1 and 6 monthsas conducted by telephone contact or office visits. Occur-

ence of major late clinical events was recorded, includingeath (all-cause), myocardial infarction, target lesion revascu-arization, and target vessel revascularization. Major adverseardiac events were defined as a composite of death, Q-waveyocardial infarction, and target vessel revascularization. All

linical events were adjudicated by source documentation byndependent physicians who were not involved in the proce-ures. All angiographic variables were determined by visualstimation by the operator at the time of procedure. This studyas conducted under the approval of the local institutional

eview board.Statistical analysis was performed using SAS 8.2 (SAS

nstitute, Cary, North Carolina). Data are expressed as mean �D for continuous variables and as percentages for categor-

cal variables. Student’s t test was used to compare contin-ous variables and chi-square test or Fisher’s exact test wassed to compare categorical variables. A p value �0.05 wasonsidered to indicate statistical significance. Initially anivariate Cox regression analysis was performed usingarious possible clinical and angiographic predictors of anyncrease in CK-MB. All univariate predictors of any in-
rease in CK-MB with a p value �0.2 were entered into the i
ultivariate model. Cox regression model was then used todentify independent predictors of CK-MB release using atepwise model selection method with an entry of 0.05 andstay of 0.1. The main end point was to determine whether

here was a significant correlation between ARU and car-iac marker levels after PCI and, if so, to perform a linearegression analysis. This was performed before and afterxcluding patients with thrombocytopenia, a hematocrit30, or chronic renal failure because as these conditions

ould interfere with results of antiplatelet function assays.

esults

emographic and clinical characteristics for the entire co-ort and aspirin-resistant versus -sensitive groups are listedn Tables 1 and 2. Mean hematocrit was 40.20 � 4.89 andean platelet count was 211.95 � 59.98. Twelve patients had

n ARU �550, producing an overall rate of aspirin-resistanceate for this group of 3.6%. Of these 12, cardiac marker levelsfter PCI were available for 9. Sixty-one of 244 patients (25%)ad CK-MB levels after PCI above the upper limit of normal,ith no differences between the aspirin-resistant group andonaspirin-resistant group (2 of 4, 50.0%, vs 59 of 240, 24.6%,espectively, p � 0.26). One hundred thirty-one of 244 patients53.8%) exhibited troponin I levels after PCI above the upperimit of normal, with no differences between the aspirin-resis-ant and nonresistant groups (2 of 4, 50%, vs 129 of 240,3.8%, respectively, p � 0.73). Results were not altered byncluding patients with chronic renal failure, anemia, or throm-ocytopenia (data not shown).

Mean PRU was 192.2 � 95.4 (the lower the PRU, theigher the inhibition of P2Y12 receptor). There was no corre-ation between levels of ARU or PRU and magnitude of

Figure 1. Lack of correlation between ARU and CK-MB levels after PCI.

Figure 2. Lack of correlation between PKU and CK-MB levels after PCI.

ncrease in CK-MB or troponin I after PCI at 16 hours or any

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1521Coronary Artery Disease/Correlates of Antiplatelet Drugs and Post-PCI CK-MB Release

ther time point after excluding patients with chronic renalailure, anemia, or thrombocytopenia (n � 48) or includinghem (data not shown). There was a positive correlation be-ween increased values of ARU and PRU (Figures 1 to 3). Weerformed a multivariate analysis to determine independentredictors of CK-MB increase after PCI. The only significantultivariate predictor of a patient sustaining any increase inK-MB was multivessel disease (odds ratio 2.2, 95% confi-ence interval 1.4 to 3.3, p � 0.0003; Table 3). The combinedate of target vessel revascularization rate and major adverseardiac events at 6 months was 8.2%, with no correlationetween ARU or PRU values and the magnitude of release ofardiac enzymes or occurrence of adverse cardiac events. Thetudy was not, however, powered to detect differences inajor adverse coronary events between aspirin-resistant and

sensitive patients.

iscussion

his study determined that, in low-risk patients undergoinglective PCI, measurements of aspirin resistance or clopi-

Figure 3. Positive correlation between ARU and PRU.

able 3ultivariate analysis: outcome of any creatine kinase-MB increase after

ercutaneous coronary intervention

bservation HazardRatio

95% CIfor Odds

Ratio

pValue

nivariate predictorsAge 1.0 0.99–1.04 0.28Men 1.4 0.72–2.6 0.33Diabetes mellitus 0.58 0.32–1.08 0.09Insulin-dependent diabetes 0.36 0.12–1.07 0.07Chronic renal failure 0.45 0.17–1.2 0.11Current smoker 1.6 0.81–3.2 0.17Previous myocardial infarction 1.1 0.60–1.98 0.77Previous PCI 0.6 0.34–1.1 0.08Previous coronary artery bypass 0.8 0.45–1.5 0.49Multivessel coronary disease 1.9 1.3–2.8 0.0015ARU �550 0.97 0.19–4.8 0.97ultivariate predictors

Current smoker 1.1 0.48–2.7 0.76History of chronic renal failure 0.52 0.17–1.6 0.24Previous PCI 0.57 0.29–1.1 0.10Insulin-treated diabetes 0.47 0.15–1.5 0.20ARU �550 0.98 0.09–10.2 0.98Multivessel coronary disease 2.2 1.4–3.4 0.0003

CI � confidence interval.

ogrel responsiveness do not correlate with measurements s

f myonecrosis. Our rate of aspirin resistance was low at.7% (12 patients). Although the precise mechanism byhich increases in CK-MB after PCI arise is uncertain, most

tudies have shown them to be associated with an increasedisk of medium-term complications. Further, there does notppear to be a cutoff, but rather a graded increase in riskith increasing levels of CK-MB.17 Serum troponin levels

re more frequently increased after PCI but appear to cor-elate even less reliably with adverse events.18,19 In thistudy, although 65 patients sustained any increase inK-MB, only a small proportion of these patients (n � 9,4%) sustained an increase �3 times the local upper limit oformal, the level that is generally associated with the greaterisk.17 Nevertheless, lack of any correlation between thehole range of values of ARU or PRU and CK-MB or

roponin I after PCI casts doubt on the usefulness of point-f-care platelet function assays, at least in this low-riskroup.

Our findings are in contrast to the study by Chen et al11

hat assessed aspirin responsiveness also using the RPFA-SA in 151 patients undergoing nonurgent PCI who hadeen pretreated with clopidogrel. Rate of aspirin resistanceas 19.2% with the incidence of any CK-MB increase

ignificantly higher in the aspirin-resistant versus the aspi-in-sensitive group. Other studies have also demonstrated anssociation between aspirin resistance and adverse cardiacvents.7,10 Possible reasons for the difference in findingsompared with those of our study are the interindividualariability in platelet response to aspirin and clopidogrelith the same dose, differences in compliance, or under-osing. More sophisticated assays are required to uncoverhe latter 2 reasons for aspirin “resistance,” as recentlyemonstrated in a detailed study by Frelinger et al,20 usingow cytometry and serum thromboxane B2 assays (unsuit-ble for point-of-care use) in 700 consecutive patients un-ergoing cardiac catheterization. This study also showedhat, despite the vast majority of patients who exhibitedood compliance and adequate dosing, arachidonic acid–nduced platelet aggregation persists and is likely to beediated by a cyclooxygenase-1- and cyclooxygenase-2–

ndependent pathway. Therefore, a significant proportion ofositive aspirin-resistance assays that resulted in healthyubjects and patients may be due to individual variability inlatelet function rather than to true biochemical resistanceo the drug. This does not invalidate the notion that de-reased responsiveness to aspirin is not clinically importantut that this phenomenon is likely to be multifactorial andherefore the therapeutic response to the data generated byoint-of-care assays may be not straightforward.

Patients also display different responses to clopidogrel,hich can be assessed by different laboratory methods

light transmission aggregometry or vasodilator-stimulatedhosphoprotein assay, neither of which have predefinedriteria). Arbitrary cutoffs have been used in previous stud-es to segregate clopidogrel responders from nonre-ponders.21 Clopidogrel resistance has been shown to cor-elate with an increased risk of adverse cardiac events buthis has been in high-risk patients. Matetzky et al22 prospec-ively studied 60 patients undergoing primary PCI for ST-levation myocardial infarction. Platelet function was as-
essed by epinephrine-induced platelet aggregation and by a

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one-and-platelet analyzer method. Patients were stratifiednto quartiles according to percent decrease of ADP-inducedlatelet aggregation. It was found that 40% in the firstuartile sustained a recurrent cardiovascular event duringhe 6-month follow-up period versus only 1 patient (6.7%)n the second quartile and none in the third or fourth quartilep � 0.007). The small number of patients is a seriousimitation of this study. In our study, it was not possible torespecify a cut-off value of PRU to separate respondersrom nonresponders. Regression analysis showed no rela-ion between PRU and measurements of myonecrosis. Thearge number of CK-MB values within the normal rangelso casts doubt as to the usefulness of point-of-care assaysf clopidogrel responsiveness in determining the risk ofschemic events after PCI in such a low-risk group. Theositive correlation between higher levels of ARU and PRUould be consistent with previous observations that patientsith aspirin resistance may be more likely to exhibit lower

evels of responsiveness to clopidogrel.23

The lack of correlation between the results of point-of-are assays of aspirin and clopidogrel resistance and mea-urements of myonecrosis may be at least in part due toignificant individual variability in platelet function. Reli-ble and reproducible tests for aspirin and clopidogrel re-istance are required. To date, the optimal level of plateletnhibition due to aspirin or clopidogrel that correlates withclinically demonstrable antithrombotic effect remains un-

lear. Intraindividual variation in platelet function with aonstant dose of antiplatelet agent makes this problematic.rospective data showing a clear relation between antiplate-

et drug resistance and clinical events is also required, as isvidence that altering therapy in response to data generatedy such assays improves clinical outcomes. Until thesessues are addressed, routine use of such point-of-care as-ays in clinical practice cannot be justified.

1. Bhatt DL, Bertrand ME, Berger PB, L’Allier PL, Moussa I, Moses JW,Dangas G, Taniuchi M, Lasala JM, Holmes DR, Ellis SG, Topol EJ.Meta-analysis of randomized and registry comparisons of ticlopidinewith clopidogrel after stenting. J Am Coll Cardiol 2002;39:9–14.

2. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, NatarajanMK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I,Fox KA, for the Clopidogrel in Unstable angina to prevent RecurrentEvents trial (CURE) Investigators. Effects of pretreatment with clopi-dogrel and aspirin followed by long-term therapy in patients undergo-ing percutaneous coronary intervention: the PCI-CURE study. Lancet2001;358:527–533.

3. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK.Effects of clopidogrel in addition to aspirin in patients with acutecoronary syndromes without ST-segment elevation. N Engl J Med2001;345:494–502.

4. Buchanan MR, Brister SJ. Individual variation in the effects of ASAon platelet function: implications for the use of ASA clinically. CanJ Cardiol 1995;11:221–227.

5. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel forcoronary stenting: response variability, drug resistance, and the effectof pretreatment platelet reactivity. Circulation 2003;107:2908–2913.

6. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL,Topol EJ. Variability in platelet responsiveness to clopidogrel among
544 individuals. J Am Coll Cardiol 2005;45:246–251.
7. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. Aprospective, blinded determination of the natural history of aspirinresistance among stable patients with cardiovascular disease. J AmColl Cardiol 2003;41:961–965.

8. Grotemeyer KH. Effects of acetylsalicylic acid in stroke patients.Evidence of nonresponders in a subpopulation of treated patients.Thromb Res 1991;63:587–593.

9. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M.Prevalence of clopidogrel non-responders among patients with stableangina pectoris scheduled for elective coronary stent placement.Thromb Haemost 2003;89:783–787.

0. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarc-tion, stroke, or cardiovascular death in patients at high risk for cardio-vascular events. Circulation 2002;105:1650–1655.

1. Chen WH, Lee PY, Ng W, Tse HF, Lau CP. Aspirin resistance isassociated with a high incidence of myonecrosis after non-urgentpercutaneous coronary intervention despite clopidogrel pretreatment.J Am Coll Cardiol 2004;43:1122–1126.

2. Tardiff BE, Califf RM, Tcheng JE, Lincoff AM, Sigmon KN,Harrington RA, Mahaffey KW, Ohman EM, Teirstein PS, BlankenshipJC, Kitt MM, Topol EJ. Clinical outcomes after detection of elevatedcardiac enzymes in patients undergoing percutaneous intervention.IMPACT-II Investigators. Integrilin (eptifibatide) to Minimize PlateletAggregation and Coronary Thrombosis-II. J Am Coll Cardiol 1999;33:88–96.

3. Kong TQ, Davidson CJ, Meyers SN, Tauke JT, Parker MA, BonowRO. Prognostic implication of creatine kinase elevation followingelective coronary artery interventions. JAMA 1997;277:461–466.

4. Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Signif-icance of mild transient release of creatine kinase-MB fraction afterpercutaneous coronary interventions. Circulation 1996;94:1528–1536.

5. Abdelmeguid AE, Ellis SG, Sapp SK, Whitlow PL, Topol EJ. Definingthe appropriate threshold of creatine kinase elevation after percutane-ous coronary interventions. Am Heart J 1996;131:1097–1105.

6. Harrington RA, Lincoff AM, Califf RM, Holmes DR Jr, Berdan LG,O’Hanesian MA, Keeler GP, Garratt KN, Ohman EM, Mark DB.Characteristics and consequences of myocardial infarction after per-cutaneous coronary intervention: insights from the Coronary Angio-plasty Versus Excisional Atherectomy Trial (CAVEAT). J Am CollCardiol 1995;25:1693–1699.

7. Harrington RA. Cardiac enzyme elevations after percutaneous coro-nary intervention: myonecrosis, the coronary microcirculation andmortality. J Am Coll Cardiol 2000;35:1142–1144.

8. Kini AS, Lee P, Marmur JD, Agarwal A, Duffy ME, Kim MC, SharmaSK. Correlation of postpercutaneous coronary intervention creatinekinase-MB and troponin I elevation in predicting mid-term mortality.Am J Cardiol 2004;93:18–23.

9. Fuchs S, Gruberg L, Singh S, Stabile E, Duncan C, Wu H, WaksmanR, Satler LF, Pichard AD, Kent KM, Kornowski R. Prognostic valueof cardiac troponin I re-elevation following percutaneous coronaryintervention in high-risk patients with acute coronary syndromes. Am JCardiol 2001;88:129–133.

0. Frelinger AL III, Furman MI, Linden MD, Li Y, Fox ML, BarnardMR, Michelson AD. Residual arachidonic acid-induced platelet acti-vation via an adenosine diphosphate-dependent but cyclooxygenase-1-and cyclooxygenase-2–independent pathway: a 700-patient study ofaspirin resistance. Circulation 2006;113:2888–2896.

1. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: areview of the evidence. J Am Coll Cardiol 2005;45:1157–1164.

2. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Golden-berg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrelresistance is associated with increased risk of recurrent atherothrom-botic events in patients with acute myocardial infarction. Circulation2004;109:3171–3175.

3. Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, DeLao T,Bray PF, Kleiman NS. Aspirin and clopidogrel drug response inpatients undergoing percutaneous coronary intervention: the role of
dual drug resistance. J Am Coll Cardiol 2006;47:27–33.

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Effect of Early Statin Treatment at Standard Doses on Long-TermClinical Outcomes in Patients With Acute Myocardial Infarction

(The Heart Institute of Japan, Department of CardiologyStatin Evaluation Program)

Michitaka Nagashima, MD, PhDa, Ryo Koyanagi, MDa, Hiroshi Kasanuki, MD, PhDa,Nobuhisa Hagiwara, MD, PhDa, Jun-ichi Yamaguchi, MD, PhDa, Nobuhiko Atsuchi, MDd,

Takashi Honda, MD, PhDd, Kazuo Haze, MD, PhDe, Tetsuya Sumiyoshi, MD, PhDb,,Mitsuyoshi Urashima, MD, PhD, MPHc, and Hiroshi Ogawa, MD, PhDa,*,

for the Heart Institute of Japan, Department of Cardiology (HIJC) Investigators

Long-term preventive effects of standard statin therapy in patients with acute myocardialinfarction (AMI) against a secondary cardiac event remain unclear. The aims of this studywere to evaluate and clarify characteristics of patients with AMI in whom standard statintherapy has beneficial effects against a secondary event in a real-world setting. Between1999 and 2004, 4,075 patients with AMI were registered and followed prospectively, ofwhom 1,404 (matched by propensity scores) were analyzed. Statin use was defined asprescription on discharge from the hospital, and the control group was not prescribedstatins at discharge. The primary end point was total mortality rate. Final follow-up wasperformed in June 2006 (median 4.1 years), and follow-up rate was 97.2%. During follow-up, 139 patients died, including 87 (12.4%) from the control group and 52 (7.4%) from thestatin group. The hazard ratio for statin therapy was 0.64 (95% confidence interval 0.45 to0.90, p � 0.011) throughout the study. Early statin therapy was strongly correlated with alower risk of cardiovascular death, less recurrence of AMI, and less heart failure. Statintherapy was particularly beneficial for men, patients >60 years of age, and patients with ahigh low-density lipoprotein cholesterol level >155 mg/dl. In conclusion, these findingssuggest that initiating standard rather than intensive statin therapy immediately after AMIdecreases long-term mortality and subsequent cardiac events. © 2007 Elsevier Inc. All
rights reserved. (Am J Cardiol 2007;99:1523–1528)
M

Tt1t1dcihfiasam(fecipe

he Heart Institute of Japan, Department of CardiologyHIJC) investigators’ project is a collaborative effort inrogress to develop a domestic epidemiologic database andmprove the quality of care of patients with cardiovascularisease.1–3 As part of that project, the aim of the presenttudy was to clarify whether standard statin therapy initiatedmmediately after acute myocardial infarction (AMI) de-reases long-term mortality and occurrence of cardiacvents in a contemporary, real-world setting.

aDepartment of Cardiology, The Heart Institute of Japan, Tokyo Women’sedical University, bDepartment of Cardiology, Sakakibara Heart Institute,

nd cDivision of Clinical Research and Development, Jikei Universitychool of Medicine, Tokyo, dDivision of Cardiology, Cardiovascular Cen-

er, Saisei-kai Kumamoto Hospital, Kumamoto, and eDivision of Cardiol-gy, Osaka City General Hospital, Osaka, Japan. Manuscript receivedovember 12, 2006; revised manuscript received and accepted January 10,007.

This study was funded by the Japan Research Promotion Society forardiovascular Diseases, Tokyo, Japan.

iE-mail address: [email protected] (H. Ogawa).

ethods

he HIJC investigators registered and followed prospec-ively 8,001 patients with coronary artery disease treated at7 hospitals in Japan from 1999 to 2004. The cohort used inhe present study involved 4,075 patients with AMI, and,404 patients matched according to propensity scores asescribed below were also analyzed. In the matching pro-ess, patients were excluded if serum triglyceride level atnitial registry was �400 mg/dl. Patients who died beforeospital discharge were also excluded. Statin use was de-ned as prescription at time of discharge from the hospital,nd the control group was defined as not being prescribedtatins at discharge. Statin prescriptions consisted of prav-statin (52%, 10 to 20 mg/day), simvastatin (19%, 5 to 20g/day), fluvastatin (7%, 10 to 60 mg/day), atorvastatin

20%, 10 to 40 mg/day), and cerivastatin (2%, withdrawnrom the market). AMI was diagnosed based on the pres-nce of symptoms, high cardiac enzyme levels, and electro-ardiographic changes.4 The study was carried out accord-ng to the principles of the Declaration of Helsinki, and therotocol was approved by the institutional review board orthics committee at each participating center. All participat-
ng patients gave written/oral informed consent before study
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nrollment. Because the HIJC project is mainly for obser-ational purposes, treatment strategies such as lipid-lower-ng drug therapy and early reperfusion treatment were left tohe discretion of the attending physicians.

The primary study outcome was death from any causeAMI, heart failure, sudden death, cerebrovascular disease,ther cardiovascular cause, or noncardiovascular cause).econdary outcomes were (1) death from cardiovascularauses; (2) death from noncardiovascular causes; (3) deathrom coronary heart disease or nonfatal AMI; (4) AMInonfatal or fatal); (5) onset of AMI, hospitalization forschemia, hospitalization for heart failure, hospitalizationor cerebrovascular disease, another hospitalization for car-iovascular cause, or death from cardiovascular disease; (6)ospitalization for ischemia; (7) hospitalization for heart

able 1haracteristics in propensity score matched patients

haracteristic

ge (yrs)enlood pressure at rest (mm Hg)SystolicDiastolicody mass index (kg/m2)eart rate (beats/min)hite blood cell (count/�l)emoglobin (g/dl)emoglobin Alc (%)eak creatine kinase (IU/ml)-reactive protein (mg/dl)erum creatinine (mg/dl)eft ventricular ejection fraction (%)ypertensionyperlipidemia*iabetes mellitusurrent smokererebrovascular diseaserevious MIrevious PCIrevious coronary artery bypass graftingo. of narrowed coronary arteries�1�2Noncoronary angiographyevascularization during hospitalizationPCICoronary artery bypass graftingoncomitant medicationsAspirinAngiotensin-converting enzyme inhibitors or angiotensin II receptor blo� blockersCalcium channel blockersNitratesipid profileTotal cholesterol (mg/dl)Triglycerides (mg/dl)High-density lipoprotein cholesterol (mg/dl)Low-density lipoprotein cholesterol (mg/dl)

Values are means � SDs, numbers of patients (percentages), or median* Total cholesterol level �220 mg/dl.

ailure; and (8) percutaneous coronary intervention (PCI; c

epeat or new lesion) or coronary artery bypass grafting.ach end point was prespecified in the original cohort studyrotocol. If a patient had �2 events, results of the first weresed in the combined end-point analysis. Incidence of end-oint events was ascertained annually and in June 2006ased on hospital records, contact with patients, or certifi-ates issued by administrative authorities. These recordsere provided to the end-point classification committee

composed of 2 experienced cardiologists), which then de-ermined and categorized each event for use in analysis.

Analyses were performed with SAS 9.1 (SAS Institute,ary, North Carolina). Because statin use was not randomlyssigned in the 4,075 patients with AMI, estimated probablese of statins in each patient took into account 36 variablesncluding demographics, risk factors, revascularization pro-

Control(n � 702)

Statins(n � 702)

p Value

63 � 12 63 � 11 NS (0.503)513 (73%) 509 (73%) NS (0.810)

132 � 28 134 � 27 NS (0.248)77 � 17 78 � 16 NS (0.571)24 � 3 24 � 3 NS (0.763)77 � 20 77 � 18 NS (0.725)

10,113 � 3,541 9,952 � 3,229 NS (0.380)14 � 2 14 � 2 NS (0.875)

6.2 � 1.5 6.1 � 1.5 NS (0.702)2,131 (1,003–4,120) 2,169 (1,036–3,925) NS (0.906)

0.3 (0.1–0.7) 0.3 (0.1–0.6) NS (0.543)0.8 (0.7–1.0) 0.8 (0.7–1.0) NS (0.729)

53 � 13 53 � 13 NS (0.634)409 (58%) 403 (57%) NS (0.746)584 (83%) 579 (82%) NS (0.723)274 (39%) 275 (39%) NS (0.956)428 (61%) 416 (59%) NS (0.513)64 (9%) 65 (9%) NS (0.926)

110 (16%) 104 (15%) NS (0.656)74 (11%) 73 (10%) NS (0.931)15 (2%) 17 (2%) NS (0.721)

361 (51%) 347 (49%)236 (34%) 252 (36%) NS (0.858)105 (15%) 103 (15%)

565 (80%) 573 (82%) NS (0.586)21 (3%) 19 (3%) NS (0.748)

642 (91%) 652 (93%) NS (0.321)491 (70%) 508 (72%) NS (0.317)270 (38%) 274 (39%) NS (0.827)204 (29%) 205 (29%) NS (0.953)409 (58%) 402 (57%) NS (0.705)

212 � 38 213 � 40 NS (0.484)123 (84–182) 123 (86–178) NS (0.621)

47 � 14 47 � 14 NS (0.970)136 � 34 137 � 38 NS (0.627)

quartile ranges).

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1525Coronary Artery Disease/Statins for AMI

ine (Table 1) and then propensity scores (1/[1 �xp(��=x)]) were calculated using a multiple logisticegression model.5,6 The final model included 23 variablesage, gender, systolic and diastolic blood pressures, bodyass index, heart rate, log[peak creatine kinase], log[C-

eactive protein], log[serum creatinine], hypertension, hy-erlipidemia, smoking, cerebrovascular disease, previousyocardial infarction, number of diseased vessels, PCI and

oronary artery bypass grafting during hospitalization, as-irin use, angiotensin-converting enzyme inhibitor or an-iotensin II receptor blocker use, �-blocker use, nitrate use,nd total cholesterol level). Mean propensity score was 0.27range 0.01 to 0.95), and the model had an area under theeceiver-operating characteristics curve value of 0.87. Weere able to match 702 control patients to 702 statin-treatedatients with these 3-digit score matches. This sample of,404 patients had 75% power to detect a decrease of 35%n risk of all-cause death at 5 years, with a 2-sided p value

0.05.7 Data are presented as mean � SD and are mediansith interquartile ranges or frequencies. Student’s t test orspin-Welch t test was used to compare groups with respect

o normally distributed continuous variables, and Mann-hitney U test was used for other variables. Chi-square test

r Fisher’s exact test was used to compare nominally scaledariables. Cumulative probabilities of event curves werestimated with the Kaplan-Meier method. To evaluate theffect of statins with respect to subsequent events, conven-ional Cox proportional hazards models were used. Further,o evaluate effects within time-specific intervals, a Coxonproportional hazard model using time-dependent vari-bles was used.8 In subgroup analysis, heterogeneity offfects was evaluated in the model. Proportional hazardsssumption was confirmed by the log (�log survival func-ion). Effects of profile, linearity, interaction, and collinear-ty in all generalized linear models were examined usingegression diagnostic analysis. Two-tailed p values �0.05

igure 1. Hazard ratio for primary and secondary end points. CABGardiovascular disease.

ere considered to indicate a statistically significant differ- p

nce. All analyses were performed at an independent bio-tatistics and datacenter (STATZ Institute, Inc., Tokyo,apan).

esults

haracteristics of the control and statin groups after pro-ensity score matching are presented in Table 1. Matched-air patients were well balanced, including demographics,isk factors, revascularization procedures, concomitantedications, and lipid levels. This study involved patientsith AMI and average cholesterol levels.The final follow-up of the 1,402 patients was performed

n June 2006, by which time the study population hadccrued 5,389 person-years of follow-up (median 4.1 years

nary artery bypass grafting; CHD � coronary heart disease; CVD �

igure 2. Kaplan-Meier estimates of the incidence of the primary end point.aplan-Meier 1-, 3-, and 5-year cumulative survival rates were 95.4%,1.4%, and 86.6%, respectively, in the control groups, and 97.3%, 94.9%,nd 90.0%, respectively, in the statin group. CI � confidence interval.

� coro

er patient, follow-up rate 97.2%). During the follow-up

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eriod, 139 patients died, 87 (12.4%) in the control groupnd 52 (7.4%) in the statin group (Figure 1). Hazard ratiosere 0.64 (95% confidence interval 0.45 to 0.90, p � 0.011)

n the statin group during the entire study period and 0.5795% confidence interval 0.32 to 1.02, p � 0.059) duringhe first year. Effects of secondary end points in the statinroup are also shown in Figure 1. Early statin therapy wastrongly correlated with a significant decrease in the inci-ence of the remaining secondary end points, i.e., deathrom coronary heart disease or nonfatal AMI, fatal or non-atal AMI, major adverse cardiac events, revascularizationrocedures, and hospitalization for heart failure. There waso significant difference in the rate of hospitalization forschemia including unstable angina between the 2 groups. Inonsequence, early statin treatment for AMI was stronglyorrelated with improved late outcome compared with theontrol group (Figure 2).

To evaluate the heterogeneity of statin effects with re-pect to total mortality rate, subgroup analysis was alsoerformed. Except for a history of hypertension, there wereo statistical interactions among subgroups. However, aecreasing tendency (interaction test, p �0.20) of statinffects for total mortality was observed in the subgroups withlow total cholesterol level (�240 mg/dl) and a low low-

ensity lipoprotein cholesterol level (�155 mg/dl; Figure 3).

iscussion

ur results suggest that early statin use after AMI decreases

Figure 3. Estimates of the hazard ratio for the primary end point acc

he risk of patient death from any cause and decreases the C

umber of subsequent cardiovascular events in the longerm. Most patients with AMI have cholesterol levels thatre not markedly high.9 Cholesterol levels in our studypproximate those in epidemiologic studies of patients withoronary heart disease. It appears that Japanese patientsith AMI undergo PCI more frequently than patients inestern countries.1,10,11 Further, it is necessary to consider

ossible racial and ethnic aspects that may have affected theresent results. It is well known that the Japanese populationas a lower age-standardized coronary heart disease mor-ality rate and relatively small physical stature comparedith Western populations.12

Swedish registry results have indicated that initiation oftatin treatment at or before hospital discharge in survivorsf AMI is associated with a lower subsequent 1-year mor-ality rate.13 Other previous studies have also suggested thatarly statin treatment is beneficial in stabilizing vulnerablelaque after acute coronary events.14–18 Our results areonsistent with those of other studies for a 1-year period.

In patients who had had a history of AMI and averageholesterol levels, results of the Cholesterol And Recurrentvents (CARE) trial demonstrated that decreasing low-den-ity lipoprotein cholesterol to average to low levels signif-cantly decreased the number of recurrent coronary eventsuring 5-year follow-up.19 In subgroup analysis in theARE trial, the decrease in the rate of coronary events with

tatin administration tended to be influenced by cholesterolevel. Our findings are also consistent with those of the

to baseline characteristics (statin treatment group vs control group).

ARE trial. Although the effects of statins did not show a

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1527Coronary Artery Disease/Statins for AMI

ignificant interaction, the absolute benefits of statins wereikely to be greater in patients at higher risk for majorardiac events. The effect was smaller in patients withypertension compared with those without. This is consis-ent with a previous report of pooled data analysis.20

In the Multicenter Study for Aggressive Lipid-Loweringtrategy by HMG-CoA Reductase Inhibitors in Patientsith Acute Myocardial Infarction (MUSASHI-AMI),21 a

ecent randomized trial, the investigators clearly demon-trated that early statin therapy at standard doses decreasedecurrent cardiovascular events. However, they failed toemonstrate that standard statin therapy decreased the re-urrence of AMI up to 24 months of follow-up. In contrast,n the present study, we showed the beneficial effect oftandard statin therapy on the preventive effect of recur-ence of AMI during the mean follow-up period of 4.1ears. Our findings suggest that the beneficial effects oftatin use on total mortality rate were from decreased car-iovascular events. This longer-term benefit could haveeen due to continuous lipid lowering or the result of thearly benefit of stabilizing vulnerable plaque soon after thenset of AMI. Further, it could be possible that these ben-fits were due to pleiotropic effects.22–25 However, thereas no significant heterogeneity in C-reactive protein levels

t discharge in subgroup analysis (test for interaction, p �.964).

In the present study, Kaplan-Meier curves began to di-erge early and risk decrease was greater than in random-zed, controlled trials. In addition to being a high-risk pop-lation for AMI, it must be considered that the population inhis study was taken from registry data. In contrast to aandomized, controlled trial, patients who had co-morbidityomplicating AMI, even those requiring drug therapy foreart failure or arrhythmias, were not excluded. The previ-us randomized, controlled trials might have underesti-ated the effects of statins due to strict enrollment criteria

o ensure internal validity and avoid drug interactions. Theresent results may thus have greater generalizability thanhose of many previous randomized, controlled trials thatuggested statin efficacy in patients with AMI.

The major limitation of the present study is that it isased on a data-driven post hoc analysis of a cohort study.herefore statin use was not allocated randomly. The orig-

nal control and statin groups had major differences in theirovariates including lipid levels. Although analysis of theffects of statin use on mortality and morbidity rates waserformed with the powerful propensity score matchingechnique, this control was limited to variables for whichata were available. Our study is inferior in comparativealidity compared with a randomized, controlled trial. Fur-her, absence of exclusion criteria might lead to relativelyreater interactions or heterogeneity of subgroups such asypertension. Other limitations included lack of precisenformation on the timing of statin initiation, statin dose,uration of treatment, noncompliance, and insufficientafety data during the follow-up period. Despite the limita-ions of this study, results for various end points and sub-roups are internally consistent. Further, total mortality rate
as a completely unbiased end point.
1

cknowledgment: We express our appreciation to the clin-cal research co-ordinators and Katsunori Shimada (STATZnstitute, Inc.) for HIJC study administration and indepen-ent statistical analysis.

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2. Yamaguchi J, Kasanuki H, Ishii Y, Yagi M, Ogawa H, Fujii SY,Koganei H, Okada H, Kimura H, Horie T, et al. Prognostic signifi-cance of serum creatinine concentration for in-hospital mortality inpatients with acute myocardial infarction who underwent successfulprimary percutaneous coronary intervention (from the Heart Instituteof Japan Acute Myocardial Infarction [HIJAMI] Registry). Am JCardiol 2004;93:1526–1528.

3. Nagashima H, Kasanuki H. The status of lipid management in 1,836patients with coronary artery disease: a multicenter survey to evaluate thepercentage of Japanese coronary artery disease patients achieving thetarget low-density lipoprotein cholesterol level specified by the JapanAtherosclerosis Society. J Atheroscler Thromb 2005;12:338–342.

4. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarc-tion redefined—a consensus document of the Joint European Soci-ety of Cardiology/American College of Cardiology Committee forthe redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959 –969.

5. D’Agostino RB Jr. Propensity score methods for bias reduction in thecomparison of a treatment to a non-randomized control group. StatMed 1998;17:2265–2281.

6. Rubin DB, Thomas N. Matching using estimated propensity scores:relating theory to practice. Biometrics 1996;52:249–264.

7. Lakatos E. Sample sizes based on the log-rank statistic in complexclinical trials. Biometrics 1988;44:229–241.

8. SAS Institute. SAS/STAT User’s Guide, Version 8, Volume 3. Cary,NC: SAS Institute, 1999:2622–2628.

9. Kannel WB. Range of serum cholesterol values in the populationdeveloping coronary artery disease. Am J Cardiol 1995;76(suppl):69C–77C.

0. Kinjo K, Sato H, Sakata Y, Nakatani D, Mizuno H, Shimizu M,Nishino M, Ito H, Tanouchi J, Nanto S, Hori M. Relation of C-reactiveprotein and one-year survival after acute myocardial infarction withversus without statin therapy. Am J Cardiol 2005;96:617–621.

1. Ishihara M, Kojima S, Sakamoto T, Asada Y, Tei C, Kimura K,Miyazaki S, Sonoda M, Tsuchihashi K, Yamagishi M, et al. Acutehyperglycemia is associated with adverse outcome after acute myo-cardial infarction in the coronary intervention era. Am Heart J 2005;150:814–820.

2. Menotti A, Puddu PE, Lanti M, Kromhout D, Blackburn H, NissinenA. Twenty-five–year coronary mortality trends in the seven countriesstudy using the accelerated failure time model. Eur J Epidemiol 2003;18:113–122.

3. Stenestrand U, Wallentin L. Early statin treatment following acutemyocardial infarction and 1-year survival. JAMA 2001;285:430–436.

4. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, BelderR, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Intensive versusmoderate lipid lowering with statins after acute coronary syndromes.N Engl J Med 2004;350:1495–1504.

5. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D,Zeiher A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin on earlyrecurrent ischemic events in acute coronary syndromes: the MIRACLstudy: a randomized controlled trial. JAMA 2001;285:1711–1718.

6. Aronow HD, Topol EJ, Roe MT, Houghtaling PL, Wolski KE, LincoffAM, Harrington RA, Califf RM, Ohman EM, Kleiman NS, et al. Effectof lipid-lowering therapy on early mortality after acute coronary syn-dromes: an observational study. Lancet 2001;357:1063–1068.

7. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, WhiteHD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, et al. Earlyintensive vs a delayed conservative simvastatin strategy in patientswith acute coronary syndromes: phase Z of the A to Z trial. JAMA2004;292:1307–1316.

8. Wiviott SD, de Lemos JA, Cannon CP, Blazing M, Murphy SA,McCabe CH, Califf R, Braunwald E. A tale of two trials: a comparison

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9. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG,Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E.The effect of pravastatin on coronary events after myocardial infarction inpatients with average cholesterol levels. Cholesterol and Recurrent EventsTrial investigators. N Engl J Med 1996;335:1001–1009.

0. Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, HawkinsCM, Keech A, Packard C, Simes J, Byington R, Furberg CD. Effect ofpravastatin on coronary disease events in subgroups defined by coro-nary risk factors: the Prospective Pravastatin Pooling Project. Circu-lation 2000;102:1893–1900.

1. Sakamoto T, Kojima S, Ogawa H, Shimomura H, Kimura K, Ogata Y,Sakaino N, Kitagawa A. Effects of early statin treatment on symptom-atic heart failure and ischemic events after acute myocardial infarction
in Japanese. Am J Cardiol 2006;97:1165–1171.
2. Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyondlipid lowering—are they clinically relevant? Eur Heart J 2003;24:225–248.

3. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S,Flaker GC, Braunwald E. Inflammation, pravastatin, and the risk ofcoronary events after myocardial infarction in patients with averagecholesterol levels. Cholesterol and Recurrent Events (CARE) Investi-gators. Circulation 1998;98:839–844.

4. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapyon C-reactive protein levels: the pravastatin inflammation/CRP eval-uation (PRINCE): a randomized trial and cohort study. JAMA 2001;286:64–70.

5. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-termeffects of pravastatin on plasma concentration of C-reactive protein.The Cholesterol and Recurrent Events (CARE) Investigators. Circu-
lation 1999;100:230–235.

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Comparison of Multidetector 64-Slice Computed TomographicAngiography to Coronary Angiography to Assess the

Patency of Coronary Artery Bypass Grafts

Refat Jabara, MDa,*, Nicolas Chronos, MDa, Larry Klein, MDb, Steven Eisenberg, MDa,Rebecca Allen, BSNa, Shannon Bradford, BBAa, and Stephen Frohwein, MDa

This study prospectively evaluated the diagnostic accuracy of 64-slice computed tomo-graphic angiography (CTA) in assessing the patency of coronary artery bypass graftscompared with invasive coronary angiography. In total 147 bypass grafts (100 venousgrafts and 47 mammary artery grafts) were evaluated in 50 consecutive patients. Contrast-enhanced 64-slice CTA was performed and compared with invasive angiography. Thecomputed tomographic angiographic scan protocol used 64- � 0.5-mm slice collimationand 0.33-second gantry rotation time during simultaneous electrocardiographic gating.Patients with a heart rate >65 beats/min received � blockers. Overall 145 of 147 bypassgrafts (98.6%) were detected by CTA; 2 nonvisualized grafts were occluded at the time ofinvasive angiography. Of the grafts visualized, 28 were totally occluded, 103 were patent,and 14 had significant stenoses that were confirmed by invasive angiography. Ninety-fivepercent (111 of 117) of patent grafts demonstrated good run-off distal to anastomoses butwithout an ability to accurately evaluate the presence of retrograde flow; 83% (97 of 117)of distal anastomoses were adequately evaluated, whereas the remaining 17% (20 of 117)were not well visualized due to vascular clips and/or calcification artifacts. Two grafts werenot demonstrated by invasive angiography but were detected by CTA and found to bewidely patent. In conclusion, multidetector 64-slice CTA is a valuable tool for directvisualization of coronary bypass grafts and assessment of their patency. Dysfunctionalbypass grafts can be detected with high diagnostic accuracy. © 2007 Elsevier Inc. All
rights reserved. (Am J Cardiol 2007;99:1529–1534)
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ecent advances in temporal and spatial resolutions of mul-islice computed tomography (MSCT) have made this tech-ique an attractive noninvasive alternative to conventionalnvasive angiography in the evaluation of coronary arteryisease.1–14 Currently, the ability of 64-slice multidetectoromputed tomographic angiography (CTA) to assess coro-ary bypass graft patency has not been established. Recentlyublished appropriateness criteria governing usage ofSCT have not clearly established a definitive role forSCT in evaluation of coronary artery bypass grafts.15 This

tudy prospectively evaluated the diagnostic accuracy of4-slice CTA to assess coronary artery bypass grafts com-ared with invasive coronary angiography.

ethods

his study was designed as a prospective, blinded, standardross-sectional technologic assessment comparing 64-sliceultidetector CTA with invasive coronary angiography.he target study population included patients with previousoronary artery bypass grafting who were being evaluated

aSaint Joseph’s Research Institute/Saint Joseph’s Hospital of Atlanta,eorgia; and bUniversity of North Carolina, Chapel Hill, North Carolina.anuscript received November 23, 2006; revised manuscript received and

ccepted January 10, 2007.*Corresponding author: Tel: 404-843-6082; fax: 404-843-6051.

1E-mail address: [email protected] (R. Jabara).


y invasive coronary angiography for standard clinical in-ications. Patients underwent cardiac CTA within 3 weeksf the invasive angiogram. Patients with a history of renalnsufficiency (serum creatinine level �1.5 mg/dl), contrastllergy, or atrial fibrillation were excluded. This study waspproved by the hospital institutional review board, and allatients signed an informed consent.

Coronary vessel angiography was performed in the stan-ard fashion by experienced operators. Two orthogonaliews of each vessel were obtained and evaluated by 2xperienced cardiologists who were blinded to the results ofSCT. A visual estimate of diameter decreased was used to

escribe stenosis severity. Significant stenosis was defineds �50% diameter stenosis. Invasive angiography was re-arded as the gold standard technique.

Contrast-enhanced MSCT was performed by a 64-sliceomputed tomographic scanner (Siemens Sensation 64,orchheim, Germany). All patients received metoprolol 50g orally the morning of the study and patients with a heart

ate �65 beats/min at the time of the study received addi-ional intravenous metoprolol until the heart rate decrease to

65 beats/min. Patients underwent full noncontrast CT ofhe chest before the cardiac computed tomographic angio-ram that was interpreted by a board certified radiologist.he scanning protocol for cardiac CTA had 64- � 0.5-mmlice collimation and 330-ms gantry rotation time with si-ultaneous electrocardiographic gating. Tube voltage was

20 kV with an effective tube current of 710 to 850 mA.

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mages were reconstructed with 0.75-mm slice thickness at.5-mm increment.

A patient was placed on the gantry, attached to a moni-oring device, and connected to a dual injector (Mallinck-odt, Hazelwood, Missouri) loaded with 110 ml of intrave-ous contrast in the first injector and 50 ml of normal salinen the second. The flow rate for the contrast and saline werereset at 5 ml/s. The window of the cardiac computedomographic angiographic scan was placed at the level ofhe top of the left clavicle and the inferior border was theardiac apex and/or the inferior wall of the left ventricle.ateral borders of the scanning region were the lateralorders of the heart. The bolus tracking method was seedith placement of the region of interest within the aortic

rch distal to the take-off of the left subclavian artery topproximate the arrival of contrast to the myocardium fromhe left internal mammary artery. Contrast (110 ml; Om-ipaque 350, GE Healthcare, Atlanta, Georgia) was givenntravenously at a rate of 5 ml/s and imaging acquisitionas performed automatically with transaxial images ob-

ained in the craniocaudal axial direction once 100 HU waschieved at the region of interest.

Post-acquisition image processing was performed afterompletion of scanning. A preview series was created at0-ms increments of the entire RR interval at the level of theight coronary artery to establish the best imaging time toiew the bypass conduits and the native coronary arteries.ne to three 50-ms timing intervals with the best resolutionere chosen for reconstruction. The postprocessing stage

ncluded multiplanar reconstruction and maximum intensityrojection evaluated in transaxial orientation and 3-dimen-ional volume rendering techniques that were used to eval-ate coronary arterial anatomy, vessel patency, lesion se-erity, and plaque composition. Two experienced readers,linded to the results of invasive angiography but aware ofhe operative procedure, evaluated the multislice computedomograms by consensus reading.

When comparing MSCT with invasive angiography we

able 1linical characteristics of study population (n � 50)

en/women 46/4ge (yrs) 64 � 7eart rate (beats/min) 60 � 6

nterval after surgery (yrs) 8.1 � 4.8 (range 3 mos to 18 yrs)erum creatinine (mg/dl) 1.1 � 0.2table angina pectoris 24 (48%)cute coronary syndrome 26 (52%)iabetes mellitus 17 (34%)ypertension* 15 (30%)yperlipidemia† 42 (84%)moker 17 (34%)ody mass index (kg/m2) 28 � 4revious myocardial infarction 21 (42%)revious percutaneous coronary

intervention27 (54%)

* Defined as blood pressure �140/90 mm Hg and/or use of antihyper-ensive medication.

† Defined as total serum cholesterol level �200 mg/dl and/or use of aipid-lowering agent.

alculated the sensitivity, specificity, positive predictive value, W

nd negative predictive value in addition to corresponding 95%onfidence intervals (CI). The 95% CIs were calculated usinginomial distribution. Continuous variables were expresseds mean � SD and categorical variables as proportions.wo-sample t test, chi-square, and Fisher’s exact tests weresed to determine if the parameters were significantly dif-erent between the 2 modalities.

esults

ll patients underwent multislice computed tomographicngiographic examinations without complications. A totalf 147 bypass grafts (100 venous grafts and 47 mammaryrtery grafts) were evaluated in 50 consecutive patients.atient characteristics are listed in Table 1.

Overall, 145 of 147 bypass grafts (98.6%) were detectedy CTA (Figure 1). The 2 nonvisualized grafts were totallyccluded at the time of the invasive angiogram; the rightnternal mammary artery was grafted to an obtuse marginalranch and the left internal mammary artery was grafted tohe left anterior descending artery. Of the grafts visualized,8 were totally occluded, 103 were patent, and 14 hadignificant stenoses that were confirmed by invasive angiog-aphy (Table 2 and Figure 2). Ninety-five percent (111 of17) of the patent grafts demonstrated good run-off distal tonastomoses. Eighty-three percent (97 of 117) of the distalnastomoses could be well visualized (Figure 3), whereas theemaining 17% (20 of 117) were not well visualized due toetallic vascular clips and/or calcification artifacts (Figure 4).his was more apparent with arterial grafts because 15 of these0 poorly visualized anastomoses were left internal mam-ary artery grafts and the remaining 5 were saphenous vein

rafts. Two grafts were not demonstrated by invasive an-iography but were accurately detected by CTA and foundo be widely patent; 1 graft was the right internal mammaryrtery grafted to the left anterior descending artery, and thether was a Y-graft originating from the inferolateral part ofhe aortic arch that was grafted to the right coronary arterynd the midobtuse marginal branch (Figure 5).

Overall sensitivity for detecting totally occluded graftsas 93.3% (CI 77.9 to 99.2) with specificity of 100% (CI6.9 to 100); the positive predictive value was 100% (CI 87.7o 100), and the negative predictive value was 98.3% (CI 94.1o 99.8). Sensitivity for detecting grafts with significant steno-is (�50% diameter stenosis) was 100% (CI 76.8 to 100) withpecificity of 100% (CI 96.5 to 100); the positive predictivealue was 100% (CI 76.8 to 100), and the negative predictivealue was 100% (CI 96.5 to 100).

Comparison of procedural characteristics between 64-lice MSCT and invasive angiography in patients with pre-ious coronary bypass grafts is presented in Table 3. Totalrocedure time and actual x-ray exposure time were moreavorable with MSCT but overall radiation exposure wasigher with MSCT. Overall contrast utilization was higheror invasive angiography (although statistically higher, a0-ml difference of contrast is probably not consideredlinically significant) and there was 1 serious complicationelated to invasive angiography, whereas none occurreduring MSCT.

Evaluation of retrograde or competitive flow was limited.
e defined retrograde flow as the ability to identify contrast

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1531Coronary Artery Disease/Diagnostic Accuracy of 64 MSCT in Assessing CABG

n an occluded native coronary artery proximal to the anas-omosis of the coronary artery bypass conduit, with theresumption that contrast in the native vessel originatedrom the bypass graft. Using this definition, retrograde flowas observed in only 5% of cases (7 of 145) by MSCT

ompared with 40% (58 of 145) by invasive angiographyp �0.001).

Interpretation of noncontrast CT performed beforeSCT demonstrated 4 abnormalities that warranted further

valuation or follow-up examinations. One patient had annterior mediastinal mass that had the appearance of mi-rated thymus tissue, and 3 patients had enlarged medias-inal lymph nodes.

iscussion

n our study the bypass grafts of 50 patients were evaluatedafely and accurately with MSCT, which compared favor-bly with invasive coronary angiography. Overall scanning

igure 1. Volume rendered still image of (A) right and (B) left anterior obrtery (LIMA) grafted to mid left anterior descending artery (LAD) and 4 sabtuse marginal 2 (OM2), and distal right coronary artery (RCA), respect

able 2haracteristics of bypass grafts evaluated by 64-slice computed tomograp

raft Type Number Patent Total

eft internal mammary artery 43 37ight internal mammary artery 2 2aphenous vein graft 100 64otal 145 103

Note that 40% (15 of 37) of the distal anastomoses of left internal mam* Greater than 50% diameter stenosis.

ime and radiation exposure were higher than previously

eported for MSCT in native vessels due to the size of thecanning region required to evaluate internal mammary andenous bypass grafts and native vasculature.16,17

Advantages of MSCT over invasive angiography wereell defined and considerable. Ease of testing for patients,

ncluding its noninvasive nature, was clearly advantageous.oreover, in our study 2 grafts not identified by invasive

oronary angiography were easily detected by MSCT andound to be widely patent. In addition, the position of theypass grafts in relation to other grafts and adjacent thoracicnatomical structures was defined more readily and accu-ately with MSCT than with invasive angiography. Thisay be advantageous for patients being considered for re-

eat or additional cardiac surgical procedures by allowingurgeons to map the position of the grafts with respect to theverlying sternum, thus increasing the margin of safety tovoid damage to viable grafts during surgical manipula-ions.

ews from a 70-year-old man with 5 bypass grafts: left internal mammarys vein grafts (SVG’s) grafted to diagonal (Diag), obtuse marginal 1 (OM1),raft patency and inter-relations are easily seen.

iography

uded Significant Stenosis* Poorly Visualized Anastomoses

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tudy compare favorably.18–24 Most of these previous re-orts were with 16-slice MSCT and, to the best of ournowledge, the present study is the third report to use

igure 2. Demonstration of significant ostial stenosis (arrowheads) of angiography. (A) Maximum intensity projection from MSCT. (B) Invasive

igure 3. Maximum intensity projection of patent saphenous venous graftrafted to an obtuse marginal branch demonstrating good anastomoticisualization. Abbreviations as in Figure 1.

4-slice MSCT in evaluating bypass conduits. However, r

mportant significant limitations of MSCT compared withnvasive angiography were clearly identifiable. Only 83% ofistal anastomoses of arterial or venous grafts were accu-ately evaluated and this was more apparent with left inter-al mammary artery grafts (60%; Table 2). A possible

nous venous graft to a diagonal branch that was validated by invasiveraphy. LV � left ventricle. Other abbreviations as in Figure 1.

igure 4. Volume rendering example of poor anastomotic visualization dueo vascular clips. RIMA � right internal mammary artery; other abbrevi-tions as in Figure 1.

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eason for the difference between mammary and venous

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1533Coronary Artery Disease/Diagnostic Accuracy of 64 MSCT in Assessing CABG

raft evaluations is that there were more vascular clipsssociated with arterial grafts compared with venous graftst anastomotic sites in our patient population. Moreover, thebility to detect retrograde flow from the grafted vesselould not be accurately defined, and due to inherent limita-ions of multislice computed tomographic technology, com-etitive flow also could not be evaluated. An ability tovaluate retrograde and competitive flow from bypass graftss important in the overall evaluation of coronary bypassonduits. In addition, ability to accurately evaluate the na-ive vasculature of these patients was limited. Technicalifficulties of evaluating bypass grafts and native vascula-ure simultaneously, presence of widespread severe calcifi-ations encountered in severe progressive native coronary

igure 5. Y-graft originating from the inferolateral portion of the aorticrch with the anterior limb grafted to the right coronary artery and theateral limb grafted to the mid obtuse marginal branch. This graft was notemonstrated by invasive angiography but was easily detected by 64-sliceTA and found to be widely patent. Abbreviations as in Figures 1 and 2.

able 3omparison of procedural characteristics between 64-slice multisliceomputed tomography and invasive coronary angiography in patientsith coronary bypass grafts

haracteristic InvasiveAngiography

64-slice MSCT p Value

-ray time (s) 444 � 270 19.3 � 0.6 �0.001rocedure duration (min) 44.7 � 14.4 7.2 � 4.4 �0.001ontrast total (ml) 130 � 48 110 � 10 0.002adiation dose (mSv) 9.0 � 2.7 14.1 � 3.8 �0.001omplications 1* 0 NS

Values are means � SDs or numbers of patients.* One patient had a retroperitoneal hematoma as a complication of

nvasive diagnostic angiography, which was treated conservatively.

rtery disease, and large number of coronary stents in our

tudy population (54% of native arteries and 18% of grafts)ere the major limiting factors. Ropers et al24 attempted

ecently to evaluate the native vasculature of a similarroup, with some success (91% of native coronary segmentsere considered evaluable, and of these segments there wassensitivity of 86% and specificity of 76% with MSCT

ompared with invasive angiography), but in contrast to ourtudy the investigators excluded patients with stents in na-ive or grafted vessels and patients with acute coronaryyndrome. Further clinical investigation and technologicmprovements in MSCT may allow a better combined eval-ation of native and bypass vasculatures.

In conclusion, our results add to the growing body ofedical evidence for using MSCT in patients after coronary

rtery bypass graft operation. However, due to known lim-tations of MSCT such as high radiation exposure, contrastdministration, and inability to perform the study in patientsith atrial fibrillation, more studies are needed beforeSCT is declared an acceptable tool in the evaluation of

hese patients.

cknowledgment: We thank Marti Taylor, MSN, Karenllen, RN, Polly Carter, and Valerie White for their assis-

ance in the recruitment process; Brad Godwin, RT, andohn Bauer, RT, for their expert technical assistance; andeith Robinson, PhD, for his helpful comments.

1. Leber AW, Becker A, Knez A, von Ziegler F, Sirol M, Nikolaou K,Ohnesorge B, Fayad ZA, Becker CR, Reiser M, Steinbeck G, Boek-stegers P. Accuracy of 64-slice computed tomography to classify andquantify plaque volumes in the proximal coronary system: a compar-ative study using intravascular ultrasound. J Am Coll Cardiol 2006;47:672–677.

2. Achenbach S, Moselewski F, Ropers D, Ferencik M, Hoffmann U,MacNeill B, Pohle K, Baum U, Anders K, Jang IK, Daniel WG, BradyTJ. Detection of calcified and noncalcified coronary atheroscleroticplaque by contrast-enhanced, submillimeter multidetector spiral com-puted tomography: a segment-based comparison with intravascularultrasound. Circulation 2004;109:14–17.

3. Hausleiter J, Meyer T, Hadamitzky M, Kastrati A, Martinoff S,Schomig A. Prevalence of noncalcified coronary plaques by 64-slicecomputed tomography in patients with an intermediate risk for signif-icant coronary artery disease. J Am Coll Cardiol 2006;48:312–318.

4. Raff GL, Gallagher MJ, O’Neill WW, Goldstein JA. Diagnostic ac-curacy of noninvasive coronary angiography using 64-slice spiralcomputed tomography. J Am Coll Cardiol 2005;46:552–557.

5. Fine JJ, Hopkins CB, Ruff N, Newton FC. Comparison of accuracy of64-slice cardiovascular computed tomography with coronary angiog-raphy in patients with suspected coronary artery disease. Am J Cardiol2006;97:173–174.

6. Leber AW, Knez A, von Ziegler F, Becker A, Nikolaou K, Paul S,Wintersperger B, Reiser M, Becker CR, Steinbeck G, Boekstegers P.Quantification of obstructive and nonobstructive coronary lesions by64-slice computed tomography: a comparative study with quantitativecoronary angiography and intravascular ultrasound. J Am Coll Cardiol2005;46:147–154.

7. Schuijf JD, Pundziute G, Jukema JW, Lamb HJ, van der Hoeven BL,de Roos A, van der Wall EE, Bax JJ. Diagnostic accuracy of 64-slicemultislice computed tomography in the noninvasive evaluation ofsignificant coronary artery disease. Am J Cardiol 2006;98:145–148.

8. Mollet NR, Cademartiri F, van Mieghem CA, Runza G, McFadden EP,Baks T, Serruys PW, Krestin GP, de Feyter PJ. High-resolution spiralcomputed tomography coronary angiography in patients referred fordiagnostic conventional coronary angiography. Circulation 2005;112:2318–2323.

9. Leschka S, Alkadhi H, Plass A, Desbiolles L, Grunenfelder J,Marincek B, Wildermuth S. Accuracy of MSCT coronary angiography

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with 64-slice technology: first experience. Eur Heart J 2005;26:1482–1487.

0. Achenbach S, Giesler T, Ropers D, Ulzheimer S, Derlien H, Schulte C,Wenkel E, Moshage W, Bautz W, Daniel WG, Kalender WA, BaumU. Detection of coronary artery stenoses by contrast-enhanced, retro-spectively electrocardiographically-gated, multislice spiral computedtomography. Circulation 2001;103:2535–2538.

1. Kopp AF, Schroeder S, Kuettner A, Baumbach A, Georg C, Kuzo R,Heuschmid M, Ohnesorge B, Karsch KR, Claussen CD. Non-invasivecoronary angiography with high resolution multidetector-row com-puted tomography. Results in 102 patients. Eur Heart J 2002;23:1714–1725.

2. Flohr T, Ohnesorge B. Heart rate adaptive optimization of spatial andtemporal resolution for electrocardiogram-gated multislice spiral CTof the heart. J Comput Assist Tomogr 2001;25:907–923.

3. Flohr T, Prokop M, Becker C, Schoepf UJ, Kopp AF, White RD,Schaller S, Ohnesorge B. A retrospectively ECG-gated multislicespiral CT scan and reconstruction technique with suppression of heartpulsation artifacts for cardio-thoracic imaging with extended volumecoverage. Eur Radiol 2002;12:1497–1503.

4. Giesler T, Baum U, Ropers D, Ulzheimer S, Wenkel E, Mennicke M,Bautz W, Kalender WA, Daniel WG, Achenbach S. Noninvasivevisualization of coronary arteries using contrast-enhanced multidetec-tor CT: influence of heart rate on image quality and stenosis detection.AJR 2002;179:911–916.

5. Hendel RC, Patel MR, Kramer CM, Poon M, Hendel RC, Carr JC,Gerstad NA, Gillam LD, Hodgson JM, Kim RJ, et al. ACCF/ACR/SCCT/SCMR/ASNC/NASCI/SCAI/SIR 2006 appropriateness criteriafor cardiac computed tomography and cardiac magnetic resonanceimaging: a report of the American College of Cardiology FoundationQuality Strategic Directions Committee Appropriateness CriteriaWorking Group, American College of Radiology, Society of Cardio-vascular Computed Tomography, Society for Cardiovascular MagneticResonance, American Society of Nuclear Cardiology, North AmericanSociety for Cardiac Imaging, Society for Cardiovascular Angiographyand Interventions, and Society of Interventional Radiology. J Am Coll
Cardiol 2006;48:1475–1497.
6. Coles DR, Smail MA, Negus IS, Wilde P, Oberhoff M, Karsch KR,Baumbach A. Comparison of radiation doses from multislice com-puted tomography coronary angiography and conventional diagnosticangiography. J Am Coll Cardiol 2006;47:1840–1845.

7. Zanzonico P, Rothenberg LN, Strauss HW. Radiation exposure ofcomputed tomography and direct intracoronary angiography: risk hasits reward. J Am Coll Cardiol 2006;47:1846–1849.

8. Pache G, Saueressig U, Frydrychowicz A, Foell D, Ghanem N, KotterE, Geibel-Zehender A, Bode C, Langer M, Bley T. Initial experiencewith 64-slice cardiac CT: non-invasive visualization of coronary arterybypass grafts. Eur Heart J 2006;27:976–980.

9. Achenbach S, Moshage W, Ropers D, Nossen J, Bachmann K. Non-invasive, three-dimensional visualization of coronary artery bypassgrafts by electron beam tomography. Am J Cardiol 1997;79:856–861.

0. Ropers D, Ulzheimer S, Wenkel E, Baum U, Giesler T, Derlien H,Moshage W, Bautz WA, Kalender WA, Achenbach S. Investigation ofaortocoronary artery bypass grafts by multislice spiral computed to-mography with electrocardiographic gated image reconstruction. Am JCardiol 2001;88:792–795.

1. Chiurlia E, Menozzi M, Ratti C, Romagnoli R, Modena MG. Fol-low-up of coronary artery bypass graft patency by multislice computedtomography. Am J Cardiol 2005;95:1094–1097.

2. Anders K, Baum U, Schmid M, Ropers D, Schmid A, Pohle K, DanielWG, Bautz W, Achenbach S. Coronary artery bypass graft (CABG)patency: assessment with high-resolution submillimeter 16-slice mul-tidetector-row computed tomography (MDCT) versus coronary an-giography. Eur J Radiol 2006;57:336–344.

3. Nieman K, Pattynama PM, Rensing BJ, Van Geuns RJ, De Feyter PJ.Evaluation of patients after coronary artery bypass surgery: CT angio-graphic assessment of grafts and coronary arteries. Radiology 2003;229:749–756.

4. Ropers D, Pohle FK, Kuettner A, Pflederer T, Anders K, Daniel WG,Bautz W, Baum U, Achenbach S. Diagnostic accuracy of noninvasivecoronary angiography in patients after bypass surgery using 64-slicespiral computed tomography with 330-ms gantry rotation. Circulation
2006;114:2334–2341.

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Relation of Aortic Valve Calcium to Myocardial Ischemic Perfusion in IndividualsWith a Low Coronary Artery Calcium Score

John Ho, MD*, Shannon FitzGerald, PhD, John Cannaday, MD, Lisa Stolfus, RN, Dana Weilbacher,Yvette Henderson, Tiffany Newman, Robin Whitehead, and Nina Radford, MD

The absence of coronary artery calcium (CAC) is associated with minimal atherosclerosis.Nonetheless, morbid and mortal cardiovascular events occur in patients with low CAC.This study attempts to identify whether calcific deposits outside the coronary arteries ortraditional cardiovascular risk variables are associated with myocardial ischemia in pa-tients with low CAC scores. From 1998 to 2006, a total of 605 patients with an AgatstonCAC score of 0 to 10 were referred for stress echocardiography or myocardial perfusionimaging. There was a low rate (1.2%) of myocardial ischemia. Seven of 303 patients (2.3%)had ischemia on perfusion imaging. Zero of 302 stress echocardiograms were abnormal.Traditional risk-factor analysis did not predict the presence of ischemia. No differences inage, gender, or self-reported hyperlipidemia, diabetes mellitus, tobacco use, hypertension,or family history of premature heart disease were noted. Contrary to previous belief,patients with myocardial ischemia were not younger or female. Aortic valve calcium (AVC)was associated with ischemia (p � 0.02), with a >10-fold likelihood of having ischemiadetected by MPS versus those without AVC (20.0% vs 1.7%). In conclusion, a CAC score<10 is associated with a low rate of myocardial ischemia. AVC may identify a subset ofpatients who may be at higher risk. © 2007 Elsevier Inc. All rights reserved. (Am J
Cardiol 2007;99:1535–1537)
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ow coronary artery calcium (CAC) scores are associatedith a low cardiovascular event rate.1–9 Nonetheless,orbid and mortal cardiovascular events occur in pa-

ients with low CAC scores. In this study, we endeavor todentify possible risk factors that would suggest the pres-nce of obstructive coronary artery disease in individualsith a low CAC score. Are traditional cardiovascular risk

actors related to inducible myocardial ischemia as de-ected by a myocardial perfusion study (MPS) in theseow-risk patients? Does the presence of extracoronaryalcium in the aortic valve or elsewhere suggest periph-ral vascular disease and thus an increased risk of coro-ary artery disease?

ethods and Results

rom 1998 to 2006, a total of 4,069 individuals underwentardiovascular risk assessment by their physician and cor-nary artery scoring using electron-beam computed tomog-aphy. Of these, 1,317 had a low CAC score, defined as angatston score of 0 to 10. Individuals with known cardio-ascular disease (n � 57) were eliminated from subsequentnalysis. Self-reported clinical and demographic data werenalyzed for the remaining 1,260 patients.

If their physician thought it clinically appropriate, pa-ients were referred for a stress imaging study to evaluateor the presence of ischemia. Clinical indications for furtherardiovascular evaluation in these patients with low CACcores included the presence of chest pain, multiple cardio-

Cooper Clinic, Dallas, Texas. Manuscript received November 6, 2006;evised manuscript received and accepted January 10, 2007.

ME-mail address: [email protected] (J. Ho).

ascular risk factors, or an abnormal electrocardiogram. Ineneral, patients perceived to be low risk were not referredor testing (655 of 1,260, 52%). Patients perceived to be atow to intermediate risk were referred for stress echocardi-graphy, and those perceived to be intermediate or high riskere referred for nuclear stress testing.Approximately 1/4 of patients, or 302 of 1,260 (24%),

ere referred for stress echocardiography. An abnormaltress echocardiogram was defined as a stress-induced wallotion abnormality. The remaining patients (24%) were

eferred for an MPS. An abnormal MPS result was defineds a reversible perfusion defect on either thallium-201tress-delay reinjection or technetium-99m sestamibi or tet-afosmin rest-stress protocols.

Overall, 7 of 605 patients (1.2%) had an abnormal testesult. Despite a 30% prevalence of �1 risk factor, thereere no abnormal stress echocardiograms. Compared withatients referred for stress echocardiography, patients re-erred for MPS were a higher risk subgroup with a higherrevalence of hyperlipidemia and diabetes mellitus. In ad-ition, this group was older, more frequently men, moreverweight, and tended to have a family history of prema-ure heart disease (Table 1). Despite this higher risk profile,here was a low frequency of abnormal MPS results (2.3%,

of 303). Two of these 7 patients had a low ischemicurden, with a summed difference score (SDS) �4. Threef these 7 had a moderate ischemic burden (10 � SDS �5),hereas 2 had a high ischemic burden (SDS � 10). On

ollow-up, all patients with either a moderate or high ischemicurden underwent revascularization.

In the setting of a low CAC score, traditional cardiovas-ular risk factors were not associated with an abnormal
PS result (Table 2). No significant differences in age,
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ender, or self-reported status for hypertension, hyperlipid-mia, diabetes mellitus, tobacco use, or family history ofremature heart disease were noted. The presence of chestain was more common in patients with an abnormal MPSesult compared with those with a normal MPS result71.4% vs 38.0%, respectively), but this did achieve statis-ical significance (p � 0.11).

In the subgroup referred for an MPS, the presence ofxtracoronary artery calcium was analyzed to assess itstility as a predictor of inducible ischemia in individualsith low CAC scores. Ten of 303 patients (3.3%) had aorticalve calcium (AVC), whereas 7 of 303 (2.3%) had mitralalve or mitral annular calcium. Calcium in the thoracicorta was much more prevalent (124 of 303, 40.9%). Cal-ium in the thoracic aorta or mitral valve/annulus was notssociated with an abnormal MPS result. However, AVCad a statistically significant association (Table 2). Patientsith AVC (10 of 303) had a �10-fold likelihood of having

schemia versus those without AVC (293 of 303, 20.0% vs.7%, p � 0.02). This finding, although statistically signif-cant, is based on only 2 individuals with AVC of 7 indi-iduals with an abnormal MPS result. Thus, the utility ofVC as a clinical risk prediction tool requires validation in

able 1verall characteristics of patients with a coronary artery calcium scoref 0 to 10 referred for a myocardial perfusion study (MPS) or stresschocardiogram

MPS(n � 303)

Stress Echocardiogram(n � 302)

p Value

ge (yrs) 54 � 8 53 � 9 0.24en 174 (57%) 109 (36%) �0.001yperlipidemia 158 (52%) 91 (30%) �0.001iabetes mellitus 13 (4%) 3 (1%) 0.01ypertension 102 (34%) 94 (31%) 0.50urrent-smoker 45 (15%) 44 (15%) 0.92besity 72 (24%) 34 (11%) �0.001amily history of coronary

artery disease122 (40%) 113 (37%) 0.50

Data presented as mean � SD or absolute number (percent).

able 2haracteristics of patients with low coronary artery calcium with normalersus abnormal myocardial perfusion study (MPS) results

Normal MPS(n � 296)

Abnormal MPS(n � 7)

p Value

ge (yrs) 55 � 8 56 � 10 0.62en 168 (57%) 6 (86%) 0.25yperlipidemia 155 (52%) 3 (43%) 0.71iabetes mellitus 13 (4%) 0 (0%) 1.0ypertension 100 (34%) 2 (29%) 1.0urrent smoker 45 (15%) 0 (0%) 0.60besity 70 (24%) 2 (29%) 0.67amily history of coronary

artery disease120 (41%) 2 (29%) 0.71

hest pain 110 (37%) 5 (71%) 0.11VC 8 (3%) 2 (29%) 0.02

Data presented as mean � SD or absolute number (percent).

larger study population. m

iscussion

ultiple studies have shown a strong graded relation withncreasing CAC and incident cardiovascular morbidity andortality. Conversely, the lower the CAC score, the more

avorable the prognosis.1–9 In the diabetic population, aroup with a high risk of cardiovascular events, the absencef CAC identifies a subgroup with a cardiovascular riskquivalent to that of patients without diabetes.10

Recent appropriateness guidelines and scientific state-ents recommended against the use of an MPS in patientsith a CAC score �100.11,12 The present study supports

hese guidelines, especially for those with a CAC score10. In this analysis, only 1.2% of patients with a CAC

core �10 had an abnormal myocardial stress imaging testesult, with none of the stress echocardiograms and only.3% of MPSs showing ischemia. This result comparesicely with the 1.6% frequency of an ischemic MPS resultoted by Berman et al13 in patients with no detectable CAC.n the same study, there were no ischemic MPS results inhose with a CAC score of 1 to 9 and a 2.4% frequency inhose with a CAC score of 10 to 99. In a previous study bye et al,14 there were no ischemic MPS results in patientsith a CAC score �10.Patients with obstructive heart disease with a low CAC

core are believed to represent fibrous or lipid-laden plaqueshat have yet to undergo calcification, presumably in youngemales. However, the results of this study do not supporthis notion. Compared with patients with normal perfusion,hose with an abnormal MPS result were of similar age andore likely to be male. In addition, no significant differ-

nces in self-reported hyperlipidemia, diabetes mellitus, to-acco use, hypertension, or family history of prematureeart disease were noted.

The low-risk nature of a low CAC score may not be asobust in patients with chest pain. Berman et al13 observedn increased frequency of ischemia in symptomatic versussymptomatic patients, but only in patients with a CACcore �10. In a study comparing CAC and stress echo-ardiography, there was a nonsignificant trend towardore abnormal stress echocardiographic results in pa-

ients with chest pain.15 In this study, chest pain alsohowed a favorable, but statistically insignificant, trendoward an ischemic MPS result (p � 0.11). This trenday explain the obstructive heart disease noted in symp-

omatic patients presenting to the emergency departmentespite a low CAC score.

A number of previous studies have shown an increasedisk of cardiovascular events in association withVC.16 –18 In the study by Barasch et al,16 aortic valve

clerosis was associated with a 1.13 hazard ratio of in-ident myocardial infarction. In another study by Otto etl,17 patients with aortic valve sclerosis had about a 50%ncreased risk of myocardial infarction and cardiovascu-ar death at a mean follow-up of 5 years. AVC may be aanifestation of peripheral vascular disease. The results

f this study suggest that the risk associated with AVCay also extend to patients with low CAC scores, al-

hough this association was based on a very small numberf cases. Identifying patients with low CAC scores who
ay warrant further cardiovascular risk stratification is

cct

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1537Preventive Cardiology/AV Calcium in Low CAC Patients

hallenging. The clinical utility of AVC as a cardiovas-ular risk prediction tool in this setting warrants addi-ional investigation.

1. LaMonte M, FitzGerald S, Church T, Barlow C, Radford N, Levine B,Pippin J, Gibbons L, Blair S, Nichaman M. Coronary artery calciumscore and coronary heart disease events in a large cohort of asymp-tomatic men and women. Am J Epidemiol 2005;162:1–9.

2. Taylor A, Bindeman J, Feuerstein I, Cao F, Brazaitis M, O’Malley P.Coronary calcium independently predicts incident premature coronaryheart disease over measured cardiovascular risk factors. Mean three-year outcomes in the Prospective Army Coronary Calcium (PACC)Project. J Am Coll Cardiol 2005;46:807–814.

3. Arad Y, Goodman K, Roth M, Newstein D, Guerci A. Coronarycalcification, coronary disease risk factors, C-reactive protein, andatherosclerotic cardiovascular disease events. The St. Francis HeartStudy. J Am Coll Cardiol 2005;46:158–165.

4. Greenland P, LaBree L, Azen S, Doherty T, Detrano R. Coronaryartery calcium score combined with Framingham score for risk pre-diction in asymptomatic individuals. JAMA 2004;291:210–215.

5. Kondos G, Hoff J, Sevrukov A, Daviglus M, Garside D, Devries S,Chomka E, Liu K. Electron-beam tomography coronary artery calciumand cardiac events. A 37-month follow-up of 5635 initially asymp-tomatic low-to-intermediate-risk adults. Circulation 2003;107:2571–2576.

6. Shaw L, Raggi P, Schisterman E, Berman D, Callister T. Prognosticvalue of cardiac risk factors and coronary artery calcium screening forall-cause mortality. Radiology 2003;228:826–833.

7. Keelan P, Bielak L, Ashai K, Jamjourn L, Denktas A, Rumberger J,Sheedy P, Peyser P, Schwartz R. Long-term prognostic value ofcoronary calcification detected by electron-beam computed tomogra-phy in patients undergoing coronary angiography. Circulation 2001;104:412–417.

8. Wong N, Hsu J, Detrano R, Diamond G, Eisenberg H, Gardin J.Coronary artery calcium evaluation by electron beam computed to-mography and its relation to new cardiovascular events. Am J Cardiol2000;86:495–498.

9. Arad Y, Spadaro L, Goodman K, Newstein D, Guerci A. Prediction ofcoronary events with electron beam computed tomography. J Am Coll
Cardiol 2000;36:1253–1260.
0. Raggi P, Shaw L, Berman D, Callister T. Prognostic value of coronarycalcium screening in subjects with and without diabetes. J Am CollCardiol 2004;43:1663–1669.

1. Brindis R, Douglas P, Hendel R, Peterson E, Wolk M, Allen J, PatelM, Raskin I. ACCF/ASNC appropriateness criteria for single-photonemission computed tomography myocardial perfusion imaging(SPECT MPI): a report of the American College of Cardiology Foun-dation Quality Strategic Directions Committee Appropriateness Crite-ria Working Group and the American Society of Nuclear Cardiology.J Am Coll Cardiol 2005;46:1587–1605.

2. Budoff M, Achenbach S, Blumenthal R, Carr J, Goldin J, Greenland P,Guerci A, Lima J, Rader D, Rubin G, Shaw L, Wiegers S. Assessmentof coronary artery disease by cardiac computed tomography: a scien-tific statement from the American Heart Association Committee onCardiovascular Imaging and Intervention, Council on CardiovascularRadiology and Intervention, and Committee on Cardiac Imaging,Council on Clinical Cardiology. Circulation 2006;114:1761–1791.

3. Berman D, Wong N, Gransar H, Miranda-Peats R, Dahlbeck J, HayesS, Friedman J, Kang X, Polk D, Hachamovitch R, Shaw L, RozanskiA. Relationship between stress-induced myocardial ischemia and ath-erosclerosis measured by coronary calcium tomography. J Am CollCardiol 2004;44:923–930.

4. He Z, Hedrick T, Pratt C, Verani M, Aquino V, Roberts R, MahmarianJ. Severity of coronary artery calcification by electron beam computedtomography predicts silent myocardial ischemia. Circulation 2000;101:244–251.

5. Ramakrishna G, Breen J, Mulvagh S, McCully R, Pellikka P. Rela-tionship between coronary artery calcification detected by electron-beam computed tomography and abnormal stress echocardiography.Association and prognostic implications. J Am Coll Cardiol 2006;48:2125–2131.

6. Barasch E, Gottdiener J, Larsen E, Chaves P, Newman A. Cardiovas-cular morbidity and mortality in community-dwelling elderly individ-uals with calcification of the fibrous skeleton of the base of the heartand aortosclerosis. The Cardiovascular Health Study. Am J Cardiol2006;97:1281–1286.

7. Otto C, Lind B, Kitzman D, Gersh B, Siscovick D. Association ofaortic-valve sclerosis with cardiovascular mortality and morbidity inthe elderly. N Engl J Med 1999;341:142–147.

8. Aronow W, Ahn C, Shirani J, Kronzon I. Comparison of frequency ofnew coronary events in older subjects with and without valvular aortic
sclerosis. Am J Cardiol 1999;83:599–600.

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Comparison of Rosuvastatin Versus Atorvastatin in South-AsianPatients at Risk of Coronary Heart Disease (from the IRIS Trial)

Prakash C. Deedwania, MDa,*, Milan Gupta, MDb, Michael Stein, MDc, Joseph Ycas, PhDc,and Alex Gold, MDc, for the IRIS Study Group

In a large randomized trial of statin therapy in patients of South-Asian origin withhypercholesterolemia, 740 patients in the United States and Canada received 6 weeks oftreatment with rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg. A total of 485 patients(66%) were categorized as being at high risk of coronary heart disease and had a NationalCholesterol Education Program Adult Treatment Panel III treatment goal of low-densitylipoprotein (LDL) cholesterol <100 mg/dl (<2.6 mmol/L). LDL cholesterol decreased by45% with rosuvastatin 10 mg versus 40% with atorvastatin 10 mg (p � 0.0023) and by 50%with rosuvastatin 20 mg versus 47% with atorvastatin 20 mg (p � NS). National Choles-terol Education Program Adult Treatment Panel III LDL cholesterol goal achievementrates in high-risk patients (all patients) were 76% (79%) and 88% (89%) with rosuvastatin10 and 20 mg, respectively, compared with 70% (76%) and 81% (85%) with atorvastatin 10and 20 mg, respectively. Rosuvastatin and atorvastatin were well tolerated. There were noclinically relevant differences between statins in adverse events or incidence of creatinekinase >10 times the upper limit of normal, alanine aminotransferase >3 times the upperlimit of normal on 2 consecutive occasions, or proteinuria or hematuria over the relativelyshort duration of treatment. In conclusion, statin therapy was well tolerated and effectivein decreasing LDL cholesterol in patients of South-Asian origin, with the 10- and 20-mgdoses of rosuvastatin and atorvastatin allowing most patients to reach recommended LDLcholesterol goals. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:
1538–1543)
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he importance of decreasing low-density lipoprotein (LDL)holesterol is clearly delineated in the National Cholesterolducation Program (NCEP) Adult Treatment Panel (ATP) IIIuidelines,1 and lipid reduction has become standard therapy inlmost all patients at high cardiovascular risk.2 South Asiansave been historically under-represented in clinical trials; thus,he lipid effects of statins in this specific at-risk populationemain unclear. The Investigation of Rosuvastatin In Southsians (IRIS) study therefore was conducted to evaluate the

ipid-modifying effects of rosuvastatin and atorvastatin inouth Asians with hypercholesterolemia residing in the Unitedtates and Canada.

ethods

his 6-week randomized open-label trial (4522US/0006)as conducted at 108 centers in the United States andanada. After a 6-week dietary lead-in phase during whichll lipid-lowering treatments were discontinued, eligible pa-ients were randomly assigned to 1 of 4 treatment arms

aVeterans Affairs Central California Health Care System and Univer-ity of California-San Francisco, Fresno, California; bMcMaster Universitynd William Osler Health Centre, Brampton, Ontario, Canada; andAstraZeneca, Wilmington, Delaware. Manuscript received October 4,006; revised manuscript received December 20, 2006, and accepted Jan-ary 10, 2007.

This study was sponsored by AstraZeneca, Wilmington, Delaware.*Corresponding author: Tel.: 559-228-5325; fax: 559-228-6961.

fE-mail address: [email protected] (P.C. Deedwania).


rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg) forweeks. Patients eligible for randomized treatment were

elf-described South-Asian individuals (originating fromndia, Pakistan, Bangladesh, Sri Lanka, Nepal, or Bhutan)ged �18 years with coronary heart disease (CHD) or CHDisk equivalent1 and LDL cholesterol �100 mg/dl (�2.6mol/L); or �2 risk factors, 10-year CHD risk 10% to

0%, and LDL cholesterol �130 mg/dl (�3.4 mmol/L); oror 1 risk factor and LDL cholesterol �160 mg/dl (�4.1mol/L).1

For eligibility for randomized treatment, LDL choles-erol levels had to be within 15% of each other and �300

g/dl (�7.8 mmol/L) on 2 consecutive measurements, andriglycerides had to be �500 mg/dl (�5.6 mmol/L) duringhe lead-in phase. Exclusion criteria included a history ofomozygous familial hypercholesterolemia or known type I,II, or V hyperlipoproteinemia; active arterial disease (e.g.,nstable angina, myocardial infarction, transient ischemic at-ack, cerebrovascular accident, coronary artery bypass graft-ng, or angioplasty within 3 months of entry); uncontrolledypertension; poorly controlled diabetes (hemoglobin A1c

9% or fasting glucose �180 mg/dl [�9.9 mmol/L]); ac-ive liver disease or dysfunction indicated by hepaticransaminase or bilirubin levels �2 times the upper limit oformal; unexplained serum creatine kinase level �3 timeshe upper limit of normal; and serum creatinine �2.0 mg/dl�177 �mol/L).

The primary outcome measure was percentage change
rom baseline in LDL cholesterol at 6 weeks. Secondary
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1539Preventive Cardiology/Rosuvastatin Versus Atorvastatin in South Asians

utcome measures included proportions of patients reachingCEP ATP III LDL cholesterol goals1; percentage change

rom baseline in non–high-density lipoprotein (non-HDL)holesterol, HDL cholesterol, total cholesterol, and triglyc-rides; and safety. The safety evaluation included monitor-ng adverse events; laboratory evaluation, including clinicalhemistry, hematology, and urinalysis; assessment of vitaligns; and physical examination. Adverse events were sum-arized using Medical Dictionary for Regulatory Activities

MedDRA)-preferred terms.3Analyses of all laboratory samples were performed at a

entral laboratory (Medical Research Laboratories, High-and Heights, Kentucky), as described previously.4,5 Effi-acy analyses used the intention-to-treat population (all pa-ients who received study treatment and had �1 baselineeasurement before randomization and 1 measurement af-

er baseline for �1 lipid variable) with the last observationarried forward. For the primary efficacy variable, percent-ge change in LDL cholesterol from baseline were com-ared for rosuvastatin 10 mg versus atorvastatin 10 and 20g and for rosuvastatin 20 mg versus atorvastatin 20 mg. A

oninferiority test with a 6% absolute inferiority marginas first performed for the primary efficacy variable. Com-arisons using analysis of variance were made for superi-

igure 1. (A) Patient disposition. (B) Trial design. ATV � atorvastatin;SV � rosuvastatin.

rity using a Bonferroni adjustment6 for multiple compari-

ons, with a significance level of 0.017. Analysis of varianceas used to compare changes in all other lipid variables,ith no testing for noninferiority. Proportions of patients

eaching ATP III LDL cholesterol goals were calculated,nd data were descriptively summarized. Safety data wereescriptively summarized.

esults

total of 2,373 patients entered the dietary lead-in phaseFigure 1). Of these, 740 patients were randomly assigned toreatment with rosuvastatin 10 or 20 mg or atorvastatin 10r 20 mg (Figure 1). Treatment groups were well balancedor age, gender, and CHD risk (Table 1). Patients had aean age of 56 years, and 68% were men. CHD or CHD

isk equivalent was present in 62% of patients. Diabetes wasresent in 44% of all patients, and hypertension was presentn 61%. Overall, 67% of rosuvastatin patients and 65% oftorvastatin patients were at high risk of CHD.

Data from 709 patients were analyzed for efficacy in thentention-to-treat population, and 734 patients were in-luded in the safety population. A total of 680 patients92%) completed randomized treatment (Figure 1). Of the0 discontinuing treatment (35 rosuvastatin recipients and5 atorvastatin recipients), the most common reasons foriscontinuation were adverse events (14 rosuvastatin, 7torvastatin), protocol noncompliance (11 rosuvastatin, 9torvastatin), and withdrawal of consent (8 rosuvastatin,atorvastatin).Baseline lipid levels and lipid ratios and changes at 6 weeks

re shown in Figure 2 and Table 2. After 6 weeks, LDLholesterol decreased significantly more with rosuvastatin 10g than with atorvastatin 10 mg (p � 0.0023). The decrease

n LDL cholesterol with rosuvastatin 20 mg was not statis-ically different from the decrease with atorvastatin 20 mgFigure 2).

Rosuvastatin 10 mg produced a significantly greater de-rease in non-HDL cholesterol compared with atorvastatin0 mg (Figure 2). HDL cholesterol increased from baseline,ith no significant differences observed between treatmentroups (Figure 2). Apolipoprotein A-I increased from base-ine for patients using both doses of rosuvastatin and ator-astatin 10 mg, but increased very little for those usingtorvastatin 20 mg, leading to a significant difference be-ween rosuvastatin 10 mg and atorvastatin 20 mg (Figure 2).he lower level of apolipoprotein A-I response with ator-astatin 20 mg is consistent with the lower HDL cholesterolesponse with the same dose of atorvastatin (Figure 2). Noifferences between the 10-mg groups or between the0-mg groups were observed with respect to decreases inotal cholesterol or triglycerides.

In diabetic patients, mean LDL cholesterol lowering withosuvastatin 10 mg (n � 72) was 46%, whereas LDL cho-esterol lowering with atorvastatin 10 mg (n � 86) was9%. Using rosuvastatin 20 mg (n � 75), LDL cholesterolecrease was 50%, and using atorvastatin 20 mg (n � 77),he decrease was 47%. These LDL cholesterol responses iniabetic patients were within 1% of the decreases seen in theverall intention-to-treat population for each treatment armFigure 2).

Most patients in all treatment groups reached ATP III

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DL cholesterol goals (79% and 89% with rosuvastatin 10nd 20 mg, respectively, 76% and 85% with atorvastatin 10nd 20 mg, respectively). Rosuvastatin brought 76% to 88%f high-risk patients to the LDL cholesterol goal of �100g/dl (�2.6 mmol/L; Figure 3). After this study was

tarted, an updated ATP III treatment algorithm for “very-igh-risk” patients with established cardiovascular diseaselus multiple, severe, or poorly controlled risk factors sug-ested an optional, very aggressive LDL cholesterol goal of70 mg/dl (�1.8 mmol/L).7 Targets in this range are also

able 1emographics and baseline characteristics

ariable Rosuvastatin 10 mg(n � 189)

R

ge (yrs) 56.8 � 11.4en/women 121 (64%)/68 (36%) 13ody mass index (kg/m2) 27.0 � 4.0�30 35 (19%)HD/CHD risk equivalent 118 (62%)iabetes mellitus 75 (40%)ypertension 121 (64%)CEP ATP III risk categoriesHigh 125 (66%)Medium 51 (27%)Low 13 (7%)

Values expressed as mean � SD or number (percent).

igure 2. Least-squares (LS) mean percentage of change from baseline in por noninferiority of rosuvastatin 10 mg versus atorvastatin 20 mg showedpper limit of 6.0%; (B) non-HDL cholesterol (non-HDL-C); (C) HDL ch

eing considered for general high-risk patients. An explor- (

tory analysis of high-risk patients in this study found that2% and 56% reached this goal at 6 weeks with rosuvastatin0 and 20 mg compared with 18% and 42% with atorva-tatin 10 and 20 mg, respectively (Figure 3).

All treatments were well tolerated, as shown by dataisted in Table 3. The most common adverse events overallere myalgia (3%), constipation (2%), headache (2%), as-

henia (1%), and arthralgia (1%). Discontinuation due toreatment-related adverse events was rare, occurring in 9osuvastatin recipients (2.4%) and 3 atorvastatin recipients

atin 20 mg182)

Atorvastatin 10 mg(n � 185)


� 10.9 55.8 � 11.1 55.2 � 10.6)/46 (25%) 125 (68%)/60 (32%) 120 (65%)/64 (35%)� 4.0 27.5 � 4.3 27.0 � 4.5(20%) 40 (22%) 33 (18%)(65%) 109 (59%) 116 (63%)(44%) 87 (47%) 82 (45%)(61%) 112 (61%) 104 (57%)

(67%) 114 (62%) 124 (67%)(20%) 55 (30%) 42 (23%)(13%) 16 (9%) 18 (10%)

and secondary end points at 6 weeks. (A) LDL cholesterol (LDL-C): a test% confidence interval of �2.0% to 6.1%, which missed the prespecified

ol; and (D) apolipoprotein A-I (Apo A-I). Abbreviations as in Figure 1.

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o study treatments. One rosuvastatin-treated patient diedrom postsurgical multisystem organ failure, and 1 atorva-tatin patient died from myocardial infarction. Neither deathas considered related to study treatment. No patient had an

ncrease in alanine aminotransferase �3 times the upperimit of normal on 2 consecutive occasions. One atorvasta-in patient had an increase in serum creatine kinase �10imes the upper limit of normal that was not accompanied byuscle symptoms. Two atorvastatin patients had increases in

rine protein from none or trace at baseline to �2�. Renalailure was reported by an investigator for 1 patient receivingtorvastatin 20 mg, but the patient recovered and was notithdrawn from the study. This adverse event was not consid-

red related to study treatment. Central laboratory resultshowed that no patient had a doubling of serum creatinineevel. No case of rhabdomyolysis was observed.

iscussion

RIS is the first large-scale randomized lipid-lowering trialn an exclusively South-Asian population in North America.

any persons of South-Asian origin are candidates fortatin treatment according to NCEP ATP III guidelines.1his trial shows that statin treatment is effective in decreas-

ng LDL cholesterol in South-Asian patients with hypercho-esterolemia. After 6 weeks of treatment with rosuvastatinr atorvastatin 10 or 20 mg, most patients achieved ATP III

igure 3. Proportions of high-risk patients (CHD, CHD risk equivalent [clin-cal forms of atherosclerotic disease, diabetes], or 10-year risk for CHD

20%) who reached (A) ATP III LDL cholesterol goal of �100 mg/dl (�2.6mol/L) at 6 weeks and (B) the optional ATP III LDL cholesterol goal of �70

s

vastatin 20 mg(n � 171)



31, 6.03 � 0.80 241 � 37, 6.23 � 0.96 237 � 34, 6.13 � 0.88�35 � 1 �28 � 1 �33 � 1

61, 1.98 � 0.69 196 � 79, 2.21 � 0.89 187 � 71, 2.11 � 0.80�22 � 2 �20 � 2 �19 � 2

23, 1.46 � 0.23 154 � 28, 1.54 � 0.28 150 � 27, 1.50 � 0.27�38 � 1 �30 � 1 �37 � 1

3.5 � 0.8 3.8 � 1.0 3.7 � 1.1�52 � 1 �43 � 1 �49 � 1

5.4 � 1.1 5.8 � 1.3 5.6 � 1.4�38 � 1 �33 � 1 �36 � 1

4.4 � 1.1 4.8 � 1.3 4.6 � 1.4�47 � 1 �40 � 1 �44 � 1

1.0 � 0.2 1.1 � 0.3 1.1 � 0.3�39 � 1 �32 � 1 �37 � 1

able 2aseline lipid levels and least-squares mean (LSM) percentage change at 6 week

Rosuvastatin 10 mg(n � 183)

Rosu

otal cholesterolBaseline, mg/dl, mmol/L (mean � SD) 237 � 37, 6.13 � 0.96 233 �LSM % change (�SE) �31 � 1riglyceridesBaseline, mg/dl, mmol/L (mean � SD) 184 � 72, 2.07 � 0.81 175 �LSM % change (�SE) �19 � 2polipoprotein BBaseline, mg/dl, mmol/L (mean � SD) 151 � 29, 1.51 � 0.29 146 �LSM % change (�SE) �34 � 1DL cholesterol/HDL cholesterolBaseline, (mean � SD) 3.7 � 1.0LSM % change (�SE) �48 � 1*otal cholesterol/HDL cholesterolBaseline, (mean � SD) 5.6 � 1.3LSM % change (�SE) �35 � 1on-HDL cholesterol/HDL cholesterolBaseline, (mean � SD) 4.6 � 1.3LSM % change (�SE) �43 � 1polipoprotein B/apolipoprotein A-IBaseline, (mean � SD) 1.1 � 0.3LSM % change (�SE) �36 � 1

g/dl (�1.8 mmol/L) at 6 weeks. Abbreviations as in Figure 2.

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DL cholesterol target levels, including most of those at highisk of CHD. Rosuvastatin treatment brought 76% to 88% ofigh-risk patients in this trial to the NCEP ATP III LDLholesterol goal for high-risk patients of �100 mg/dl (�2.6mol/L). Rosuvastatin 10 mg decreased LDL and non-HDL

holesterol to a significantly greater extent than atorvastatin 10g (p � 0.0023 and p � 0.0124, respectively).South Asians appear to be at heightened risk of CHD.

ase–control studies suggest that South Asians, particularlyhose living in urban settings, experience a 50% to 100%igher risk of dying from CHD compared with Caucasianopulations.8,9 The prevalence of and mortality associatedith this disease are also increased in the estimated 3.5illion South Asians in North America.10–12 NCEP ATP III

uidelines emphasize the importance of decreasing choles-erol in South Asians.1 The Canadian Cardiovascular Societyecommended a stronger target for high-risk patients of LDLholesterol �2.0 mmol/L (�77 mg/dl).13 Figure 3 indicateshat rosuvastatin and atorvastatin can help South Asians meetggressive lipid goals set by these guidelines.

Results of the IRIS trial add to the information obtainedrom the trials, which studied African-American and His-anic-American populations, respectively.14,15 These 3 tri-ls, conducted in populations that have been historicallynder-represented in clinical trials, provided data regardinghe safety and effectiveness of statin regimens in decreasingDL cholesterol and improving other lipid measures inthnically diverse populations who are increasingly recog-ized as at risk of CHD.

Results of IRIS showed that rosuvastatin 10 and 20 mgave efficacy in decreasing LDL, non-HDL, and total cho-esterol, similar to that seen in trials of other populations.4owever, in this South-Asian population, there was not a

ignificantly greater differential response to rosuvastatin 10r 20 mg compared with atorvastatin 20 mg. These dataighlight the value of examining therapeutic responses inifferent populations. These data also indicate the need forurther research to confirm and understand possible differ-nces. A consistent feature of comparative trials of otheropulations studied to date was that rosuvastatin in doses of0 to 40 mg produced significantly larger decreases in LDLholesterol than atorvastatin.4,5,14,15 Our findings indicatehat therapy with rosuvastatin or atorvastatin is well toler-ted and effective in decreasing LDL cholesterol in hyper-holesterolemic patients of South-Asian origin, and no newafety concerns were identified in this patient populationuring 6 weeks of statin therapy.

cknowlegment: We gratefully acknowledge the investi-

able 3dverse event categories

Rosuvastatin 10 mg(n � 189)

ny adverse event 57 (30%)dverse event leading to death 0 (0%)dverse event leading to discontinuation 6 (3.2%)erious adverse event 1 (0.5%)

ators (see Appendix), their co-investigators, and study co- M

rdinators, and the patients who participated in this trial. Welso thank BioScience Communications of New York, Nework, which provided editorial assistance on behalf of As-

raZeneca, Wilmington, Delaware.

ppendix

he following investigators participated in the IRIS trial andonstituted the IRIS Study Group:

United States: Nicola Abate, MD, Dallas, TX; Kulhushan Aggarwal, MD, Columbia, MO; Aman Amanul-

ah, MD, Philadelphia, PA; Mahesh Amin, MD, Clearwater,L; Jayendra S. Amin, MD, Tustin, CA; Nabil S. Andrawis,D, Burke, VA; Samir Arora, MD, Columbus, OH; Mo-

ammed Ashraf, MD, Madera, CA; George Bakris, MD,hicago, IL; Bhola N. Banik, MD, Plainview, NY; Steven. Belt, MD, West Orange, NJ; Robert Edward Benton,D, Troy, NY; Rupinder S. Brar, MD, Yuba City, CA;

racy Brobyn, MD, Cherry Hill, NJ; Daniel E. Buffington,harmD, Tampa, FL; Robert Burton, MD, Anaheim, CA;hiayu Chen, MD, Riverside, CA; Jacob Cherian, MD,olumbia, MD; Jatinder Chopra, MD, Tulare, CA; Frankole, MD, Fayetteville, GA; Harry Collins, MD, Edison,J; Kamlesh N. Dave, MD, Hopewell, VA; Bakul Desai,D, Jersey City, NJ; Gurmej S. Dhillon, MD, Fresno, CA;arwan Edris, MD, Mission Viejo, CA; Ira Jay Goldberg,D, New York, NY; Bruce Gordon, MD, New York, NY;mbrish Gupta, MD, Arlington, VA; Anjan Gupta, MD,ilwaukee, WI; Narendra K. Gupta, MD, Duluth, GA;

etsuo Ishimori, MD, Bakersfield, CA; Prahalad B. Jajodia,D, Fresno, CA; Romesh Japra, MD, Freemont, CA; John. Joseph, MD, Carrollton, TX; Basant K. Khandelwal,D, Glen Burnie, MD; Akther Kotha, MD, San Diego, CA;

urushotham Kotha, MD, San Diego, CA; Christian An-rew Paul Kovats, DO, Oviedo, FL; Mahesh P. Krishnan,D, Fairfax, VA; Rita R. Kumar, MD, Culver City, CA;

harad Lakhanpal, MD, Dallas, TX; Jagat Mehta, MD,ochester, NY; Nicholas H.E. Mezitis, MD, New York,Y; Rupa Mongia, MD, Princeton, NJ; Sandip K. Mukher-

ee, MD, Guliford, CT; Mani Nallasivan, MD, Merced, CA;uneet Narayan, MD, Burke, VA; Parimal Parikh, MD,ew Orleans, LA; Jyotin Patel, MD, Languna Niguel, CA;eenakshi Patel, MD, Centerville, OH; Rajesh J. Patel,D, Jersey Shore, PA; Monica Perlman, MD, La Jolla, CA;achakonda Prabhu, MD, Dallas, TX; Nalini Grace Prem-

ingh, MD, Kansas City, KS; Krishna Pudi, MD, Simpson-ille, SC; Marina Raikhel, MD, Torrance, CA; K.B. Ra-anathan, MD, Germantown, TN; Manfred Ramos, MD,ew York, NY; Satti Sethu-Kumar Reddy, MD, Cleveland,H; Jane L. Rohlf, MD, Trenton, NJ; Mohammed Saad,

suvastatin 20 mg(n � 179)



55 (31%) 48 (26%) 55 (30%)1 (0.6%) 1 (0.5%) 0 (0%)8 (4.5%) 2 (1.1%) 5 (2.7%)2 (1.1%) 2 (1.1%) 1 (0.5%)

Ro

D, Alhambra, CA; Gilbert R. Salazar, MD, San Antonio,

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X; Smita N. Sampat, MD, Parsipanny, NJ; Joseph Sapon-ro, MD, Jupiter, FL; Charles L. Schulman, MD, Brookline,A; Barry Seidman, MD, Delray Beach, FL; Mahesh P.

hah, MD, Prince Frederick, MD; Jeffery G. Shanes, MD,elrose Park, IL; Brahma N. Sharma, MD, Pittsburg, PA;akesh K. Sharma, MD, Clearwater, FL; Manvinder Singh,D, Westmont, IL; Narendra Singh, MD, Atlanta, GA;ibhuti N. Singh, MD, St. Petersburg, FL; Stevan A. Smal-

ow, MD, Bensalem, PA; Stephen R. Smith, MD, Balti-ore, MD; Wally R. Smith, MD, Richmond, VA; Dannyugimoto, MD, Chicago, IL; D.P. Suresh, MD, Cincinnati,H; Satinder Swarooop, MD, Fountain Valley, CA; Mark. Vacker, MD, Davie, FL; Kris Vijayaraghavan, MD,cottsdale, AZ; Mark J. Weinstein, MD, Lawrenceville, NJ;ames H. West, MD, Roswell, GA.

Canada: Darryl Ableman, MD, Coquitlam, BC; Nareshggarwal, MD, Brampton, ON; Ronald Akhras, MD, Mon-

real, PQ; Arvinder Grover, MD, Mississauga, ON; Anilupta, MD, Brampton, ON; Anil Gupta, MD, Toronto, ON;nup Gupta, MD, Toronto, ON; Milan Gupta, MD, Bramp-

on, ON; Subodh Kanani, MD, Mississauga, ON; Paul Kan-ampuzha, MD, Mississauga, ON; Naresh Kumar, MD,hitby, ON; Kieth Kwok, MD, Etobicoke, ON; Akbar V.A.

alani, MD, New Westminster, BC, Tse Li Luk, MD, Win-ipeg, MB, Jamuna Makhija, MD, Vancouver, BC; Manishaingi, MD, Mississauga, ON; Pravinsagar Mehta, MD,innipeg, MB; Adi K. Mudaliar, MD, Vancouver, BC;shok Mukherjee, MD, Scarborough, ON; Shah Nawaz,D, Sudbury, ON; Tamara Nguyen, MD, Westmount, PQ;. Shekhar Pandey, MD, Cambridge, ON; Deepti Pasricha,D, Markham, ON; Nouhad Saliba, MD, Montreal, PQ;

alima Shariff, MD, Surrey, BC; Parmjit Sohal, MD, Sur-ey, BC; Tariq Vakani, MD, Burlington, ON.

1. National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III). Third Report of the Expert Panelon National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421.

2. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C,Kirby A, Sourjina T, Peto R, Collins R, Simes R, for the Cholesterol
Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cho-
lesterol-lowering treatment: prospective meta-analysis of data from90,056 participants in 14 randomised trials of statins. Lancet2005;366:1267–1278.

3. Maintenance and Support Services Organization (MSSO) of the Inter-national Federation of Pharmaceutical Manufacturers and Associations(IFPMA) acting as trustee for the International Conference on Har-monisation (ICH) Steering Committee. Medical Dictionary for Regu-latory Activities. Available at: http:www.meddramsso.com/mssoweb/index.htm. Accessed August 24, 2006.

4. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, MillerE, Cain VA, Blasetto JW, for the STELLAR Study Group. Compari-son of the efficacy and safety of rosuvastatin versus atorvastatin,simvastatin, and pravastatin across doses (STELLAR trial). Am JCardiol 2003;92:152–160.

5. Steiner P, Freidel J, Bremmer W, Stein E. Standardization of micro-methods for plasma cholesterol, triglyceride and HDL-cholesterol withthe Lipid Research Clinics’ methodology [abstract]. J Clin ChemBiochem 1981;19:850–851.

6. Miller RG Jr. Simultaneous Statistical Inference. 2nd Ed. New York,New York: Springer-Verlag, 1981.

7. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hun-ninghake DB, Pasternak RC, Smith SC Jr, Stone NJ, for the Coordi-nating Committee of the National Cholesterol Education Program.Implications of recent clinical trials for the National Cholesterol Ed-ucation Program Adult Treatment Panel III guidelines. Circulation2004;110:227–239.

8. Deedwania PC, Gupta R. Prevention of coronary heart disease in Asianpopulations. In: Wong ND, ed. Preventive Cardiology. New York,New York: McGraw-Hill, 2000:503–516.

9. Gupta M, Singh N, Verma S. South Asians and cardiovascular risk:what clinicians should know. Circulation 2006;113:e924–e929.

0. Gupta M, Brister S. Is South Asian ethnicity an independent cardio-vascular risk factor? Can J Cardiol 2006;22:193–197.

1. US Census Bureau. Census 2000; search term “Asian.” Available at:http://www.census.gov. Accessed August 24, 2006.

2. Statistics Canada, 2001. Search term “South Asian.” Available at:http://www40.statcan.ca. Accessed August 24, 2006.

3. McPherson R, Frohlich J, Fodor G, Genest J. Canadian CardiovascularSociety position statement—recommendations for the diagnosis andtreatment of dyslipidemia and prevention of cardiovascular disease.Can J Cardiol 2006;22:913–927.

4. Ferdinand KC, Clark LT, Watson KE, Neal RC, Brown CD, KongBW, Barnes BO, Cox WR, Zieve FJ, Isaacsohn J, et al, for the ARIESStudy Group. Comparison of efficacy and safety of rosuvastatin versusatorvastatin in African-American patients in a six-week trial. Am JCardiol 2006;97:229–235.

5. Lloret R, Ycas J, Stein M, Haffner S, for the STARSHIP Study Group.Comparison of rosuvastatin versus atorvastatin in Hispanic-Americanswith hypercholesterolemia from the STARSHIP trial. Am J Cardiol
2006;98:768–773.
http://www.meddramsso.com/mssoweb/index.htm

http://www.meddramsso.com/mssoweb/index.htm

http://www.census.gov

http://www40.statcan.ca

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Effect of Candesartan and Various Inflammatory Markerson Maintenance of Sinus Rhythm After Electrical

Cardioversion for Atrial Fibrillation

Arnljot Tveit, MDa,*, Ingebjørg Seljeflot, PhDb, Irene Grundvold, MDc, Michael Abdelnoor, PhDb,Pal Smith, MD, PhDa, and Harald Arnesen, MD, PhDb,c

Inflammatory markers, their relation to maintenance of sinus rhythm after electricalcardioversion for atrial fibrillation (AF), and the effect of candesartan were investigated ina double-blind placebo-controlled study (CAPRAF). One hundred seventy-one patientswith persistent AF were randomly assigned to receive candesartan 8 mg/day or placebo for3 to 6 weeks before and candesartan 16 mg/day or placebo for 6 months after electricalcardioversion. Serum levels of high-sensitivity C-reactive protein (hs-CRP), tumor necrosisfactor-�, interleukin-6, P-selectin, E-selectin, CD-40 ligand, and vascular cell adhesionmolecule-1 were measured at baseline and end of study. Compared with patients with arelapse of AF, patients still in sinus rhythm at 6 months after cardioversion (n � 40) hadlower baseline hs-CRP and E-selectin levels: median 2.36 mg/L (25th, 75th percentiles 1.28,4.09) versus 3.44 mg/L (25th, 75th percentiles 1.66, 6.05, p � 0.031) and 32 ng/ml (25th,75th percentiles 23, 42) versus 37 ng/ml (25th, 75th percentiles 28, 51, p � 0.042),respectively. Neither sustained sinus rhythm for 6 months nor treatment with candesartan hadan impact on measured concentrations of markers of inflammation. In conclusion, low hs-CRPand E-selectin at baseline were associated with maintenance of sinus rhythm after electrical
cardioversion. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1544–1548)
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reatment with angiotensin-converting enzyme inhibitors orngiotensin receptor blockers was shown to decrease thencidence of atrial fibrillation (AF) in hypertensive pa-ients1,2 and those with left ventricular dysfunction.3–5 An-iotensin II may induce vascular inflammation througheveral mechanisms,6,7 and treatment with angiotensin-con-erting enzyme inhibitors and angiotensin receptor blockersas associated with a decrease in inflammatory markers inatients with hypertension and coronary artery disease.8–11

hus, the preventive effects of angiotensin receptor block-rs against AF could be mediated by attenuated inflamma-ion in the cardiac wall. The present study is a prespecifiedubset analysis of the Candesartan in the Prevention ofelapsing Atrial Fibrillation (CAPRAF) Study.12 Briefly,71 patients undergoing planned electrical cardioversion forersistent AF were randomly assigned to receive candesar-an 8 mg/day (n � 86) or matching placebo (n � 85) for 3o 6 weeks before and candesartan 16 mg/day or placebo for

months after electrical cardioversion (Figure 1). We hy-othesized that (1) lower levels of inflammatory markers at

aDepartment of Internal Medicine, Asker & Baerum Hospital, Rud;Center for Clinical Research and cDepartment of Cardiology, Ullevalniversity Hospital, Oslo, Norway. Manuscript received October 19, 2006;

evised manuscript received and accepted January 10, 2007.This study was sponsored by the Regional Health Corporation of

astern Norway, Hamar, and the Medical Research Foundation, Asker &aerum Hospital, Rud, Norway. AstraZeneca, Molndal, Sweden, provided

he study medication, and AstraZeneca, Oslo, Norway, supported the studyith a grant to cover laboratory analyses.

*Corresponding author: Tel.: 47-971-71-773; fax: 47-67-55-0993.
lE-mail address: [email protected] (A. Tveit).

aseline predict maintenance of sinus rhythm after electricalardioversion, (2) maintenance of sinus rhythm is associ-ted with a decrease in inflammatory marker levels, and (3)reatment with candesartan decreases inflammatory markerevels compared with placebo.

ethods

ll patients provided written informed consent in accor-ance with the revised Declaration of Helsinki before en-ollment. The study was approved by the Regional Ethicsommittee and the Norwegian Medicines Agency and reg-

stered at the Website www.clinicaltrials.gov.Blood samples for analysis of inflammatory markers

ere available at baseline for 168 patients and at end oftudy for 91 patients (Figure 1). Patients who experiencedecurrence of AF during 6 months of follow-up had theirlood sample drawn at that time. Venous blood samplesere drawn between 8 and 9 A.M. after an overnight fast.erum was prepared within 1 hour by centrifugation at,000g at room temperature for 15 minutes. Blood wasollected and stored on ice until platelet-poor plasma wasbtained within 30 minutes using centrifugation at 2,000gor 20 minutes. All samples were kept frozen at �70°C untilnalyzed. Vascular cell adhesion molecule-1 (VCAM-1),-selectin, P-selectin, tumor necrosis factor-� (TNF-�), in-

erleukin-6 (IL-6), and CD40 ligand were analyzed usingommercial enzyme-linked immunosorbent assay methodsR&D System, Abingdon, Oxon, United Kingdom), as wasigh-sensitivity C-reactive protein (hs-CRP, DRG Diagnos-ics, DRG Instruments GmbH, Marburg, Germany). P-Se-
ectin was measured in citrated plasma, and CD40 ligand, in
www.AJConline.org

http://www.clinicaltrials.gov

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1545Arrythmias and Conduction Disturbances/Candesartan, Inflammation, and Atrial Fibrillation

thylenediaminetetraacetic acid plasma. Otherwise, serumas used. Interassay coefficients of variation were 5.2% forCAM-1, 5.3% for E-selectin, 7.2% for P-selectin, 8.5%

or TNF-�, 10.7% for IL-6, 9.7% for CD40 ligand, and5% for hs-CRP.Data are expressed as mean � SD for normally distrib-

ted continuous variables and median (25th, 75th percen-iles) for continuous variables that are not normally distrib-ted. Categorical variables are presented as frequenciespercent). Continuous variables were examined for statisti-al significance using Student’s t test or Mann-Whitney Uest, depending on distribution. Categorical data were com-ared using chi-square test or Fisher’s exact test whenppropriate. The impact of continuous clinical variablesn inflammatory variables was analyzed using bivariateonparametric correlations (Spearman’s correlation coef-cient denoted rs). Wilcoxon’s matched-pairs test wassed to compare baseline and end-of-study levels ofnflammatory markers. Effect of treatment with candesar-an and rhythm outcome on inflammatory markers werenalyzed using the Mann-Whitney U test comparinghange from baseline to end of study relative to baselineevels. Kaplan-Meier survival curves for hs-CRP and-selectin quartiles were compared using log-rank test.ox regression models including potential confounding

actors were used to investigate whether hs-CRP and

igure 1. Flowchart of the CAPRAF Study. Numbers in parenthesis are theumber of patients at each stage for whom blood samples were available.R � sinus rhythm.

-selectin quartiles were independent predictors of AF o

ecurrence. In Kaplan-Meier survival analysis and Coxegression models, unsuccessful cardioversion was codeds a recurrence of AF with 0 days’ duration of sinushythm. A two-tailed p value �0.05 was considered sig-ificant. SPSS 12.0.1 software (SPSS Inc, Chicago, Illi-ois) was used for statistical calculations.

esults

atient profiles are listed in Table 1. Duration of AF beforeandomization was unknown in 95 patients (56%) andnown in 76 patients (40 in the candesartan group, 36 in thelacebo group, median 11 and 10 weeks, respectively).

IL-6 levels were significantly higher in patients withypertension and/or coronary heart disease than patientsithout these conditions (p � 0.001). There was also a

endency toward higher E-selectin levels in patients with hy-ertension and/or coronary heart disease (p � 0.082), whereas

able 1aseline characteristics of the study population (n � 171)

ariable

ge (yrs) 64 � 11omen/men 39/132

ody mass index (kg/m2) 26 � 4ypertension 51 (29.8%)oronary heart disease 16 (9.4%)iabetes mellitus 12 (7.0%)hronic obstructive pulmonary disease 12 (7.0%)urrent cigarette smoking 25 (14.6%)edications used

Digitoxin 22 (12.9%)� blockers 62 (36.3%)Verapamil 59 (34.5%)Other calcium channel blocker 18 (10.5%)Diuretics 17 (9.9%)Statins 23 (13.5%)ystolic blood pressure (mm Hg) 134 � 17iastolic blood pressure (mm Hg) 83 � 9eart rate (beats/min) 85 � 16eft atrial diameter (long axis view, mm) 46.2 � 5.5eft atrial area (apical 4-chamber view, cm2) 27.0 � 5.2ractional shortening (%) 29.9 � 7.3

Values presented as mean � SD or number (percent).

able 2aseline levels of inflammatory variables and cardiovascular disease

ariable Hypertensionand/or Coronary

Heart Disease(n � 58)

No Hypertensionor Coronary

Heart Disease(n � 110)

p Value

NF-� (pg/ml) 1.94 (1.51, 2.62) 1.74 (1.34, 2.45) 0.138L-6 (pg/ml) 3.86 (2.48, 6.05) 2.53 (1.58, 4.14) 0.001s-CRP (mg/L) 3.07 (1.54, 6.10) 3.00 (1.48, 4.95) 0.466D40 ligand (pg/ml) 193 (119, 484) 208 (106, 473) 0.949-selectin (ng/ml) 36.6 (27.3, 44.9) 34.9 (29.1, 42.3) 0.656CAM-1 (ng/ml) 708 (520, 865) 636 (516, 840) 0.507-Selectin (ng/ml) 40 (29, 53) 34 (27, 45) 0.082

Values presented as median (25th; 75th percentiles). p Value indicatesignificance for the difference between groups.

ther markers were not significantly different (Table 2).

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Statistically significant correlations were found betweenge and IL-6 (rs � 0.359, p �0.001), hs-CRP (rs � 0.167,� 0.031), and VCAM-1 (rs � 0.170, p � 0.028). Fur-

hermore, there were significant correlations between E-electin and TNF-� (rs � 0.259, p � 0.001), hs-CRP (rs �.165, p � 0.033), P-selectin (rs � 0.301, p �0.001), andCAM-1 (rs � 0.203, p � 0.008). There was also a weak

orrelation between E-selectin and IL-6 that was not statis-ically significant (rs � 0.133, p � 0.087).

Patients still in sinus rhythm 6 months after electricalardioversion (n � 40) were compared with patients withither unsuccessful cardioversion or a relapse of AF (n �13). hs-CRP and E-selectin levels were significantly lowern patients still in sinus rhythm at 6 months after cardiover-ion. There was also a tendency toward lower P-selectinevels in patients remaining in sinus rhythm (p � 0.080).aseline TNF-�, Il-6, CD40 ligand, and VCAM-1 levelsere not statistically different between patients who did andid not remain in sinus rhythm (Table 3).

Kaplan-Meier survival analysis of hs-CRP quartileshowed that risk of AF recurrence was similar in the 3owest quartiles, whereas a significantly higher relapse

igure 2. Kaplan-Meier curves of the probability of survival free of AF.ighest quartile of hs-CRP versus the 3 lowest quartiles. EC � electrical

ardioversion.

able 3aseline levels of inflammatory variables versus rhythm outcome

ariable Sinus Rhythmat 6 mo(n � 40)

UnsuccessfulCardioversion orAF Recurrence

(n � 113)

p Value

NF-� (pg/ml) 1.78 (1.35, 2.80) 1.86 (1.43, 2.53) 0.773L-6 (pg/ml) 3.27 (2.00, 5.24) 2.77 (1.99, 4.81) 0.627s-CRP (mg/L) 2.36 (1.28, 4.09) 3.44 (1.66, 6.05) 0.031D40 ligand (pg/ml) 188 (110, 583) 214 (112, 532) 0.934-selectin (ng/ml) 31.5 (25.6, 41.2) 35.6 (29.4, 42.8) 0.080CAM-1 (ng/ml) 628 (494, 840) 659 (522, 848) 0.689-selectin (ng/ml) 32 (23, 42) 37 (28, 51) 0.042

Values presented as median (25th, 75th percentiles). p Value indicatesignificance for the difference between groups.

robability was found in patients with hs-CRP levels in the e

ighest quartile, corresponding to hs-CRP �5.22 mg/L (p �.028; Figure 2). Adjusting for age as a potential con-ounder in a Cox regression model, highest quartile hs-CRPas found to be an independent predictor of recurrence with aR of 1.6 (95% confidence interval [CI] 1.1 to 2.4, p � 0.027).

Similarly, patients with E-selectin levels in the highestuartile (corresponding to E-selectin �47 ng/ml) had aigher relapse probability compared with the lower 3 quar-iles (p � 0.073; Figure 3). Adjusting for age and theresence of hypertension or coronary heart disease, theighest quartile of E-selectin was found to be border-ine significant as an independent predictor of AF recur-ence with a RR of 1.5 (95% CI 1.0 to 2.3, p � 0.060).

Blood samples for inflammatory marker measurementere available at baseline and end of study for 38 patientsho maintained sinus rhythm during 6 months’ follow-up

nd 53 patients with a relapse of AF. In the latter group,edian duration of sinus rhythm after electrical cardiover-

ion was 8 days (25th, 75th percentiles 7, 11). Medianalues for all markers were unchanged after 6 months ininus rhythm, except for TNF-�, which decreased slightlyTable 4). However, TNF-� levels were also lower at end oftudy in patients with recurrence of AF, and relativehanges from baseline to end of study were not significantlyifferent between patients in sinus rhythm and patients withrelapse of AF.Inflammatory marker values were available at baseline

nd end of study for 40 patients in the candesartan groupnd 51 in the placebo group. Baseline values, end-of-studyalues, and relative changes from baseline were compared.rrespective of outcome after cardioversion, there were notatistically significant differences between the candesartannd placebo groups for any of the inflammatory markersnalyzed (data not shown).

iscussion

his study shows that higher hs-CRP and E-selectin levelst baseline were associated with recurrence of AF after

igure 3. Kaplan-Meier curves of the probability of survival free of AF.ighest quartile of E-selectin versus the 3 lowest quartiles. Abbreviation as

n Figure 2.

lectrical cardioversion, whereas maintenance of sinus

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1547Arrythmias and Conduction Disturbances/Candesartan, Inflammation, and Atrial Fibrillation

hythm for 6 months per se was not associated with aecrease in inflammatory marker levels. Finally, treatmentith candesartan did not decrease inflammatory marker

evels compared with placebo.At baseline, patients with hypertension and/or coronary

eart disease had significantly higher IL-6 and a tendencyoward higher E-selectin levels than patients without theseonditions. No such difference was seen for the other mark-rs analyzed.

High levels of 2 inflammatory markers measured beforeardioversion were associated with a higher recurrence ratef AF in this study, namely,. hs-CRP and E-selectin. Otherarkers were not related to rhythm outcome, with the pos-

ible exception of P-selectin. Kaplan-Meier survival analy-is of hs-CRP levels showed a significantly higher relapserobability in patients with hs-CRP levels in the highestuartile compared with the other quartiles. The same patternas found for E-selectin, which was not statistically signif-

cant. Adjusting for potential confounding factors, the high-st quartile of hs-CRP and, to a lesser degree, E-selectinere shown to be independent risk factors for AF recur-

ence, with RRs of 1.6 and 1.5, respectively.Thus, of the different inflammatory markers investigated

n our study, hs-CRP was the one most significantly relatedo rhythm outcome, whereas IL-6 was related more to con-omitant cardiovascular disease. The link between CRP andF is poorly understood. hs-CRP levels may reflect only

ystemic inflammation; however, CRP itself also washown to induce endothelial and smooth muscle cell prolif-ration, affect endothelial function, and induce the produc-ion of cell adhesion molecules.13 Thus, there may be aausal role of the CRP molecule in the local inflammatoryrocesses and structural remodeling of the atrial wall duringF. Baseline E-selectin levels were also significantly higher

n patients who experienced a relapse of AF compared withatients remaining in sinus rhythm. E-Selectin is an endo-helial cell–specific adhesion molecule, and increased cir-ulating levels of this marker are suggested to reflect endo-helial activation or dysfunction. Thus, not only degree ofnflammation, but also endothelial activation (or dysfunc-ion) is associated with rhythm outcome after electricalardioversion for persistent AF.

Restoration and maintenance of sinus rhythm for 6onths after electrical cardioversion for AF had no effect

able 4arkers of inflammation at baseline and 6 months’ follow-up

ariable Patients Remaining in Sinus Rhyt(n � 38)

Baseline End of Study

NF-� (pg/ml) 1.78 (1.36, 2.81) 1.63 (1.24, 2.43)L-6 (pg/ml) 3.27 (2.06, 5.09) 2.57 (1.70, 4.98)s-CRP (mg/L) 2.36 (1.37, 4.30) 2.10 (1.26, 3.40)D40 ligand (pg/ml) 172 (107, 608) 187 (110, 425)-Selectin (ng/ml) 31.9 (26.0, 42.4) 32.8 (27.1, 43.0)CAM-1 (ng/ml) 636 (517, 860) 689 (545, 950)-Selectin (ng/ml) 32 (23, 41) 33 (24, 44)

Values presented as median (25th, 75th percentiles).p Value indicates significance of the difference between baseline and e

n markers of inflammation, indicating that inflammatory

ctivity in patients with AF is not affected by cardioversiono sinus rhythm. Furthermore, there were no differencesetween patients remaining in sinus rhythm and patientsith unsuccessful cardioversion or a relapse of AF regard-

ng change from baseline to end of study for any of thearkers analyzed.Treatment with candesartan had no effect on the recur-

ence rate of AF after electrical cardioversion in theAPRAF Study.12 In concert with this, no effect of this

reatment on inflammatory markers was seen. Our findingsontrast with other reports of the effect of angiotensin re-eptor blockers on inflammatory markers in hypertensiveatients and patients with coronary heart disease.8–11 Thisay indicate that inflammatory processes in patients withF are not easily affected by medical treatment, at least noty short-term treatment with drugs targeting the renin-an-iotensin system. Recently, it was shown that more directnti-inflammatory drugs such as methylprednisolone mayodulate inflammation in patients with AF, possibly also

ssociated with a favorable rhythm outcome.14 However,ide effects of corticoids are frequent, and alternative med-cal strategies targeting inflammatory processes wouldherefore be more attractive.

Due to the limited number of patients with both baselinend end-of-study blood samples available, this study is notowered to detect minor effects of sinus rhythm mainte-ance or treatment with candesartan. Patients with heartailure were not included in our study.12 Hence, an effect ofreatment with angiotensin receptor blockers on inflamma-ory markers in such patients cannot be excluded. Durationf treatment was relatively short. Thus, longer treatmentith angiotensin receptor blockers, particularly in patientsith AF with concomitant heart failure, might yield a dif-

erent result.

cknowledgment: We thank the clinical research nursesona Olufsen, RN, and Anne Kari Brun, RN, and medical

aboratory technologist Theresa Mai for excellent technicalssistance.

1. L’Allier PL, Ducharme A, Keller PF, Yu H, Guertin MC, Tardif JC.Angiotensin-converting enzyme inhibition in hypertensive patients isassociated with a reduction in the occurrence of atrial fibrillation. J Am

Patients With Recurrence of AF(n � 53)

Value Baseline End of Study p Value

.013 1.94 (1.59, 2.61) 1.48 (1.31, 2.09) 0.001

.137 2.77 (1.73, 4.78) 2.81 (1.55, 5.17) 0.849

.563 3.65 (2.11, 6.18) 3.93 (2.03, 6.81) 0.307

.166 166 (104, 410) 150 (90, 422) 0.102

.872 32.7 (28.7, 42.2) 34.0 (28.1, 43.0) 0.466

.568 698 (536, 918) 693 (594, 918) 0.068

.489 37 (28, 47) 41 (31, 50) 0.191

udy values.

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Coll Cardiol 2004;44:159–164.

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2. Wachtell K, Lehto M, Gerdts E, Olsen MH, Hornestam B, Dahlof B,Ibsen H, Julius S, Kjeldsen SE, Lindholm LH, Nieminen MS, De-vereux RB. Angiotensin II receptor blockade reduces new-onset atrialfibrillation and subsequent stroke compared to atenolol: the LosartanIntervention For End Point Reduction in Hypertension (LIFE) study.J Am Coll Cardiol 2005;45:712–719.

3. Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M,Guerra PG, Ducharme A. Enalapril decreases the incidence of atrialfibrillation in patients with left ventricular dysfunction: insight fromthe Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circu-lation 2003;107:2926–2931.

4. Maggioni AP, Latini R, Carson PE, Singh SN, Barlera S, Glazer R,Masson S, Cere E, Tognoni G, Cohn JN. Valsartan reduces the incidenceof atrial fibrillation in patients with heart failure: results from the ValsartanHeart Failure Trial (Val-HeFT). Am Heart J 2005;149:548–557.

5. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolaprilreduces the incidence of atrial fibrillation after acute myocardial in-farction in patients with left ventricular dysfunction. Circulation 1999;100:376–380.

6. Das UN. Is angiotensin-II an endogenous pro-inflammatory molecule?Med Sci Monit 2005;11:RA155–RA162.

7. Cheng ZJ, Vapaatalo H, Mervaala E. Angiotensin II and vascular
inflammation. Med Sci Monit 2005;11:RA194–RA205.
8. Manabe S, Okura T, Watanabe S, Fukuoka T, Higaki J. Effects ofangiotensin II receptor blockade with valsartan on pro-inflammatorycytokines in patients with essential hypertension. J Cardiovasc Pharmacol 2005;46:735–739.

9. Dohi Y, Ohashi M, Sugiyama M, Takase H, Sato K, Ueda R. Cande-sartan reduces oxidative stress and inflammation in patients with es-sential hypertension. Hypertens Res 2003;26:691–697.

0. Koh KK, Quon MJ, Han SH, Chung WJ, Lee Y, Shin EK. Anti-inflammatory and metabolic effects of candesartan in hypertensivepatients. Int J Cardiol 2006;108:96–100.

1. Schieffer B, Bunte C, Witte J, Hoeper K, Boger RH, Schwedhelm E,Drexler H. Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and plateletaggregation in patients with coronary artery disease. J Am Coll Cardiol200421;44:362–368.

2. Tveit A, Grundvold I, Olufsen M, Seljeflot I, Abdelnoor M, ArnesenH, Smith P. Candesartan in the prevention of relapsing atrial fibrilla-tion. Int J Cardiol 2006, in press.

3. Jialal I, Devaraj S, Venugopal SK. C-Reactive protein: risk marker ormediator in atherothrombosis? Hypertension 2004;44:6–11.

4. Dernellis J, Panaretou M. Effect of C-reactive protein reduction onparoxysmal atrial fibrillation. Am Heart J 2005;150:1064.e7–
1064.e12.

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Factors Influencing Blood Pressure Response to TrandolaprilAdd-On Therapy in Patients Taking Verapamil SR (from the

International Verapamil SR/Trandolapril [INVEST] Study)

Martin Brunner, MDa,b,d, Rhonda M. Cooper-DeHoff, PharmDc, Yan Gong, PhDa,b,Jason H. Karnes, BAa,b, Taimour Y. Langaee, PhDa,b, Carl J. Pepine, MDc, and

Julie A. Johnson, PharmDa,b,c,*, for the INVEST Investigators

Factors such as age and race/ethnicity might influence blood pressure (BP) response todrugs. Therapeutic response to the angiotensin-converting enzyme inhibitor trandolaprilused as add-on therapy to stable calcium channel blocker therapy with verapamil sustainedrelease 240 mg was addressed in a racially/ethnically diverse group of 1,832 hypertensivepatients with coronary artery disease. Furthermore, the association with a polymorphism(1166A¡C) in the angiotensin II type 1 receptor gene (AGTR1) was tested. BP responsewas compared between groups using analysis of covariance after adjustment for covariatesassociated with BP response. Genotyping was performed using polymerase chain reactionand pyrosequencing. Trandolapril decreased mean unadjusted systolic and diastolic BPs by�9.1 � 17.3 (SD) and �4.1 � 10.1 mm Hg, respectively. The percentage of patients withBP under control (<140/90 mm Hg) increased from 6.7% to 41.3% (p <0.0001). AdjustedBP response was significantly associated with age and baseline systolic and diastolic BP(p <0.0001). Whereas the decrease in systolic BP was more pronounced in youngerpatients, the opposite was observed for diastolic BP decrease. Diastolic BP response wasalso significantly associated with race. Specifically, the adjusted diastolic BP decrease wassignificantly smaller in Hispanics and blacks than whites (p � 0.0032 and p � 0.0069,respectively). However, Hispanics achieved a decrease in systolic BP and an increase in BPcontrol similar to the other ethnic groups. There was no genetic association betweenAGTR1 1166A¡C genotype and BP response. In conclusion, trandolapril add-on therapywas effective in increasing BP control, with age and baseline BP associated with bothsystolic and diastolic BP response. Race was associated with diastolic BP response,although the difference is likely not to be clinically significant and AGTR1 genotypewas not associated with BP response. © 2007 Elsevier Inc. All rights reserved. (Am J
Cardiol 2007;99:1549 –1554)
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e assessed factors associated with the response to add-onherapy with the angiotensin-converting enzyme (ACE) in-ibitor trandolapril, including race/ethnicity, angiotensin IIype 1 receptor (AGTR1) genotype, age, and clinical factorsn hypertensive patients with coronary artery disease. Pa-ients were selected from the INternational VErapamil SR/

aDepartment of Pharmacy Practice, College of Pharmacy, bCenter forharmacogenomics, cDivision of Cardiology, College of Medicine, Uni-ersity of Florida, Gainesville, Florida; and dDepartment of Clinical Phar-acology, Medical University of Vienna, Vienna, Austria. Manuscript

eceived November 13, 2006; revised manuscript received and acceptedanuary 10, 2007.

This study was supported by Grants No. HL74730, HL68834,L69758, and RR17568 from the National Institutes of Health, Bethesda,aryland, and grants from Abbott Laboratories, Abbott Park, Illinois, and

he University of Florida Opportunity Fund, Gainesville, Florida. Dr.runner was supported by the Erwin Schrödinger Fellowship Program of

he Austrian Science Fund (J 2403-B11), Vienna, Austria. Mr. Karnes wasupported by a grant from the American Heart Association (0515074B), St.etersburg, Florida.

*Corresponding author: Tel.: 352-273-6007; fax: 352-273-6121.
dE-mail address: [email protected] (J.A. Johnson).

randolapril STudy (INVEST), an ethnically diverse mul-icenter trial that included white and black patients withypertension and 1 of the largest Hispanic patient popula-ions reported.

ethods

he INVEST rationale, design, inclusion and exclusion cri-eria, treatment strategies, and main results were publishedn detail elsewhere. Briefly, after an extensive cardiovascu-ar history and physical examination, patients were ran-omly assigned to either a verapamil sustained releaseSR)–trandolapril– or atenolol-hydrochlorothiazide–basedntihypertensive strategy. Patients were evaluated every 6eeks for the first 6 months and then biannually for �2ears to assess blood pressure (BP) and adverse outcomes.he detailed BP measurement method was published pre-iously.1,2 The INVEST on-line data system provided de-ailed tracking of study medication prescriptions.3 From997 to 2003, follow-up of 61,835 patient-years was accu-ulated, and each strategy provided excellent BP control

�70% of patients achieved BP �140/90 mm Hg) without
ifferences in BPs between strategies. The strategies were
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qually effective in preventing the composite primary out-ome of all-cause death, nonfatal myocardial infarction, oronfatal stroke.1

Genetic samples were collected as part of the GENEticubstudy of INVEST (INVEST-GENES) of 5,979 subjectsrom 184 sites in mainland United States and Puerto Rico tolucidate the contribution of genetic variants to interpatientnd interdrug variations in response and outcome duringntihypertensive drug therapy.4 Both studies were approvedy appropriate institutional review boards and, in the case ofNVEST-GENES, by the University of Florida, whicherved as the central institutional review board for all par-icipating sites in the genetic substudy. Written informedonsent for participation in both the main INVEST and theenetic substudy was provided by each patient.

A total of 1,832 INVEST patients randomly assigned tohe verapamil SR strategy who received monotherapy witherapamil SR 240 mg and had trandolapril (1, 2, or 4 mg)dded to their treatment because of failing to meet BP goalsere included in this analysis. Response to ACE-inhibitor

ddition was assessed by comparing BP readings from 2isits, the first reading obtained at the visit that led torescription of trandolapril and the second reading obtainedt the next follow-up visit. In other words, BP change wasssessed before and after the addition of trandolapril. Only

able 1atient baseline characteristics

INVEST(n � 1,832)

INVEST GENES(n � 551)

ge, mean (yrs) 66.3 � 10.0 65.8 � 9.8omen 975 (53.2%) 317 (57.5%)

thnicityWhite 792 (43.2%) 193 (35.0%)Black 332 (18.1%) 80 (14.5%)Hispanic 641 (35.0%) 242 (43.9%)Other 67 (3.7%) 36 (6.5%)ody mass index (kg/m2) 29.6 � 5.7 29.7 � 5.8aseline Systolic BP (mm Hg) 150.5 � 17.6 151.3 � 17.4aseline diastolic BP (mm Hg) 86.7 � 10.9 87.5 � 10.3aseline heart rate (beats/min) 75.8 � 9.5 75.1 � 9.4yocardial infarction 542 (29.6%) 125 (22.7%)ngina pectoris 1,225 (66.9%) 410 (74.4%)troke/transient ischemic attack 110 (6.0%) 38 (6.9%)eripheral vascular disease 207 (11.3%) 56 (10.2%)mokerPast 790 (43.1%) 208 (37.8%)With in last 30 d 235 (12.8%) 58 (10.5%)iabetes mellitus* 525 (28.6%) 159 (28.9%)ypercholesterolemia† 940 (51.3%) 278 (50.5%)spirin or other antiplatelet drug 859 (46.9%) 228 (41.4%)ther nonsteroidal anti-inflammatory

drugs315 (17.2%) 125 (22.7%)

ntidiabetic medication 448 (24.5%) 132 (24.0%)ny lipid-lowering drug 685 (37.4%) 205 (37.2%)

INVEST-GENES patients represent a subgroup of INVEST patientsho were genotyped for AGTR1 1166A¡C. Data presented as number

percentage of population) or mean � SD.* History of diabetes or antidiabetic medication use.† History of hypercholesterolemia or lipid-lowering medication use.

atients with BP readings at these 2 visits were included in m

igure 1. Systolic (open bars) and diastolic (filled bars) BP decreasesmm Hg) after the addition of trandolapril to verapamil SR 240 mgonotherapy according to race/ethnicity (upper panel), age groups (middle

anel), and trandolapril dose (lower panel) and adjusted for systolic andiastolic BP before trandolapril addition and other covariates found to bessociated with BP response (age, gender, race, trandolapril dose, diabetes
ellitus, and body mass index). Results presented as mean � SE.

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1551Systemic Hypertension/Blood Pressure Response, Age, and Genotype

he final analysis. BP control is defined as achieving BP140/90 mm Hg at the follow-up visit.Determination of race/ethnicity was self-identified using

atient report with interaction by the site investigator,hoosing all that were applicable of the options on theNVEST data collection form of white, black, Hispanic,sian, and “other.” Patients of mixed race/ethnicity could

hoose �1 category. Hispanic was used as a race rather thanthnicity term. Due to comparably small sample sizes,sians and the multiracial group were defined as other for

nalysis. Of these 1,832 INVEST patients, 551 also con-ented to participate in INVEST-GENES, provided geneticamples, and were subsequently genotyped for AGTR1166A¡C.

Genomic DNA was isolated from buccal genetic samplessing commercially available kits (PureGene, Gentra Sys-ems Inc, Minneapolis, Minnesota) and normalized to 20g/�l. Genotyping for the AGTR1 1166A¡C polymorphismas performed using polymerase chain reaction (PCR) fol-

igure 2. Ranges of systolic (left column) and diastolic BP (right column)n whites (upper row), Hispanics (middle row), and blacks (lower row). Humber of patients. The superimposed curve shows the normal distributio

owed by pyrosequencing (PSQ; Pyrosequencing, Uppsala, b

weden). Primers used for PCR reaction and PSQ were 5=-CCCTCAGATAATGTAAGC-3= (PCR forward), 5=-Bio-TCGGTTCAGTCCACATAATG-3= (PCR reverse), and se-uencing primer 5=-ACTTCACTACCAAATGAGC-3=. TheCR mixture (12.50 �l) consisted of 6.25 �l of HotStarTaqaster Mix Kit (Qiagen Inc, Valencia, California), 1 �l of

CR primers (10 pmol/�l), 1 �l of dimethyl sulfoxide,.25 �l of water, and 40 ng of DNA. PCR was performednder the conditions of 95°C for 15 minutes; 40 cyclesonsisting of denaturation at 95°C for 30 seconds, annealingt 54°C for 30 seconds, and extension at 72°C for 30econds; and final extension for 7 minutes. PSQ was per-ormed under standard conditions for sequence determina-ion and allele designation in a Biotage PSQ HS 96 SystemBiotage AB, Uppsala, Sweden), and data were capturedsing PSQ HS 96 SNP software.

Analysis of covariance was used to compare BP responseo ACE inhibitor addition adjusting for systolic or diastolicP before ACE inhibitor addition and covariates found to

es after the addition of trandolapril to verapamil SR 240 mg monotherapys show changes in BP in equal-sized bins of 5 mm Hg for the respectivedata sets.

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ethod. Age was considered a continuous variable with 1egree of freedom. For presentation purpose, patients werelso categorized into four 10-year age groups. BP controlefore and after trandolapril treatment was compared usingcNemar’s test for matched pairs. The t test was used for

ontinuous variables and chi-square test was used for cate-orical variables. A p value �0.05 was considered statisti-ally significant. Hardy-Weinberg equilibrium was tested

igure 3. Increase in BP control (�140/90 mm Hg) after the addition ofrandolapril to verapamil SR 240 mg monotherapy according to race/thnicity (upper panel), age groups (middle panel), and trandolapril doselower panel). Results given as percentage of the different subgroups.

sing chi-square test with 1 degree of freedom. Due to the a

mall number of patients homozygous for the C allele, A/Cnd C/C genotypes were collapsed for further analysis.

esults

etailed demographic and baseline characteristics for theain study population and subgroup of patients with geno-

ype data are listed in Table 1.Separated according to de-ade, 544 patients were aged 50 to 59 years, 590 were 60 to9 years, 502 were 70 to 79 years, and 196 were �80 years.ean time from trandolapril addition to BP response as-

essment was 74.5 � 89.1 days. Median duration of vera-amil monotherapy before the addition of trandolapril was1 days (interquartile range 42 to 97 days). Most whites84.0%), Hispanics (90.5%), and others (88.1%) werereated with 2 mg of trandolapril, whereas in 85.2% offrican-American patients, trandolapril was initiated at 4g, in addition to verapamil SR 240 mg/d, as suggested by

he INVEST protocol.ACE inhibitor addition decreased mean unadjusted sys-

olic and diastolic BPs by �9.1 � 17.3 and �4.1 � 10.1m Hg to mean unadjusted systolic and diastolic BPs of

39.7 � 17.5 and 80.1 � 10.3 mm Hg, respectively. Afterdjusting for covariates and multiple comparisons, no sta-istically significant differences were observed for systolicP decreases in different races/ethnicities, whereas diastolicP decrease was significantly smaller in Hispanics andlacks than whites (Figure 1). The adjusted systolic BPecrease was significantly greater in younger patients (50 to9 years) compared with those aged 70 to 79 yearsFigure 1). It is of interest to note that the effect of age is inpposite directions for systolic and diastolic BP, withounger patients having better systolic BP response andlder patients having better diastolic BP response. Figure 2hows ranges of systolic and diastolic BP responses afterrandolapril addition in the different racial/ethnic groupsnd that both ranges and average responses are similar byace/ethnicity. It also highlights the wide range of responsesround the mean. Overall, trandolapril therapy significantlyncreased the percentage of patients with BP under controlrom 6.7% before trandolapril addition to 41.3% afterdd-on therapy (p �0.0001). Figure 3 shows increases inercentages of patients with BP control according to race/thnicity, age group, and trandolapril dose. There were noifferences among these groups.

In the cohort with DNA samples provided, minor allelerequencies for AGTR1 1166A¡C were 0.30 for whites,.06 for blacks, 0.24 for Hispanics, and 0.28 for others.enotype frequencies did not deviate from Hardy-Weinberg

quilibrium. Adjusted mean systolic/diastolic BPs after theddition of trandolapril to verapamil SR monotherapy were42.6 � 1.3/82.0 � 0.7 mm Hg for A/A homozygotes and40.6 � 1.4/81.4 � 0.8 mm Hg for C-allele carriers (p �.17 and p � 0.48). The corresponding adjusted meanystolic BP decreases for A/A and C/C genotypes were5.9 � 1.3 and �7.9 � 1.5 mm Hg (p � 0.17). Adjustedean diastolic BP decreases were �2.9 � 0.7 and �3.4 �

.8 mm Hg, respectively (p � 0.47). After adjusting forovariates, AGTR1 genotype was not significantly associ-ted with either systolic or diastolic BP response (p � 0.17
nd p � 0.48, respectively). In whites, the lowest adjusted

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1553Systemic Hypertension/Blood Pressure Response, Age, and Genotype

ystolic and diastolic BP values after trandolapril additionere seen in patients homozygous for the A allele (Table 2).

n blacks and Hispanics, the opposite was observedTable 2). Due to the small number of others, this patientroup is not reported in the final analysis.

iscussion

n the present study, we address the therapeutic response ton ACE inhibitor used as add-on therapy to a calciumhannel blocker in a large ethnically diverse population. Wehow that diastolic BP response is modestly influenced byace/ethnicity and age, whereas race/ethnicity does not in-uence systolic BP response. AGTR1 1166 genotype alsoas not associated with BP response.To our knowledge, these are the first data for the com-

ination of trandolapril and verapamil SR in a Hispanicatient population with hypertension and coronary arteryisease. These patients responded well to add-on therapyith 2 mg of trandolapril and achieved a decrease in systolicP (Figures 1 and 2) and an increase in BP control

Figure 3) similar to those of other racial/ethnic groupshen analysis was adjusted for confounding factors. How-

ver, compared with whites, trandolapril addition led to atatistically smaller diastolic BP decrease, although thisifference could be argued to be of limited clinical signif-cance given the small absolute difference and that diastolicP tends to be easier to control than systolic BP. That theiastolic BP response difference in Hispanics is of limitedlinical significance is also supported because Hispanicsad the numerically highest increase in percentage of BPontrol with trandolapril addition (39.0%) versus increasesf 34.1% in whites and 27.1% in blacks. In a recent publi-ation, the Hispanic cohort of INVEST also yielded betterP control compared with the non-Hispanic cohort after 24onths of treatment with a mean of 2.4 drugs required to

chieve BP control.5 From the present analysis, one mightonclude that a substantial proportion of BP control after 24onths can be attributed to trandolapril addition to vera-

amil SR, which justifies the administration of these drug

able 2djusted mean systolic and diastolic blood pressure (BP) and systolic and

elease monotherapy in different races/ethnicities according to AGTR1 11

A

A/A

hite 139.9 � 2.5/77.7 � 1.4lack 143.9 � 6.3/82.8 � 3.3ispanic 144.6 � 2.7/85.3 � 1.4

Sy

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hite �8.5 � 2.5/�5.6 � 1.4lack �7.0 � 6.3/�3.1 � 3.4ispanic �3.3 � 2.7/�0.5 � 1.4

C Allele carriers were combined in 1 group. p Values were adjusted fo

lasses in Hispanics. The Hispanic subpopulation of the a

resent study was recruited from countries in North andentral America and the Caribbean, with a high percentage

rom Puerto Rico. Thus, our results may not be fully gen-ralizable to Hispanics with other ancestry, which is em-hasized by recent studies showing variable prevalences ofypertension among Hispanic patients from the Unitedtates, Mexico, and Europe.6

Although Hispanics have not been well represented inypertension trials to date, there are many examples ofifferences between blacks and whites with respect torevalence, pathophysiological characteristics, target-organamage, and responses to hypertension treatment.7,8 Forlack patients with hypertension, for example, a decreasedherapeutic response to ACE inhibitor treatment waseported,9 although more aggressive dosing compensatedor the observed differences and led to similar BP decreasesn blacks and whites.10 The present study is in line withhese findings, showing no significant differences in systolicP decreases and BP control in blacks compared with thether races/ethnicities when trandolapril was added to ve-apamil. However, black patients received a higher tran-olapril dose (4 mg) according to the INVEST protocol,2hich increased the percentage of blacks with BP �140/90m Hg by approximately 30% (Figure 3). To further in-

rease the percentage of patients with controlled BP, blackatients are likely to require �2 drugs, shown in a previousubanalysis of INVEST that reported that 62.1% of blackatients in the verapamil SR arm of the trial achieved BPontrol at 24 months, most of them with �3 antihyperten-ive drugs.11

Finally, to test whether genetic variants affect BP re-ponse to trandolapril addition, we assessed the contributionf the most frequently studied AGTR1 single-nucleotideolymorphism (rs5186), which shows an adenine (A) toytosine (C) transversion (1166A¡C). This was based ontudies reporting associations between 1166A¡C geno-ype, hypertension, and/or cardiovascular disease,12–15 al-hough sometimes with conflicting results.16,17 Comparedith other genetic studies that usually concentrated on white

lic BP decreases after the addition of trandolapril to verapamil sustainedC genotype (n � 551)

Systolic/Diastolic BP (mm Hg)

Allele Carriers p Value(systolic/diastolic BP)

0 � 2.4/79.5 � 1.4 0.63/0.121 � 7.8/80.1 � 4.1 0.22/0.363 � 3.0/83.9 � 1.2 0.11/0.19

iastolic BP Decrease (mm Hg)

Allele Carriers p Values(systolic/diastolic BP decrease)

4 � 2.4/�3.7 � 1.4 0.63/0.169 � 7.8/�6.3 � 4.2 0.22/0.296 � 3.0/�1.9 � 1.5 0.11/0.12

le comparisons. Results presented as mean � SE.

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rovides genetic data for a comparatively large Hispanicopulation and shows that allele frequencies in Hispanicsere similar to those reported for Caucasians, with theajority of patients homozygous for the wild-type A

llele.13 Although we failed to show an association betweenGTR1 1166A¡C genotype and BP response, there wereuggestions that the magnitude of BP decrease was influ-nced by genotype and race (Table 2). These findings areonsistent with previous studies reporting higher systolic18

nd diastolic BPs19 in white patients with the C/C genotype,ut higher BPs in black carriers of the A allele.18 1166A¡Cingle-nucleotide polymorphism is located in an untrans-ated region of the AGTR1 gene and might not be functionaltself. The genotype-driven discordance of BP data in dif-erent populations suggests that 1166A¡C might be ininkage disequilibrium with 1 or several mutations of func-ional importance, and the linkage disequilibrium mightiffer between whites, blacks, and Hispanics. Data from thenternational HapMap Project showed racial/ethnic differ-nces in linkage disequilibrium structure for the AGTR1ene.20 Furthermore, to overcome the limitations of candi-ate single-nucleotide polymorphism studies, race/ethnic-ty-specific linkage disequilibrium and haplotype patternshould be taken into account, for example, through a tag–ingle-nucleotide polymorphism approach.21 Ultimately,pproaches that consider multiple genes together in a sta-istical model will be needed to help understand the role ofenetics on variable antihypertensive response.22

1. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, KoweyP, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, KeltaiM, et al, for the INVEST Investigators. A calcium antagonistvs a non-calcium antagonist hypertension treatment strategyfor patients with coronary artery disease. The International Vera-pamil-Trandolapril Study (INVEST): a randomized controlled trial.JAMA 2003;290:2805–16.

2. Pepine CJ, Handberg-Thurmond E, Marks RG, Conlon M, Cooper-DeHoff R, Volkers P, Zellig P. Rationale and design of the Interna-tional Verapamil SR/Trandolapril Study (INVEST): an Internet-basedrandomized trial in coronary artery disease patients with hypertension.J Am Coll Cardiol 1998;32:1228–1237.

3. Cooper-DeHoff R, Handberg E, Heissenberg C, Johnson K. Electronicprescribing via the Internet for a coronary artery disease and hyper-tension megatrial. Clin Cardiol 2001;24(suppl):SV14–SV6.

4. Keltai M, Johnson JA, Kowey PR, Ried LD, Tueth M. INVESTsubstudies: design and patient characteristics. Clin Cardiol 2001;24(suppl):SV9–SV11.

5. Cooper-DeHoff RM, Aranda JM Jr, Gaxiola E, Cangiano JL, Gar-cia-Barreto D, Conti CR, Hewkin A, Pepine CJ, for the INVESTInvestigators. Blood pressure control and cardiovascular outcomesin high-risk Hispanic patients—findings from the International Ve-rapamil SR/Trandolapril Study (INVEST). Am Heart J 2006;151:1079 –1086.

6. Lorenzo C, Serrano-Rios M, Martinez-Larrad MT, Gabriel R, Williams
K, Gonzalez-Villalpando C, Stern MP, Hazuda HP, Haffner S. Prevalence
of hypertension in Hispanic and non-Hispanic white populations.Hypertension 2002;39:203–208.

7. Bosworth HB, Dudley T, Olsen MK, Voils CI, Powers B, GoldsteinMK, Oddone EZ. Racial differences in blood pressure control: poten-tial explanatory factors. Am J Med 2006;119:70.e9–70.e15.

8. Gadegbeku CA, Lea JP, Jamerson KA. Update on disparities in thepathophysiology and management of hypertension: focus on AfricanAmericans. Med Clin North Am 2005;89:921–933.

9. Wright JT Jr, Dunn JK, Cutler JA, Davis BR, Cushman WC, Ford CE,Haywood LJ, Leenen FH, Margolis KL, Papademetriou V, et al, forthe ALLHAT Collaborative Research Group. Outcomes in hyperten-sive black and nonblack patients treated with chlorthalidone, amlodip-ine, and lisinopril. JAMA 2005;293:1595–1608.

0. Weir MR, Gray JM, Paster R, Saunders E. Related differing mecha-nisms of action of angiotensin-converting enzyme inhibition in blackand white hypertensive patients. The Trandolapril Multicenter StudyGroup. Hypertension 1995;26:124–130.

1. Jamerson K, Champion A, Zhou Q, Pepine C. Verapamil- and atenololbased strategies are equally effective in black patients with hyperten-sion and coronary artery disease: a sub-analysis of the InternationalVerapamil SR-Trandolapril study (INVEST) (abstr). Am J Hypertens2005;18(suppl 1):S109A.

2. Baudin B. Polymorphism in angiotensin II receptor genes and hyper-tension. Exp Physiol 2005;90:277–282.

3. Bonnardeaux A, Davies E, Jeunemaitre X, Fery I, Charru A, Clauser E,Tiret L, Cambien F, Corvol P, Soubrier F. Angiotensin II type 1 receptorgene polymorphisms in human essential hypertension. Hypertension1994;24:63–69.

4. Miller JA, Thai K, Scholey JW. Angiotensin II type 1 receptor genepolymorphism predicts response to losartan and angiotensin II. KidneyInt 1999;56:2173–2180.

5. Rubattu S, Di Angelantonio E, Stanzione R, Zanda B, Evangelista A,Pirisi A, De Paolis P, Cota L, Brunetti E, Volpe M. Gene polymor-phisms of the renin-angiotensin-aldosterone system and the risk ofischemic stroke: a role of the A1166C/AT1 gene variant. J Hypertens2004;22:2129–2134.

6. Ono K, Mannami T, Baba S, Yasui N, Ogihara T, Iwai N. Lack ofassociation between angiotensin II type 1 receptor gene polymorphismand hypertension in Japanese. Hypertens Res 2003;26:131–134.

7. Ortlepp JR, Breithardt O, Ohme F, Hanrath P, Hoffmann R. Lack ofassociation among five genetic polymorphisms of the renin-angioten-sin system and cardiac hypertrophy in patients with aortic stenosis. AmHeart J 2001;141:671–676.

8. Hindorff LA, Heckbert SR, Tracy R, Tang Z, Psaty BM, EdwardsKL, Siscovick DS, Kronmal RA, Nazar-Stewart V. Angiotensin IItype 1 receptor polymorphisms in the Cardiovascular Health Study:relation to blood pressure, ethnicity, and cardiovascular events.Am J Hypertens 2002;15:1050 –1056.

9. Barbeau P, Kulharya A, Harshfield G, Snieder H, Davis H, Treiber F.Association between angiotensin II type I receptor polymorphism andresting hemodynamics in black and white youth. Ethn Dis 2002;12:68–71.

0. Tapper W, Collins A, Gibson J, Maniatis N, Ennis S, Morton NE. Amap of the human genome in linkage disequilibrium units. Proc NatlAcad Sci U S A 2005;102:11835–11839.

1. Su S, Chen J, Zhao J, Huang J, Wang X, Chen R, Gu D, for the BeijingAtherosclerosis Study. Angiotensin II type I receptor gene and myo-cardial infarction: tagging SNPs and haplotype based associationstudy. The Beijing Atherosclerosis Study. Pharmacogenetics 2004;14:673–681.

2. Johnson JA, Turner ST. Hypertension pharmacogenomics: current
status and future directions. Curr Opin Mol Ther 2005;7:218 –225.

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Value of Myocardial Viability Estimation Using Dobutamine StressEchocardiography in Assessing Risk Preoperatively Before

Noncardiac Vascular Surgery in Patients With Left VentricularEjection Fraction <35%

Stefanos E. Karagiannis, MDa, Harm H.H. Feringa, MDa, Radosav Vidakovic, MDa,Ron van Domburg, PhDa, Olaf Schouten, MDa, Jeroen J. Bax, MDb, George Karatasakis, MDc,

Dennis V. Cokkinos, MDc, and Don Poldermans, MDa,*

Patients with heart failure (HF) scheduled for vascular surgery have an increased risk ofadverse postoperative outcome, and stratification usually depends on dichotomous riskfactors. A quantitative prognostic model for patients with HF was developed using wallmotion patterns during dobutamine stress echocardiography (DSE). A total of 295 consec-utive patients (mean age 67 � 12 years) with ejection fraction <35% were studied. DuringDSE, wall motion patterns of dysfunctional segments were scored as scar, ischemia, orsustained improvement. Cardiac death and myocardial infarction were noted periopera-tively and during 5 years of follow-up. Of 4,572 dysfunctional segments; 1,783 (39%) hadischemia, 1,280 (28%) had sustained improvement, and 1,509 (33%) had scar. In 212patients, >1 ischemic segment was present; 83 had only sustained improvement. Periop-erative and late cardiac event rates were 20% and 30%, respectively. Using multivariateanalysis, number of ischemic segments was associated with perioperative cardiac events(odds ratio per segment 1.6, 95% confidence interval 1.05 to 1.8), whereas number ofsegments with sustained improvement was associated with improved outcome (odds ratioper segment 0.2, 95% confidence interval 0.04 to 0.7). Multivariate independent predictorsof late cardiac events were age and ischemia. Sustained improvement was associated withimproved survival. In conclusion, DSE provides accurate risk stratification of patients withHF undergoing vascular surgery. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol
2007;99:1555–1559)
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reoperative cardiac risk assessment for patients undergo-ng major vascular surgery is a challenging entity. Patientsre mainly stratified according to the number of dichoto-ous cardiac risk factors.1,2 At present, risk stratification of

atients with heart failure (HF) scheduled for vascular sur-ery mainly depends on left ventricular (LV) function at restecause patients with LV dysfunction have decreased long-erm survival after major vascular surgery.3–5 However, theresence of myocardial viability, in other words, dysfunc-ional segments that improve after inotropic stimulation,ight enhance preoperative risk stratification. Quantifica-

ion of dobutamine stress echocardiography (DSE) resultsould help in this aspect. We tried according to the Bayes-

an principle to change the before-test probability in morerecise after-test quantification of risk and therefore stratifyatients with HF more accurately. The aim of our study is tossess prognostic implications of ischemia or sustained im-rovement as the 2 main patterns of response of viable

aDepartment of Cardiology, Erasmus MC, Rotterdam; bDepartment ofardiology, Leiden University, Leiden, The Netherlands; and cFirst De-artment of Cardiology, Onassis Cardiac Surgery Centre, Athens, Greece.anuscript received November 14, 2006; revised manuscript received and

ccepted January 10, 2007.*Corresponding author: Tel: 311-0463-9222; fax: 311-0463-4957.

sE-mail address: [email protected] (D. Poldermans).


issue to DSE in patients with known LV ejection fraction35% undergoing major vascular surgery.

ethods

he study population included 295 consecutive patientsith known LV ejection fraction �35% who were referred

o the Erasmus MC (Rotterdam, The Netherlands) for majorascular noncardiac surgery from June 1999 to June 2001.ll patients underwent DSE for evaluation of viability.iabetes mellitus is defined as fasting plasma glucose �126g/dl on �2 occasions and/or requirement for insulin or

ral hypoglycemic agents according to criteria of the Amer-can Diabetes Association.6 Hypercholesterolemia is de-ned as total cholesterol of 200 mg/dl or use of a choles-

erol-lowering agent. Hypertension is defined as systoliclood pressure �140 mm Hg, diastolic blood pressure �90m Hg, or use of antihypertensive medication. The localedical ethics committee approved the study protocol. Pa-

ients gave informed consent for the study.The DSE protocol was approved by the Hospital Ethical

ommittee and performed in accordance with well-estab-ished protocols.7,8 Studies were performed using a Sonos500 imaging system (Phillips Medical Systems, Eind-oven, The Netherlands). Patients underwent a 2-dimen-
ional echocardiographic examination at rest using the stan-
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ard apical and parasternal views. Images were recorded onideotape and also digitized for comparison of differenttages. Dobutamine was administered intravenously usingn infusion pump, starting at 5 �g/kg/min followed by 10g/kg/min for 5 minutes, increasing by 10 �g/kg/min everyminutes to a maximum of 40 �g/kg/min (stage 5), and

ontinued for 6 minutes. The dobutamine infusion wastopped if a target heart rate (85% of a theoretical maximaleart rate [men: (220 � age) � 85%; women: (200 � age) �5%] was achieved. If the target heart rate was not achievednd patients had no symptoms or signs of ischemia, atropinestarting with 0.25 mg, increased to a maximum of 2.0 mg)as given intravenously at the end of stage 5 while dobut-

mine administration was continued. During the test, a 12-ead electrocardiogram was recorded every minute. Bloodressure was measured every 3 minutes. Metoprolol wasdministered (1.0 to 5.0 mg) intravenously according toeart rate response and systolic blood pressure, and aftereak stress, images were acquired to achieve a recoveryhase, defined as heart rate within 10% range of heart ratet rest. Criteria for stopping the test were (1) achievement ofarget heart rate, (2) severe and extensive new wall motionbnormalities, (3) horizontal or downsloping ST depression0.2 mV measured 80 ms after the J point or ST-segment

levation �0.2 mV in the absence of Q waves, (4) symp-omatic decrease in systolic blood pressure �40 mm Hg orystolic blood pressure �90 mm Hg, (5) hypertensionblood pressure �240/140 mm Hg), (6) occurrence of sus-ained cardiac arrhythmias, (7) severe angina pectoris, and8) intolerable adverse effects considered to be the result ofobutamine or atropine. Two experienced investigators per-ormed off-line assessment of echocardiographic imagesithout knowledge of the patient’s clinical and coronary

ngiographic data, but with knowledge of dobutamine andtropine doses used. Inter- and intraobserver agreement fornalysis of DSE studies were reported previously (92% and4%, respectively).9 Regional function was scored accord-ng to a 16-segment 5-point scoring model as 1 � normal,

� mildly hypokinetic, 3 � severely hypokinetic, 4 �kinetic, and 5 � dyskinetic. Wall-motion score index (totalcore divided by number of segments scored) was calcu-ated at rest, at low dose, and during peak stress. Myocardialiability was assessed in severely dysfunctional segments.he 4 types of wall motion responses observed were (1)iphasic pattern (ischemia): improvement in wall motion atobutamine 5, 10, or 20 mg/kg/min with worsening atigher dosages; (2) worsening only (ischemia); (3) sus-ained improvement; and (4) no change or scar. Severelyysfunctional segments showing a biphasic, sustained, ororsening response were considered viable, whereas seg-ents with unchanged wall motion were considered

carred.Evaluated end points were all-cause mortality, cardiac

eath, and nonfatal myocardial infarction. Cardiac deathas defined using clinical data of acute myocardial infarc-

ion and/or significant cardiac arrhythmias and/or refractoryongestive heart failure, together with electrocardiographicnd autopsy studies when available. Increases in cardiacsoenzymes and the development of new electrocardio-raphic changes defined a nonfatal myocardial infarction. In
atients with �1 cardiac event, the worst event was chosen t
f documented cardiac death (worst) and nonfatal infarctionless worst). Perioperative cardiac events were consideredvents that occurred within 30 days after surgery. Follow-upata were obtained in 2006. Mean long-term follow-up was0 � 24 months after DSE. Physicians who were unawaref patients’ stress test results assessed events. The presenttatus was determined by contacting the patient’s generalhysician and/or review of hospital records. The date of theast interview or review was used to calculate follow-upime.

The t test was used for continuous variables, and chi-quare test was used for categorical variables. Characteris-ics were summarized as percentages for categorical vari-bles and mean � SD for continuous variables. Univariatend multivariate analysis of clinical and echocardiographicariables with the end points were assessed using logisticegression analysis for the 30-day after-surgery period andsing a Cox proportional hazards model for long-term fol-ow-up. All clinical and representative DSE variables wereonsidered in the model regardless of their univariate sig-ificance. Variables were selected in a stepwise forwardelection manner with entry and retention set at a signifi-ance level of 0.05. The fitted model included age only forhe purpose of adjustment. All other models were based onariables selected in the stepwise algorithm, which wereeplaced by dichotomous versions to facilitate ease of clin-cal use. Risk of a variable is expressed as hazard ratio (HR)r odds ratio (OR) with a 95% confidence interval (CI). Therobability of cardiac death–free survival was calculatedsing the Kaplan-Meier method, and the resulting curvesere compared using log-rank test.10

esults

atient demographic and clinical characteristics are listed inable 1. Patients’ medications were continued during thetudy.

During DSE, heart rates increased significantly from rest

able 1tudy population characteristics (n � 295)

en 234 (79%)omen 61 (21%)ge (yrs) 67 � 12ypertension 87 (29%)iabetes mellitus 53 (18%)revious myocardial infarction 158 (54%)holesterol �200 mg/dl 77 (26%)moking 114 (39%)ngina 27 (9%)revious percutaneous coronary intervention 21 (7%)revious coronary artery bypass grafting 56 (19%)ardiac medicationsAngiotensin-converting enzyme inhibitors 100 (34%)Aspirin 23 (8%)Statins 18 (6%)� Blockers 99 (34%)Calcium channel blockers 79 (27%)Nitrates 71 (24%)Diuretics 59 (20%)Digoxin 28 (9%)

o peak stress. Rate–pressure product values at rest, low, and

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1557Heart Failure/Noncardiac Surgery in HF

eak were 8,694 � 286, 13,910 � 546, and 17,028 � 351,espectively. In 91% of patients, target heart rate waseached. Atropine was added at peak stress in 97 patientsecause the majority was on long-term �-blocker therapy.ean maximal dobutamine dose was 38 � 8 �g/kg/min.

ide effects included hemodynamically stable sustainedentricular tachycardia (�10 complexes) in 4 patients (1%),onsustained ventricular tachycardia (�10 complexes) in4 (5%), atrial fibrillation in 4 (1%), and severe hypotensionsystolic blood pressure decrease �40 mm Hg) in 4 (1%).o myocardial infarction or ventricular fibrillation was re-

orded during or attributed to DSE. Wall motion score indext rest was 2.08 � 0.50; at low dose, 1.39 � 0.44; and ateak dose, 1.89 � 0.55. Of 4,572 dysfunctional segments,,783 (39%) showed an ischemic response, 1,280 (28%) hadustained improvement, and in 1,509 (33%), motion pat-erns were unchanged during DSE and therefore defined ascar. As expected, all patients with LV dysfunction of ische-ic cause had several degrees of scar tissue. Two hundred

welve patients had �1 ischemic segment, whereas 83 pa-ients experienced only a sustained improvement duringSE. In 26 patients with severe ischemia during DSE and

ymptomatic angina not relieved by medication, the cardiacevascularization procedure preceded noncardiac surgery.

During the early perioperative period, that is, within 30ays after surgery, 6 patients died, 34 patients experiencednonfatal acute myocardial infarction, and 54 patients ex-

erienced an ischemic cardiac event (increased isoen-ymes). Of these 54 patients, 47 (87%) had shown ischemiauring DSE and 7 (13%) showed sustained improvementp �0.001). Of 34 patients with acute myocardial infarction,hese numbers were 29 (83%) and 5 (15%, p �0.001). Fourf 26 patients (15%) who underwent coronary revascular-zation before vascular surgery experienced a nonfatal myo-ardial infarction.

Univariate significant predictors of perioperative cardiacvents were cholesterol �200 mg/dl (OR 1.71, 95% CI 1.03o 2.85, p � 0.04) and ischemia during DSE (OR 2.77, 95%I 1.15 to 6.64, p � 0.001).

Multivariate analysis showed that an increased number

igure 1. Independent multivariate predictors of cardiac events within 30ays after major vascular surgery in patients with LV ejection fraction35%. MI � myocardial infarction.

f segments with sustained improvement during DSE com- 0

ared with the number of ischemic segments was associatedith improved postoperative outcome. The only multivari-

ble independent predictors of early perioperative cardiacvents were previous myocardial infarction (OR 1.5, 95%I 1.05 to 2.3), ischemia (OR 1.6, 95% CI 1.05 to 2.8), and

ustained improvement during DSE (OR 0.2, 95% CI 0.04o 0.7, Figure 1). For perioperative all-cause mortality, thenly independent predictor in multivariate analysis was ageOR 1.03, 95% CI 1.05 to 1.1).

Long-term follow-up was successful for all patients. Thell-cause mortality rate was 43% (128 patients), and 70%89 patients) of that was attributed to cardiac causes. Thir-een patients (4%) experienced a nonfatal myocardial in-arction. Overall, 102 patients (35%) experienced �1 hardardiac event. Of 128 patients who died from all causes,nly 21 had sustained improvement during DSE. Further-ore, only 11 patients with sustained improvement duringSE died from cardiac causes, and another 3 experienced aonfatal myocardial infarction. Of 26 patients who under-ent coronary revascularization before vascular surgery, 6ied from all causes and 7 experienced late cardiac events,of which were fatal myocardial infarctions.Univariate analysis for all-cause mortality showed that

-blocker use was associated with improved outcome (HR

igure 2. Kaplan-Meier curves show survival from cardiac events inatients with LV ejection fraction (LVEF) �35% who underwent majorascular surgery with sustained improvement versus ischemia during low-igh DSE.

able 2niavariate predictors of cardiac events (cardiac death and myocardial

nfarction) in patients with heart failure undergoing major vascular surgery

nivariable Predictors HR 95% CI p Value

revious myocardial infarction 1.51 1.00–2.31 0.05ypertension 1.15 0.75–1.78 0.51moking 1.05 0.70–1.57 0.84ge 1.00 0.59–1.71 0.99iabetes mellitus 1.00 0.60–1.70 0.99Blockers 0.62 0.38–0.95 0.04

tatins 0.62 0.35–1.09 0.07schemia during low-high DSE 1.65 0.93–2.92 0.06ustained improvement during low-highDSE

0.72 0.43–1.22 0.25

.61, 95% CI 0.42 to 0.89, p � 0.006). Sustained improve-

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ent (HR 0.71, 95% CI 0.49 to 1.01, p � 0.09) andschemia (HR 1.21, 95% CI 0.83 to 1.76, p � 0.30) duringSE were not significant univariable predictors. However,

n a multivariate model of clinical and echocardiographicarameters, the only independent predictors of all-causeortality were age (HR 1.05, 95% CI 1.02 to 1.07) and

schemia (HR 1.06, 95% CI 1.02 to 1.12) during DSE.Univariable predictors of cardiac events are listed in

able 2. Angina was not a significant univariate predictoror any event (HR 1.0, 95% CI 0.56 to 1.68, p � 0.55). Inhe multivariate model, age (HR 1.05, 95% CI 1.02 to 1.08)nd ischemia during DSE (HR 1.9, 95% CI 1.1 to 4.0) werendependent predictors of cardiac events, whereas sustainedmprovement (HR 0.5, 95% CI 0.3 to 0.9) proved to berotective.

Kaplan-Meier curves for the end point of cardiac eventsn patients with sustained improvement versus ischemiauring DSE are shown in Figure 2.

iscussion

his study shows the independent prognostic value of wallotion patterns during DSE in patients with LV dysfunction

ndergoing major vascular surgery for the prediction ofardiac events within 30 days after surgery and for all-causeortality and hard cardiac events during a long-term mean

ollow-up of 5 years.Our results show that sustained improvement during

SE provides a protective effect in both the early periop-rative period and for long-term cardiac events. Conversely,schemia proved to be hazardous in both early and long-erm follow-up periods. When patients with sustained im-rovement were compared with patients with ischemia dur-ng DSE, they experienced significantly fewer events in thearly perioperative period (p �0.001). Moreover, the dif-erence in survival during long-term follow-up regardingardiac events between the 2 different viability responsesuring DSE was significant (p � 0.02; Figure 2).

Ischemia during DSE also predicted decreased survivaln all-cause mortality.

Furthermore, the beneficial effect that � blockers exert inatient survival11 was reconfirmed in our study for bothll-cause mortality and late cardiac events.

It is extensively reported that cardiovascular complica-ions are the leading cause of death after noncardiac sur-ery.12–14 That was also the case in our study. We found that0% of total mortality was attributed to cardiac causes.urthermore, patients with LV dysfunction at rest hadreatly decreased long-term survival after noncardiac sur-ery.14–18 Regarding early perioperative outcome, this wasot clearly shown, maybe because of the inability of LVjection fraction at rest to provide information regardingevere underlying coronary artery disease.14 Therefore, us-ng DSE, we further stratified patients with LV dysfunctiont rest according to viability profile. Viable patients withustained improvement experienced much fewer cardiacvents during the first 30 days after surgery compared withatients with an ischemic response in low-high DSE.

This is in accordance with a previous study by Landes-erg et al.19 Although these investigators used thallium scan
nd not DSE, they similarly found that ischemia was asso-
iated with an increased incidence of troponin increaseuring the early perioperative period.19,20 Also, in a previ-us study from our group, the presence of new wall motionbnormalities during DSE was a powerful determinant ofncreased risk of perioperative events.14,21 Other studies alsohowed similar results.22–24 However, the present study ishe only 1 to our knowledge that shows a clear benefit foratients with LV dysfunction and sustained improvementuring DSE regarding early perioperative outcome. Espe-ially patients with predominantly sustained improvementre at lower risk and might respond favorably to low-dosenotropic stimulation during surgery. However, in patientsith a predominantly ischemic response, � blockers or

evascularization could be considered. Previous studiesvaluated the role of extended ischemia detection in stresschocardiography with either dobutamine.11,14,25 or dipyrid-mole26 and its correlation with late cardiac events inatients undergoing noncardiac surgery. Furthermore,he extent of fixed and reversible perfusion defects on di-yridamole thallium scintigraphy was a significant indicatorf late cardiac risk.23,27 We also found similar results re-arding the probability of all-cause mortality and long-termardiac events. However, our study population was moreomogenous because it consisted of only patients withnown LV dysfunction of ischemic origin. Moreover, weried to investigate further possible stratification of theseatients according to viability response during DSE. Usingn extensive Internet search of medical libraries, we con-luded that our study is the first to our knowledge showing

beneficial effect of a sustained improvement responseuring DSE for viability estimation in this group of patientsor the end point of long-term cardiac death.

A possible limitation of our study is that as an observa-ional one, it relied mainly upon medical records and ad-inistrative data, meaning that effects of some cardiac risk

actors could be biased. Nevertheless, most predictive val-es that we found are in concordance with previous studiesrom both our and other institutions. Another possible lim-tation could be that we did not investigate the impact ofesponse to dobutamine according to type of surgery. How-ver, the aim of our study is to provide a more accuratetratification of risk of patients with LV dysfunction irre-pective of type of scheduled surgery.

1. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA,Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, et al.Derivation and prospective validation of a simple index for predictionof cardiac risk of major non-cardiac surgery. Circulation 1999;100:1043–1049.

2. Hernandez AF, Newby LK, O’Connor CM. Preoperative evaluationfor major noncardiac surgery focusing on heart failure. Arch InternMed 2004;164:1729–1736.

3. Halm EA, Browner WS, Tubau JF, Mangano DT. Study of perioper-ative ischemia research group. Echocardiography for assessing cardiacrisk in patients having non-cardiac surgery. Ann Intern Med 1996;125:433–441.

4. Rohde LE, Polanczyk CA, Goldman L, Cook EF, Lee RT, Lee TH.Usefulness of transthoracic echocardiography as a tool for risk strati-fication of patients undergoing major non-cardiac surgery. Am J Car-diol 2001;87:505–509.

5. Andris Kazmers, Kohler TR. Very late survival after vascular surgery.
Surg Res 2002;105:109–114.

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1559Heart Failure/Noncardiac Surgery in HF

6. The Expert Committee on the Diagnosis and Classification of DiabetesMellitus. Report of the Expert Committee on the Diagnosis and Clas-sification of Diabetes Mellitus. Diabetes Care 1997;20:1183–1197.

7. American Society of Echocardiography Committee on Standards. Sub-committee on Quantitation of Two-Dimensional Echocardiograms.Recommendations for quantification of the left ventricle by two-di-mensional echocardiography. J Am Soc Echocardiogr 1989;2:358–367.

8. Armstrong WF, Pellikka PA, Ryan T, Crouse L, Zoghbi WA. Stressechocardiography: recommendations for performance and interpreta-tion of stress echocardiography. Stress Echocardiography Task Forceof the Nomenclature and Standards Committee of the American So-ciety of Echocardiography. J Am Soc Echocardiogr 1998;11:97–104.

9. Arnese M, Cornel JH, Salustri A, Maat A, Elhendy A, Reijs AE, TenCate FJ, Keane D, Balk AH, Roelandt JR. Prediction of improvementof regional left ventricular function after surgical revascularization: acomparison of low dose dobutamine echocardiography with 201Tlsingle-photon emission computed tomography. Circulation 1995;91:2748–2752.

0. Cox DR. Regression models and life-tables. J Royal Stat Soc B 1972;34:187–202.

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2. Mangano DT. Perioperative cardiac morbidity. Anesthesiology 1990;72:153–184.

3. Sicari R. Perioperative risk stratification in non cardiac surgery: role ofpharmacological stress echocardiography. Cardiovasc Ultrasound2004;2:4.

4. Poldermans D, Bax JJ, Thomson IR, Boersma E, van der Meer P,Fioretti PM, Elhendy A, van de Ven LMM, Roelandt JRTC, van UrkH. Role of dobutamine stress echocardiography for preoperative car-diac risk assessment before major cardiac surgery: a diagnostic toolcomes of age. Echocardiography 2000;17:79–91.

5. Kazmers A, Cerqueira MD, Zierler RE. Perioperative and late outcomein patients with left ventricular ejection fraction of 35% or less whorequire major vascular surgery. J Vasc Surg 1988;8:307–315.

6. Back MR, Leo F, Cuthbertson D, Johnson BL, Shames ML, BandykDF. Long-term survival after vascular surgery: specific influence ofcardiac factors and implications for preoperative evaluation. J Vasc
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7. Papaioannou GI, Heller GV. Risk assessment by myocardial perfusionimaging for coronary revascularization, medical therapy, and noncar-diac surgery. Cardiol Rev 2003;11:60–72.

8. De Bels D, Coriat P, Puybasset L. What pre-operative explorationsshould be performed in a cardiac patient scheduled for non cardiolog-ical surgery? Presse Med 2003;32:553–560.

9. Landesberg G, Mosseri M, Shatz V, Akopnik I, Bocher M, Mayer M,Anner H, Berlatzky Y, Weissman C. Cardiac troponin after majorvascular surgery: the role of perioperative ischemia, preoperative thal-lium scanning and coronary revascularization. J Am Coll Cardiol2004;44:569–575.

0. Mukherjee D, Eagle KA. Perioperative cardiac assessment for noncar-diac surgery: eight steps to the best possible outcome. Circulation2003;107:2771–2774.

1. Poldermans D, Arnese M, Fioretti PM, Salustri A, Boersma E, Thom-son IR, Roelandt JR, van Urk H. Improved cardiac risk stratification inmajor vascular surgery with dobutamine-atropine stress echocardiog-raphy. J Am Coll Cardiol 1995;26:648–653.

2. Mackey WC, Fleisher LA, Haider S, Sheikh S, Cappelleri JC, Lee WC,Wang Q, Stephens JM. Perioperative myocardial ischemic injury inhigh-risk vascular surgery patients: incidence and clinical significancein a prospective clinical trial. J Vasc Surg 2006;43:533–538.

3. Stratmann HG, Younis LT, Wittry MD, Amato M, Miller DD. Dipy-ridamole technetium-99m sestamibi myocardial tomography in pa-tients evaluated for elective vascular surgery: prognostic value forperioperative and late cardiac events. Am Heart J 1996;131:923–929.

4. Kertai MD, Boersma E, Klein J, van Urk H, Poldermans D. Optimiz-ing the prediction of perioperative mortality in vascular surgery byusing a customized probability model. Arch Intern Med 2005;165:898–904.

5. Poldermans D, Rambaldi R, Fioretti PM, Boersma E, Thomson IR, vanSambeek MR, van Urk H. Prognostic value of dobutamine-atropinestress echocardiography for peri-operative and late cardiac events inpatients scheduled for vascular surgery. Eur Heart J 1997;18(supplD):SD86–SD96.

6. Rossi E, Citterio F, Vescio MF, Pennestri F, Lombardo A, LoperfidoF, Maseri A. Risk stratification of patients undergoing peripheralvascular revascularization by combined resting and dipyridamoleechocardiography. Am J Cardiol 1998;82:306–310.

7. Eagle KA, Singer DE, Brewster DC, Darling RC, Mulley AG, BoucherCA. Dipyridamole-thallium scanning in patients undergoing vascularsurgery. Optimizing preoperative evaluation of cardiac risk. JAMA
1987;257:2185–2189.

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The Editor’s Roundtable: Acute Decompensated Heart Failure

Vincent E. Friedewald, MDa,*, Mihai Gheorghiade, MDb, Clyde W. Yancy, MDc,
James B. Young, MDd, and William C. Roberts, MDe
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cknowledgment

his CME activity is supported by an educational grantrom Scios, Inc., Fremont, California.

isclosure

r. Friedewald has no relevant financial relationships toisclose. Dr. Gheorghiade has received honoraria for speak-ng from Otsuka, Rockville, Maryland; Medtronic, Minne-polis, Minnesota; and GlaxoSmithKline, Research Trian-le Park, North Carolina. Dr. Roberts has receivedonoraria for speaking from AstraZeneca, Wilmington,elaware; Merck, North Wales, Pennsylvania; Scher-

ng Plough, Kenilworth, New Jersey; Pfizer, New York,ew York; and Novartis, East Hanover, New Jersey. Dr.ancy has received honoraria for speaking fromlaxoSmithKline, Research Triangle Park, North Caro-

ina; Novartis, East Hanover, New Jersey; consulting feesnd grant/research support from AstraZeneca, Wilming-on, Delaware; GlaxoSmithKline, Research Triangleark, North Carolina; Scios, Fremont, California; Ni-

romed, Lexington, Massachusetts; and Medtronic, Min-eapolis, Minnesota. Dr. Young has received grant/re-earch support from Abbott, Abbott Park, Illinois;mgen, Thousand Oaks, California; AstraZeneca, Wil-ington, Delaware; GlaxoSmithKline, Research Triangleark, North Carolina; Guidant, St Paul, Minnesota;edtronic, Minneapolis, Minnesota; Vasogen, Missis-

auga, Ontario, Canada; and has been a Consultant forbbott, Abbott Park, Illinois; Acorn Cardiovascular, St.aul, Minnesota; Amgen, Thousand Oaks, California;straZeneca, Wilmington, Delaware; Artesian Therapeu-

ics, Gaithersburg, Maryland; Boehringer Ingelheim, In-elheim, Germany; GlaxoSmithKline, Research Triangleark, North Carolina; Guidant, St. Paul, Minnesota;edtronic, Minneapolis, Minneapolis; Protemix, San Di-

aAssistant Editor, American Journal of Cardiology; Clinical Professor,epartment of Internal Medicine, The University of Texas Medical School

t Houston, Houston, Texas; Visiting Professor, University of Notre Dame,otre Dame, Indiana; bProfessor of Medicine, Associate Chief of theivision of Cardiology, Chief of the Cardiology Clinical Service, andirector of the Telemetry Unit Northwestern University Feinberg Schoolf Medicine, Chicago, Illinois; cMedical Director, Baylor Heart & Vascularnstitute, Chief, Cardiothoracic Transplantation, Baylor University Medi-al Center, Dallas, Texas; dChairman, Division of Medicine, Professor,epartment of Medicine, Cleveland Clinic Lerner College of Medicine ofase Western Reserve University, Cleveland, Ohio; eEditor-in-Chief,merican Journal of Cardiology; Director, Baylor Heart and Vascular

nstitute; Dean, A. Webb Roberts Center for Continuing Medical Educa-ion of Baylor Health Care System, Dallas, Texas. Manuscript received

arch 13, 2007; accepted March 13, 2007.*Corresponding author: Tel: 512-264-1611; fax: 512-264-7034.

sE-mail address: [email protected] (V. E. Friedewald).


go, California; Scios, Freemont, California; Sunshine,aumee, Ohio; Vasogen, Mississauga, Ontario, Canada;

nd World Heart, Oakland, California.

Objectives: Upon completion of the activity, the physi-ian should be able to:

1. Categorize patients according to type of ADHF.2. Treat patients according to the type of ADHF and not

treat all patients with ADHF the same.3. Divide the treatment strategies into 3 phases during

hospitalization.4. Properly use decongesting and vasodilating agents in

patients with ADHF.5. Involve the patient as a key member of the manage-

ment team.

ntroduction

ne million patients are hospitalized each year with acuteecompensated heart failure (ADHF), and 20% of them areehospitalized for this condition within 30 days of thenitial admission.1 ADHF is the most common reason forospital admission of patients �65 years of age, and 1/2f ADHF patients �70 years of age are readmitted within0 days. More than 50,000 patients die annually fromDHF, more than any single cancer.2 In the section

Evaluation and Management of Patients with Acute De-ompensated Heart Failure” in the Heart Failure Societyf America 2006 Comprehensive Heart Failure Practiceuideline,3 only 2 of 34 recommendations carried a level

A” strength of supporting evidence, highlighting theeed for much more research about ADHF. In this Edi-or’s Roundtable, the faculty discusses best managementtrategies for patients with ADHF based on the limitednowledge base.

iscussion

r. Friedewald: What is “acute decompensated heart fail-re” (ADHF)?

Dr. Yancy: ADHF applies to 2 groups of cardiac pa-ients: (1) patients having symptoms of heart failure (HF)or the first time, and (2) patients with exacerbated symp-oms of established HF.

Dr. Gheorghiade: I divide ADHF patients into 3 groups:1) worsening chronic HF (70% of all cases of acute HF);2) HF diagnosed for the first time (25%), and (3) advancedr end-stage HF—patients who do not respond to treatment5%).

Dr. Yancy: Patients with ADHF are a heterogeneousroup, and include many patients who do not have straight-orward left ventricular systolic dysfunction with its classic
igns and symptoms.
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1561Roundtable Discussion: Acute Decompensated Heart Failure

Dr. Roberts: Are patients with cor pulmonale includedn the definition of ADHF?

Dr. Yancy: Yes, because cor pulmonale is driven by leftentricular dysfunction. Patients with ADHF often havether co-morbid conditions, including chronic lung disease,enal insufficiency, diabetes mellitus, atrial dysrhythmias,nd anemia.

Dr. Georghiade: About 40% of patients with ADHFave diabetes mellitus; 50% have systemic arterial hyper-ension; and 30% have renal insufficiency.

Dr. Young: My criteria for ADHF include anyone goingo an urgent care center with symptoms due to HF oromplications of HF, such as an arrhythmia or syncope.

Dr. Roberts: What about sudden weight gain?Dr. Young: I would not call that acute decompensated

F, just worsening HF. Patients with chronic HF haveeight fluctuations of �5 pounds per week, and symptomsuctuate accordingly. Weight gain itself, however, does not

nevitably lead to a need for urgent care.Dr. Friedewald: My concern about your definition of

DHF is some other factors often determine whether aatient seeks “urgent care,” such as lack of health insurancer convenient transportation.

Dr. Roberts: I agree that a definition should not dependn where patients go after symptoms appear. They can havecute decompensation and remain at home.

Dr. Young: The natural history of ADHF is that a badvent will eventually happen and, when it does, the patientither seeks treatment or dies.

Dr. Yancy: Many European experts believe ADHF in-olves only patients with pulmonary edema. In Northmerica, however, we allow a number of different ways forDHF to be manifest.Dr. Gheorghiade: Such heterogeneity, however,

akes it difficult to do studies on these patients. We needclearer definition of ADHF. Pulmonary edema, hyper-

ension, and right-sided HF are all clinical presenta-ions. We should not confuse clinical presentation with aefinition of ADHF. ADHF classification is often donen retrospect, because it is very difficult to classify pa-ients when they are first admitted. At the time of admis-ion the clinical picture encompasses several differentrocesses— hypertension, right-sided HF, and pulmonarydema. Other parameters, like the ejection fraction,re needed to classify the patient, and they are notnown when the patient is seen for the first time. Itsually takes 24 hours before the HF patient can belassified properly. It is important to distinguish betweenlassification, which can be done later, and mode ofresentation.

Dr. Roberts: No one has mentioned etiology in theefinition of ADHF.

Dr. Gheorghiade: Initially, the etiology is not impor-ant, because a high left ventricular filling pressures the main reason a patient with ADHF comes to theospital. The immediate therapeutic goal is to reducehe filling pressure, regardless of whether the etiologys acute myocardial infarction or acute aortic regur-itation.

Dr. Roberts: Mitral stenosis is immediately correctible.
Dr. Gheorghiade: Yes, but the initial goal is to reduce i
ongestion. As soon as the patient is stable, etiologyecomes very important, because it guides to definitiveherapy. Regardless of whether the patient has hyperten-ion or aortic valve stenosis, most deaths are due to aigh filling pressure, not to a low cardiac output. Themmediate therapeutic goal in ADHF is to safely improvehe left ventricular filling pressure.

Dr. Young: Heart failure is the umbrella under which areacute,” “decompensated,” “ischemic,” “valvular,” “right-ided,” “left-sided,” and so on.

Dr. Roberts: The common denominator of ADHF isudden elevation of the left ventricular end-diastolic pres-ure?

Dr. Young: Yes.Dr. Gheorghiade: Elevation of left ventricular end-dia-

tolic pressure, however, does not have to be sudden. It cane gradual.

Dr. Roberts: Untreated, however, it eventually reaches aevel where the symptoms are intolerable, and the result isDHF.Dr. Gheorghiade: That is correct.Dr. Friedewald: What are the demographics of ADHF?Dr. Gheorghiade: The mean patient age is 75 years.

orty to 50% of patients have preserved left ventricularystolic function; 70% have a history of systemic hyperten-ion, 60% have documented coronary arterial disease; 45%re post-myocardial infarction; 30% have a history of atrialbrillation; 40% have diabetes mellitus; and 30% havehronic obstructive pulmonary disease. Secondary mitralegurgitation is common. Although ADHF is a complexntity, the patient comes to the emergency department for aingle reason: the left ventricular filling pressure is high,ausing breathlessness. Thus, the immediate treatment endoint is to eliminate dyspnea. The other abnormalities cane treated later. About 50% of patients with ADHF presento the hospital with reactive hypertension, which is anntermittent form of hypertension. These patients may beormotensive 6 hours later.

Dr. Roberts: You said that 40% of patients with ADHFave diabetes mellitus, which adults essentially do not getnless they are overweight. Is that not correct?

Dr. Yancy: Yes. Patients with HF and an increased bodyass index “do better” than persons of normal weight.Dr. Roberts: That is also true for patients with acute

yocardial infarction.Dr. Friedewald: Would you expand on reactive hyper-

ension in patients with ADHF?Dr. Gheorghiade: Among 200,000 patients in The

cute Decompensated Heart Failure National RegistryADHERE) and other registries, �50% were hypertensivet the time of their initial presentation. Many of the hyper-ensive patients, however, were normotensive prior to ad-ission; after admission, their pressures were often easy to

ontrol and were frequently normal within 6 to 24 hours.he reason for this arterial systolic pressure reactivity isctivation of neurohormones due to the high left ventricularlling pressure. Thus, this population should not be con-used with patients who have a history of hypertension,ecause the 2 are distinctly different pathophysiologicalonditions. The blood pressure cannot increase unless there
s adequate left ventricular function, so blood pressure in a

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ay indicates cardiac reserve in patients with ADHF. Pa-ients with peak systolic blood pressures of 120 mm Hg athe time of admission have a poor prognosis because theirentricles are unable to appropriately respond to increasedympathetic tone.

Dr. Yancy: Few patients with ADHF have low bloodressure or shock. In The Evaluation Study of Congestiveeart Failure and Pulmonary Artery Catheterization Effec-

iveness (ESCAPE), the patients with lower blood pressurend cardiac outputs on admission did not respond well toherapy.

Dr. Young: In both The Organized Program to Initiateifesaving Treatment in Hospitalized Patients with Heartailure (OPTIMIZE-HF) and the ADHERE registries50,000 and 100,000 patients, respectively), 50% had pre-erved left ventricular systolic function.

Dr. Gheorghiade: Most physicians treating ADHF fo-us on improving the cardiac output, although cardiac out-ut is usually normal or high in these patients, and it is nothe major problem. The treatment goal should be to reducehe pulmonary arterial wedge pressure, which, of course,orresponds with the left ventricular end-diastolic pressurethe filling pressure).

Dr. Roberts: If we could prevent systemic hypertension,ould we also prevent most cases of HF?Dr. Yancy: In the Systolic Hypertension in the Elderly

roject, among patients with coronary heart disease andystolic hypertension, concomitant administration of a thi-zide diuretic plus a � blocker led to an 80% reduction inubsequent HF. It is likely that treating hypertension to goalblood pressure at least �140/90 mm Hg) would reduce thencidence of HF by 50%. There are no prospective trials,owever, designed to prevent HF.

Dr. Roberts: Perhaps lipid-lowering or antihypertensiveherapy will prove to be the best anti-HF therapy.

Dr. Yancy: Statin therapy also may have a stabilizingffect in ADHF, possibly because of its anti-inflammatoryffect.

Dr. Young: The data on the favorable effect of statins ismpressive in HF cohorts, even when not prescribed forlevated lipids. Coupled with antihypertensive therapy, thisay be the direction we need to go to prevent symptomatic

eft ventricular diastolic dysfunction.Dr. Roberts: Do you include statins in the treatment of

atients with idiopathic dilated cardiomyopathy?Dr. Yancy: Yes, I do sometimes.Dr. Gheorghiade: Heart failure may be a consequence

f hypertension, coronary arterial disease, atrial fibrillation,nd diabetes mellitus, and all of them, of course, are treat-ent targets in ADHF, in addition to lowering the left

entricular filling pressure.Dr. Roberts: Patients with increased left ventricular

nd-diastolic pressures who have normal-sized left ventri-les and thick left ventricular walls are not the same asatients with comparable end-diastolic pressures, but whoave dilated left ventricular cavities and relatively thinalls, are they?Dr. Gheorghiade: No, because the left ventricular end-

iastolic pressure is a function of the left atrium contractinggainst a “stiff” left ventricle.

Dr. Yancy: We call a left ventricular ejection fraction h

40% “heart failure with preserved systolic function.” Aeft ventricle with an ejection fraction of 45% looksretty sick, a ventricle with an ejection fraction of 55%ooks better, and a ventricle with an ejection fraction of0% looks great. We should differentiate, however, be-ween patients with symptomatic pulmonary congestionn the presence of a normal-sized left ventricular chamberersus patients with symptomatic congestion and a di-ated left ventricular cavity.

Dr. Gheorghiade: I agree, but it is unusual for patientso have preserved left ventricular systolic function and highlling pressures, unless they have an infiltrative cardiomy-pathy (amyloidosis, for example) or systemic hyperten-ion.

Dr. Roberts: Are you talking about left ventricular wallshat are much thicker than normal versus those ventricularalls that are not thickened?Dr. Gheorghiade: Primary left ventricular diastolic dys-

unction is a rare cause of HF. Few patients with leftentricular hypertrophic cardiomyopathy develop HF.

Dr. Roberts: You said 40 to 45% of patients with HFad left ventricular diastolic failure.

Dr. Gheorghiade: Yes, but I said diastolic, not primaryiastolic HF. There is a difference. The ventricular wall maye thick, but it is not primary thickening. I distinguishetween primary diastolic dysfunction and secondary dia-tolic dysfunction. Patients with myocardial ischemia andatients with systemic hypertension both have secondaryiastolic dysfunction. Thus, there are many patients withiastolic HF, but it is not a primary form of diastolic HF.hey have thicker ventricles, but there is not always a goodorrelation between ventricular thickness and the presencef diastolic HF.

Dr. Young: This is both a structural and a mechanicalhenomenon, complicated by the reality that patients witheft ventricular systolic dysfunction have varying degrees ofiastolic dysfunction.

Dr. Roberts: But not the reverse.Dr. Young: That is correct. The one profound driver in

he process is afterload increase—which, by definition, isypertension. Because only recently has the importance ofiastolic HF been recognized, therapies primarily focusingn diastolic HF have not been designed.

Dr. Roberts: What are the most common signs or symp-oms of diastolic HF?

Dr. Gheorghiade: Of patients with ADHF, 70% edema;0% rales; 40%, a systolic precordial murmur; 40% dyspneat rest; and 30% have jugular venous distention.

Dr. Yancy: Both the European regulatory body and theood and Drug Administration state that the sine qua non ofDHF is dyspnea.Dr. Friedewald: What is the natural history of ADHF?Dr. Yancy: The death rate for the hospitalized patient

ith ADHF is low, but in some select, very well-definedroups, it is as high as 20%. Even with optimal care,owever, the 30-day risk of death is 10%. At 1 year from thendexed hospitalization, the risk of death is about 30%. Theeath rate at 1 year for ambulatory class III HF patients isbout 10%. The risk of rehospitalization is 50%. There isomething about hospitalization that changes the natural
istory, but we do not know what that is.

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Dr. Roberts: Are you saying that patients should notome to the hospital?

Dr. Yancy: No, we assume it would even be worseithout hospitalization.Dr. Friedewald: Is etiology a factor in prognosis?Dr. Gheorghiade: Yes. Data from OPTIMIZE show that

yocardial ischemia carries a far worse prognosis thanrimary cardiomyopathy. The mortality curve in patientsith class IV HF is linear between mortality and time.atients hospitalized for HF resemble the post-myocardial

nfarction curve, with a very high event rate in the first 60ays, followed by a relatively flat curve.

Dr. Gheorghiade: Etiology is the key to proper man-gement, but not for assessing prognosis.

Dr. Yancy: The precipitating cause must be addressed inpatient with ADHF. Chronic HF trials have shown no

ifference in outcomes with � blockers or angiotensin-onverting enzyme (ACE) inhibitors or any other evidence-ased therapy as a function of the etiology of left ventricularysfunction. Thus, therapy for HF is stratified according toeft ventricular function, not etiology.

Dr. Roberts: Many of these studies, however, do notnclude patients with severe aortic stenosis, mitral stenosis,oarctation of the aorta, and other such correctable condi-ions. It would be terrible to miss such a diagnosis.

Dr. Yancy: That is correct.Dr. Roberts: It appears that HF specialists are the car-

iac oncologists of heart disease, because you are focusedn longevity. Longevity, however, is not the orientation ofhe average cardiologist.

Dr. Gheorghiade: About 80% of patients with HF areot seen by a cardiologist. There are studies suggesting thatardiologists are no better in managing HF than are generalnternists.

Dr. Young: In response to Dr. Roberts’ assertion that HFpecialists are cardiac oncologists, I am reminded of aatient I saw this morning who was referred for inoperable-vessel coronary arterial disease. He had well-compen-ated class I HF. He had been told by his physician that heas going to die and that he might need a heart transplant.ow long is he going to live? Although the overall prog-osis for such patients is not good, there are categories ofF patients who do well for decades, a fact that is some-

imes lost in the descriptions of high morbidity and highortality. Such negative attitudes on the part of physicians

ause many patients with HF to go through a lot of unnec-ssary psychological angst.

Dr. Gheorghiade: I am reminded of a patient, a physi-ian, who was diagnosed years ago with end-stage HF.oday, he has a normal-sized heart. I see such patientsearly every day. Many patients with proper medical ther-py of their HF—I call them chemical, rather than mechan-cal transplants—have sufficient myocardial viability, suchhat their ejection fraction can be normalized over time.

Dr. Yancy: You are correct. HF specialists tend to thinkn 1-year and 5-year mortality constructs, much theame—as Dr. Roberts pointed out—as oncologists.

Dr. Gheorghiade: But there is a huge difference. Thencologist does not have truly life-saving therapy, whereas
F specialists do. s
Dr. Roberts: What life-saving therapies are you refer-ing to?

Dr. Gheorghiade: Beta blockers, ACE inhibitors, aldo-terone-blocking agents, cardiac resynchronization therapy,ntracardiac defibrillators, perhaps statins. Although HF is aondition with a bad prognosis, we have remedies. Theroblem is that there is a huge gap between what we can dond what is being done.

Dr. Yancy: This is true with chronic HF, where we havereatly improved therapies, but treating patients with ADHFs far less successful.

Dr. Gheorghiade: It is essential to identify the precipi-ating cause of ADHF for patients to improve. If the pre-ipitating cause is not delineated and treated, the patient willot improve. Atrial fibrillation, infection, diabetes mellitus,nemia, all must be treated. Unfortunately, this is not beingone nearly enough. I have seen patients with a hemoglobinf 5 mg/dl who were treated with diuretics; they will notmprove until the anemia is corrected. The same is true forontrolling the heart rate in atrial fibrillation. The precipi-ating cause is key to successful treatment of patients withDHF.Dr. Friedewald: I am concerned that so few HF patients

re seen by cardiologists. I would argue that every patientith HF should be evaluated at least once by a cardiologist.Dr. Gheorghiade: With 1 million annual hospitaliza-

ions for HF in the USA that desire is not possible.Dr. Yancy: Outcomes for patients with HF are deter-

ined more by factors, such as renal function, systemiclood pressure, and hemoglobin, than by etiology. Everyatient with heart failure should have a practitioner who hasHF focus, even if that person is a nurse practitioner.Dr. Roberts: What is your general workup for a patient

ith first-time ADHF?Dr. Gheorghiade: I recommend a full right and left-

ided cardiac catheterization, including coronary angiogra-hy and left ventriculography.

Dr. Yancy: The guidelines recommend cardiac catheter-zation in patients with HF and angina pectoris. No morehan 5% of patients admitted to the hospital with ADHFndergo cardiac catheterization.

Dr. Roberts: What laboratory tests do you do routinelyerform?

Dr. Gheorghiade: Tests are renal function and targetrgan function, electrolytes, Doppler echocardiogram, chestadiograph, and perhaps the brain naturetic peptide (BNP).

Dr. Roberts: Why perhaps the BNP?Dr. Yancy: The role of BNP is unresolved. It is most

seful when there is diagnostic ambiguity, whether dyspnea,or example, is due to pulmonary or cardiac disease. Whenhe likelihood of lung disease is high, the BNP does notave much diagnostic value. The BNP, however, can pro-ide unique prognostic information. Thus, while the role oferial BNP measurements is unresolved, BNP does havealue in cases of diagnostic ambiguity and for determiningrognosis.

Dr. Friedewald: How do you assess the mortality risk inpatient with ADHF?Dr. Yancy: In ADHERE, 3 measurements indicated a

2% inpatient risk of death: blood urea nitrogen �37 mg/dl,
ystolic blood pressure �115 mm Hg, and creatinine �2.75

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g/dl. When the blood urea nitrogen was �37 mg/dl andhe systolic blood pressure was �115 mm Hg, the risk ofnpatient death was only 2%.

Dr. Gheorghiade: The systolic blood pressure at theime of admission is a major predictor of risk: when it is

120 mm Hg, the in-hospital mortality is 7%, the post-ischarge mortality is 14%, and the readmission rate is 30%,ompared to an in-hospital mortality of 1% and a post-ischarge mortality of 5% when the systolic blood pressures �115 mm Hg. Systolic blood pressure is an indicator ofeft ventricular systolic function. Thus, when the systoliclood pressure is high, e.g., 190 mm Hg, the ejection frac-ion is probably well preserved. A patient with a systoliclood pressure of 120 mm Hg at admission is likely inrouble and too often that patient is treated the same as aatient with a higher systolic blood pressure. The systoliclood pressure is not only a good prognostic indicator, buthen it is low, it indicates that maximal therapy from theutset—� blockers, ACE inhibitors, aldosterone antago-ists, is warranted.

Dr. Roberts: How do you manage the blood pressure inpatient who was previously hypertensive and is admittedith ADHF with a low systolic blood pressure?Dr. Gheorghiade: That patient has a terrible prognosis.

rials have taught us that it is extremely important not toower the blood pressure further. To do so can significantlyecrease the coronary perfusion pressure. It is extremelymportant in such patients to improve cardiac function with-ut decreasing coronary perfusion, because the myocardiums likely ischemic and there is increased neurohormonalctivity that adds to the myocardial ischemia.

Dr. Roberts: Do you try at all to increase the bloodressure?

Dr. Yancy: Even though marginal or low blood pressures a risk of poor outcome, it is a terribly inappropriate targetor therapy, because the only way to increase the bloodressure is with vasoconstrictors and inotropes. Given thatlood pressure is a product of cardiac output and peripheralrterial resistance, increasing the cardiac output by reducingesistance using vasodilators and other strategies is a morehysiologic way to normalize and elevate the blood pres-ure. Fluctuations in blood pressure during ADHF mayncrease near-term event rates. Protecting the patient fromypotension is probably a better therapeutic target thanctually raising the blood pressure.

Dr. Young: It is better for the HF patient to have a lowerlood pressure and a slower heart rate, as long as the patients walking, talking, and urinating. What is most important iserfusion and organ function.

Dr. Friedewald: Does the initial blood glucose haverognostic value?

Dr. Gheorghiade: In both OPTIMIZE and in ESCAPE,here was no short-term difference in outcomes betweenatients with and without diabetes mellitus. These trials,owever, only looked at short-term differences.

Dr. Yancy: What about hyponatremia and anemia?Dr. Young: The patient’s serum sodium level should be

ormalized. Whether to treat anemia is highly controversial,ven though patients with anemia have worse short-term
nd long-term outcomes than those without anemia. o
Dr. Roberts: How do you define anemia in these pa-ients?

Dr. Young: A hemoglobin �12 mg/dl.Dr. Roberts: How do you treat hyponatremia?Dr. Young: By a variety of measures, and all focusing

n limiting the amount of free water intake versus saltntake, and, if possible, lowering the doses of diuretics. Innemic patients. thiazide-based diuretics also should bevoided.

Dr. Gheorghiade: In OPTIMIZE-HF, 25% of the pa-ients had hyponatremia. In ESCAPE, 25% of patientslso had hyponatremia, both at admission and at dis-harge. Thus, hyponatremia is common, and it is notroperly treated. The most intriguing aspect of ESCAPEas that, although patients with hyponatremia had theest clinical and hemodynamic response to therapy, com-ared to patients with normal serum sodium levels, theirost-discharge mortality was 3 times higher. Hyponatre-ia is an independent and major predictor of prognosis.yponatremia also indicates the presence of a unique

orm of HF.Dr. Yancy: Hyponatremia also correlates with the extent

f neurohormonal activation in patients with ADHF. Iould argue that treating hyponatremia has not been shown

o be beneficial and, until we have done so, it is not neces-arily a target of therapy.

Dr. Friedewald: Are results of tests for renal functionmproved by successful treatment of ADHF?

Dr. Yancy: That is not known.Dr. Friedewald: Which specific agents improve morbid-

ty and mortality in ADHF?Dr. Yancy: The therapeutic target in ADHF is primarily

emodynamic, the same as in patients with chronic HF.urrently, in patients with ADHF, the target of therapy islso hemodynamic, but good results with this strategy haveot been seen.

Dr. Gheorghiade: Treatment of ADHF can be separatednto 3 different phases: (1) early management for improvingemodynamics; (2) in-hospital management for eliminatingesidual symptoms; and (3) predischarge management formplementing life-saving therapies.

Dr. Young: The goal is to make the patient feel better, torotect the patient from end-organ damage—especially theardiorenal syndrome—and to set the stage for getting theatient out of the hospital, which primarily requires decon-estion.

Dr. Yancy: Given that ADHF is a heterogeneous diseaserocess with multiple patient phenotypes, is lowering mor-ality an appropriate target? Will a single therapeutic strat-gy for a patient population this diverse lower mortality?

Dr. Young: ADHF cannot be viewed with the sameindset as patients with acute myocardial infarction,

or example. Treatment of the latter is straight for-ard and much the same for all patients. Treating pa-

ients with HF is far more complex. While I believe thateduction in acute hospital mortality for ADHF is aaudable goal, that reduction is not going to be achievedith any 1 specific intervention. Rather, it will require a

ombination of therapies related to the 3 goals I men-ioned earlier and the 3 treatment phases Dr. Georghiade
utlined.

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Dr. Gheorghiade: Improved survival is not the issue;ather, the issue is not increasing mortality with our treat-ent.Dr. Yancy: I agree.Dr. Gheorghiade: One dilemma with ADHF is that

any therapies that improve hemodynamics—such as do-utamine—also kill myocardial cells.

Dr. Yancy: I agree that seeking a single interventionargeted towards lowering mortality is unrealistic. What isore relevant is relieving symptoms and lowering morbid-

ty while increasing mortality.Dr. Gheorghiade: The HF guidelines are based more on

pinion than facts, which we lack. The guidelines urgemproving the pulmonary arterial wedge pressure with aombination of vasodilators and diuretics, but not excessiveiuresis. We should not rely solely on diuretic therapy toelieve congestion.

Dr. Yancy: The guidelines do, however, emphasize “de-ongesting” the patient.

Dr. Gheorghiade: By using combination therapy, notingle therapy.

Dr. Young: The HF therapy is made more complex byhe need also to treat co-morbidities such as anemia, myo-ardial ischemia, hypertension, diabetes mellitus, and hy-erglycemia.

Dr. Yancy: Decongestion with diuretics is an appropri-te first step. Is the second step the administration of high-olus diuretic therapy, continuous diuretic infusion, or va-odilators combined with standard diuretic therapy?

Dr. Young: I come back to the underlying co-morbid-ties. I would treat a patient admitted with ADHF andong-standing hypertension and left ventricular systolicnd diastolic dysfunction immediately with both vasodi-ators and diuretics, relying more on the vasodilators toower the left ventricular end-diastolic pressure ratherhan being aggressive with diuretics. Diuretic use hashanged with time. It is rare for me to see a patient whoeeds to be admitted to the hospital that I do not start oncontinuous diuretic infusion. If a patient is sufficiently

olume overloaded to be admitted to the hospital, guess-ng the doses of intermittent, pulsed diuretics is much

ore problematic than guessing the dose of continuousnfusion.

Dr. Gheorghiade: For some patients, diuretics are sec-nd-line therapy. Hypertensive patients—even those witheactive hypertension—are often older, and they may haveedistribution of body fluids rather than being total bodyuid overloaded.

Dr. Friedewald: Do you not give these patients both aasodilator and a diuretic?

Dr. Gheorghiade: Yes. Most of the time, I use theombination, but not always. There should not be any-hing routine. About 50% of these patients are hyperten-ive, and the goal in these patients is to reduce the bloodressure, not reduce fluid overload. In other patients, theulmonary arterial wedge pressure may be the only tar-et. In patients who are hypertensive, there are 2 targetsor therapy: simultaneous reduction of both the bloodressure and the pulmonary arterial wedge pressure.

Dr. Friedewald: Does everyone agree that patients with
DHF should first be “decongested?”
Dr. Gheorghiade: Yes, but how to achieve that shoulde determined by how the patient presents.

Dr. Young: How often do you not give diuretics toatients admitted with ADHF?

Dr. Gheorghiade: I usually use diuretics, but I do notely solely on them, as happens too often.

Dr. Young: How often do you see acute pulmonarydema with a normal total body volume?

Dr. Gheorghiade: This occurs in about 5% of patientsith ADHF.Dr. Young: Do you give diuretics to those patients?Dr. Gheorghiade: No.Dr. Young: Most physicians do not think that way. Most

ive all patients with pulmonary edema an intravenousolus of diuretics.

Dr. Gheorghiade: The problem is mainly the quantity ofiuretics given. According to ESCAPE, the deleterious ef-ects of diuretics were not so much related to the diuretic,ut to the amount given.

Dr. Yancy: What is the role of inotropes?Dr. Young: I use them only for patients in shock or

ear-shock.Dr. Gheorghiade: I use inotropes for patients in the low

ardiac output state. There is no other choice. Most physi-ians in the USA unfortunately use inotropes in patientsith normal cardiac output.Dr. Friedewald: What is the role of vasodilators—ni-

roprusside, nitroglycerin, and nesiritide?Dr. Yancy: In patients with symptoms at rest in the

bsence of hypotension, 1 of 3 vasodilators should be used:itroprusside, nitroglycerin, or nesiritide. Nitroprusside hasn excellent profile, helping to normalize blood pressurend to relieve concomitant pulmonary congestion by reduc-ng both preload and afterload. Nitroglycerin relieves pul-onary congestion in patients with ADHF by reducing

reload.Dr. Gheorghiade: Nesiritide is an excellent choice both

or hypertensive and normotensive patients. Unfortunately,esiritide is too often used as rescue therapy in patients whoo not respond to other therapies. These patients are fre-uently hypotensive and have impaired renal function. Al-hough nesiritide is an excellent drug for ADHF patientsith normal or elevated blood pressure, it is often used inatients who are most likely to have adverse effects fromhis drug.

Dr. Roberts: How do you administer nitroglycerin forDHF?Dr. Yancy: Topically, intravenously or sublingually.Dr. Young: Nitrates are excellent drugs in ADHF when

sed correctly. These patients must be carefully monitored,atching for tachyphylaxis, and titrating the drug over time.asodilators should not be used in the hypotensive patients.t presentation, patients with ADHF may be hypertensiver normotensive or hypotensive, and each needs to be ad-ressed differently with respect to the vasodilator/diureticombination. I make such decisions very early in the coursef ADHF.

Dr. Gheorghiade: Nitroprusside requires invasive mon-toring, because it can rapidly lower the arterial blood pres-ure to zero.

Dr. Friedewald: What about oxygen?

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Dr. Yancy: Oxygen is the only pure pulmonary vasodi-ator we have. It will overcome any other influence, anddecongest” the pulmonary circulation.

Dr. Friedewald: Let’s discuss future therapies, startingith aquaretic therapy.Dr. Gheorghiade: Aquaretic therapy, or vasopressin

ntagonism, is safe, can be added to diuretic therapy, andignificantly reduces body weight, without adverse ef-ects on the heart rate, blood pressure, renal function, orerum potassium, and generally normalizes the serumodium. Theoretically, it can be used with or without aiuretic.

Dr. Yancy: Acute administration of natriuretic pep-ides improves congestion and relieves dyspnea, buterhaps not more effectively than nitroglycerin. Natri-retic peptides, however, may have adverse effects onenal function and increased risk of death 30 days afterdministration. These questions are being resolved by

very large multicenter international trial in ADHFnvolving 7,000 patients. The planning stages are under-ay for this trial, called Acute Study of Clinical Effec-

iveness of Nesiritide in Decompensated Heart FailureASCEND-HF).

Dr. Friedewald: What about devices?Dr. Young: Mechanical removal of fluid has been

round a long time. Veno–veno ultrafiltration devices toemove fluid are miniaturized, efficient, and easy to use.he UNLOAD trial and several other trials will give usreater insight into their usefulness. I believe that me-hanical fluid removal devices are going to be a goodption in the future.

Dr. Roberts: I understand that the average patient in theSA with an acute coronary event has a body mass index of

bout 29, which I suspect is the same as patients withDHF. How would significant weight loss affect the lon-evity of ADHF patients?

Dr. Young: I believe it would be very effective.Dr. Gheorghiade: The problem is that chronic HF pa-

ients are malnourished, even including some who are over-eight.Dr. Roberts: Malnourished from a protein standpoint?Dr. Gheorghiade: Yes. The heart requires a lot of pro-

ein to function properly. We are currently studying theotential role of essential amino acid supplements and otherherapies to improve nutrition in HF patients.

Dr. Friedewald: How should future trials of ADHF beonducted?

Dr. Gheorghiade: Thus far, ADHF trials have involvedatients who are not stratified. There are different popula-ions of patients with ADHF, including those with variouslood pressures, serum sodium levels, geographical differ-nces (different continents), and each of these differentatient types needs to be stratified for proper investigation.e are currently putting together a large trial that stratifies

atients admitted with acute HF into 2 groups: those treatedith standard care, and those treated with maximal aggres-

ion.Dr. Friedewald: Is it difficult to find funding for such

rials?Dr. Young: It is a horrible problem. Support is mostly

rom industry. h

Dr. Friedewald: Let’s discuss “disease management.”Dr. Yancy: Disease management in ADHF carries

ome good news. There are indicators of quality that haveeen promulgated across all hospitals in this country.sing these indicators, we recently demonstrated that

ertain therapeutic strategies, such as the use of ACEnhibitors and � blockers, appear to modify 60- to 90-dayutcomes. Such clinical trials have repetitively shownhat best practices make a difference in outcomes. When

HF patient is hospitalized, an excellent opportunityrises to place that patient on the right drugs and into theight follow-up schemes.

Dr. Friedewald: How do you determine the optimalime to discharge a patient with ADHF from the hospital?

Dr. Gheorghiade: This is a very important issue. Guide-ines do not tell us when patients are ready for discharge.lthough congestion is the main reason for admission, 50%f these patients do not lose weight during hospitalization.hen they go home, they go home with the same amount of

uid, which has shifted from the lungs, where you can stillear it with the stethoscope and see it on chest x-ray, tother portions of the body.

Dr. Yancy: I agree that we do not have a good barometeror discharge.

Dr. Gheorghiade: There are things we could do better:atching the patient climb a flight of stairs, perform a BNP,

nd determine if a patient can lie fully reclined. These areimple tasks, but they are not being done.

Dr. Yancy: I discharge the patient when the presentingymptoms are gone, there is improvement in the back-round medical therapy, and there is a well-defined plan ofare for the future.

Dr. Gheorghiade: I rely on how patients feel. I performn orthopnea test to be certain that patients can lay flat forminute, and I ask them to climb 1 flight of stairs. If they

ass these tests, and they have no signs of congestion, Iischarge them.

Dr. Young: I make certain the patient feels better com-ared to symptoms at admission, is ambulating, and isecongested. I will send a patient home with a small amountf peripheral edema. It is more important to see improve-ent than total resolution. And a long-term treatment plan

s essential.Dr. Roberts: Can we train more physicians to specialize

n treating patients with HF?Dr. Yancy: As immediate past chair of the membership

ommittee of the Heart Failure Society of America, myharge for 3 years was to try to find ways to get morerofessionals involved in treatment of patients with HF.lthough there are people who are interested in special-

zing in HF, there is a disconnect between the way werain people and the way people are hired. Physicians areypically hired according to what they can do procedur-lly, but we train people according to what they need tonow cognitively. This needs to be changed, and theeart Failure Society of America is raising the awarenessf the value of the cognitive input of HF specialists. It isur hope that we can achieve certification of HF man-gement as a recognized subspecialty. Revenue and otheruch resources, however, drive a lot of this sort of be-
avior in our society, so if we can add value to the

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esignation as a HF physician, more people will be in-erested in pursuing this subspecialty.

Dr. Young: A good HF clinician must have a goodnderstanding of renal pathophysiology, pulmonary patho-hysiology, hemodynamics and heart transplantation. Therere a lot of exciting aspects of this specialty. Reimburse-ent issues, however, hamper these efforts. Unless we cre-

te more systems to deal with the reimbursement issues, HFpecialists will continue to struggle and inadequate numbersill enter the subspecialty.Dr. Gheorghiade: The most important member of the

F team is the patient. The physician sees these patientsnce every 2 months, and the patients are with them-elves 24 hours a day, 7 days a week. So the patient is aery important component, because therapy for HF ishronic. When patients do not take their medicines and/orail to do other proper things, outcomes are bad. Theatient is the major part of the HF management team.

Dr. Friedewald: Thank you.

Needs Assessment: The need for this activity for cardi-logists and other healthcare specialists in cardiovascularedicine is based on the following premises:

1. Acute decompensated heart failure (ADHF) is a com-mon cause of morbidity and mortality.

2. ADHF is associated with many co-morbid conditions.3. ADHF is a complex, multidimensional condition de-

manding knowledge of cardiac, pulmonary, hemody-namic, and renal function.

4. Knowledge about ADHF is not as advanced as ourunderstanding of other cardiovascular conditions,such as chronic congestive heart failure and acute
myocardial infarction.
5. There is a need for more physicians to be trained intreating patients with ADHF.

Target Audience: This activity is designed for cardiol-gists and all other health care specialists caring for patientsith acute and chronic coronary heart disease.

CME Credit: The A. Webb Roberts Center for Continu-ng Medical Education of Baylor Health Care System, Dal-as, designates this educational activity for a maximum of 1MA PRA Category 1 Credit(s).™ Physicians should onlylaim credit commensurate with the extent of their partici-ation in the activity.

The A. Webb Roberts Center for Continuing Medicalducation for Baylor Health Care System, Dallas, is accred-

ted by the Accreditation Council for Continuing Medicalducation to provide continuing medical education forhysicians.

CME Instructions: After reading this article, go onlinet www.AJConline.org to register, complete a post-test withminimum score of 80%, complete an evaluation, and printcertificate.Combination of Media: Print and InternetComputer Requirements: Windows 2000, Pentium 3 orgreater, 512 ram, 80 gigabytes storageEstimated Time to Complete: 1 hourRelease Date: June 2007Termination Date: June 2008

. American Heart Association. Heart Disease and Stroke Statistics.Available at: http://circ.aha.journals.org/cgi/reprint/113/6/e85.

. American Cancer Society. Cancer Statistics 2005. Available at: http://int-caonline.amcancersoc.org/cgi/content/full/55.

. Executive Summary: HFSA 2006 Comprehensive Heart Failure Prac-
tice Guideline. J Cardiac Failure 2006;12:10–38.
http://www.AJConline.org

http://circ.aha.journals.org/cgi/reprint/113/6/e85

http://int.caonline.amcancersoc.org/cgi/content/full/55

http://int.caonline.amcancersoc.org/cgi/content/full/55

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Effect of Metoprolol on Heart Rate Variability in SymptomaticPatients With Mitral Valve Prolapse

Gülten Taçoy, MD*, Akif Serhat Balcıoglu, MD, Ugur Arslan, MD, Emre Durakoglugil, MD,Güliz Erdem, MD, Murat Özdemir, MD, and Atiye Çengel, MD

Metoprolol is widely used to eliminate symptoms in patients with mitral valve prolapse(MVP), a condition associated with enhanced sympathetic tone. In this study, effects ofmetoprolol on heart rate variability (HRV) indices were investigated in symptomaticpatients with MVP. Thirty-nine symptomatic patients with MVP (26 women, mean age26 � 7 years) and 16 age- and gender-matched controls were studied. After a baseline24-hour Holter evaluation in all subjects, patients with MVP were started on metoprololsuccinate therapy at a dose of 25 to 100 mg/d, and Holter analysis was repeated at the endof 3 months of metoprolol therapy. At the basal evaluation, all time–domain HRV indiceswith the exception of proportion of adjacent RR intervals differing by >50 ms in the24-hour recording were significantly lower in patients with MVP than controls (SD of allnormal-to-normal [NN] intervals, p � 0.013; SD of average NN intervals calculated during5-minute periods of the entire recording, p � 0.03; triangular index, p � 0.025; and squareroot of mean squared differences in successive NN intervals, p � 0.026). After metoprololtreatment, all HRV indices significantly improved compared with baseline (SD of all NNintervals, p � 0.028; SD of average NN intervals calculated during 5-minute periods of theentire recording, p � 0.043; triangular index, p � 0.004; square root of the mean squareddifferences in successive NN intervals, p � 0.021; and proportion of adjacent RR intervalsdiffering by >50 ms in the 24-hour recording, p � 0.014), and HRV indices after meto-prolol treatment were similar to those of the control group (p >0.05). In conclusion,metoprolol significantly improved impaired HRV parameters in symptomatic patients with
MVP. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1568–1570)
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he aim of this study is to determine time–domain heartate variability (HRV) indices in symptomatic patients withitral valve prolapse (MVP) and investigate effects of

hort-term metoprolol treatment on these indices.

ethods

hirty-nine symptomatic patients with MVP diagnosed us-ng transthoracic echocardiography and 16 age- and gender-atched healthy subjects were studied. Criteria for MVPere valve prolapse �2 mm above the mitral annulus in the

ong-axis parasternal view.1 The healthy volunteers did notave cardiac disease. No patient or control had a history ofyncope, sustained ventricular tachycardia, or family historyf sudden cardiac death, and none had an accompanyingardiac or noncardiac disease and concomitant use of drugs.ll underwent basal 24-hour Holter recording. Thereafter,etoprolol succinate therapy was started in all patients withVP at a dose of 50 mg/d. Metoprolol dose was adjusted

very 2 weeks according to heart rate, blood pressure, andny adverse effects. The minimum dose of metoprolol was5 mg/d, whereas the target dose was set at 100 mg/d. After

Department of Cardiology, Gazi University School of Medicine, Ankara,urkey. Manuscript received November 17, 2006; revised manuscript

eceived and accepted January 10, 2007.*Corresponding author: Tel: �90-312-202-5647; fax: �90-312-212-

012.
sE-mail address: [email protected] (G. Taçoy).

months of metoprolol treatment, 24-hour Holter examina-ion was repeated in the study group only. Informed consentas obtained from all subjects, and the study protocol was

pproved by the local ethical committee.The 24-hour Holter recording was performed on a

-channel digitized recorder (Del Mar Reynolds Medicaltd, Hertford, United Kingdom). Recordings lasting �16ours and of sufficient quality for evaluation were includedn analysis. If these criteria were not achieved, recordingsere repeated. Before analyzing the data, they were manu-

lly preprocessed. Time–domain HRV indices were ana-yzed. Using statistical methods, the square root of the meanquared differences in successive normal-to-normal (NN)ntervals, SD of all NN intervals, SD of average NN inter-als calculated during 5-minute periods of the entire record-ng, and proportion of adjacent RR intervals differing by

50 ms in the 24-hour recording (pNN50) were measured.sing geometric methods, we measured HRV triangular

ndex (total number of all NN intervals divided by theeight of the histogram of all NN intervals measured on aiscrete scale with bins of 7.8125 ms [1/128 s]). In addition,ean RR interval was measured. All measurements were

erformed in accordance with the Task Force of the Euro-ean Society of Cardiology and North American Society ofacing and Electrophysiology.2

Statistical analysis was performed using Statistical Pack-ge for Social Sciences (SPSS Inc, Chicago, Illinois), ver-
ion 11.5 software for Windows. Mann-Whitney test and
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1569Valvular Heart Disease/MVP, Heart Rate Variability, � Blocker

cNemar’s chi-square test were used for comparison ofata, when appropriate. p Value �0.05 is considered statis-ically significant.

esults

aseline properties of the MVP and control groups wereimilar (Table 1). At the basal evaluation, all time–domainRV indices except pNN50 were significantly lower in the

able 1aseline characteristics of the study population

ariable MVP Patients(n � 39)

Control Group(n � 16)

p Value

ge (yrs) 26.4 � 7.4 26.2 � 7.2 NSex (M/F) 13/26 5/11 NSV end-diastolic volume (ml) 88.51 � 18.70 94.31 � 16.22 NSV end-systolic volume (ml) 27.17 � 7.68 29.93 � 6.32 NSV ejection fraction (%) 69.12 � 3.35 67.93 � 2.35 NSA diameter (cm) 30.48 � 3.97 32.50 � 3.96 NSnterior mitral leafletthickness (mm)

4.83 � 1.21 2.91 � 0.83 �0.001

osterior mitral leafletthickness (mm)

2.99 � 1.03 2.02 � 0.81 0.002

eaflet displacement into leftatrium (mm)

4.10 � 1.62 0.80 � 0.21 �0.001

LA � left atrial; LV � left ventricular.

able 2aseline time–domain heart rate variability indices

MVP Patients(n � 39)


p Value

ean RR (ms) 763 � 87 798 � 95 0.191DNN (ms) 149 � 29 167 � 28 0.013DANN (ms) 132 � 25 150 � 28 0.030MSSD (ms) 35 � 17 45 � 21 0.026NN50 (%) 12 � 11 17 � 12 0.201I 39 � 9 44 � 7 0.025

pNN50 � proportion of adjacent RR intervals differing by � 50 ms inhe 24 hour recording; RMSSD � square root of mean squared differencesf successive NN intervals; SDANN � SD of average NN intervalsalculated over 5-minute periods of the entire recording; SDNN � SD ofll NN intervals; TI � total number of all NN intervals divided by theeight of the histogram of all NN intervals measured on a discrete scaleith bins of 7.8125 ms (1/128 s).

able 3eart rate variability indices before and after metoprolol treatment inatients with mitral valve prolapse

Before Metoprolol After Metoprolol p Value


Abbreviations as in Table 2.

VP group compared with controls (Table 2). Metoprolol t

se was associated with no adverse effects. Mean drug doset the end of 3 months was 80.1 � 23.1 mg/d.

After 3 months of metoprolol treatment, all HRV param-ters significantly improved compared with the basal eval-ation in patients with MVP (Table 3). HRV indices ofatients with MVP after metoprolol were similar to basalRV indices of control subjects (Table 4).

iscussion

he major finding of this study is that time–domain indicesf HRV are significantly depressed in symptomatic patientsith MVP, and these depressed indices can be improvedith short-term metoprolol therapy.Findings in patients with MVP with regard to HRV have

een inconsistent. Han et al3 found that time–domain andrequency–domain indices of HRV were lower in childrenith MVP than controls. Digeos-Hasnier et al4 showed thatRV parameters were not different between patients with

nd without MVP. They suggested that the asymptomaticVP population they studied most likely did not have high

nough sympathetic activity to create depressed HRV indi-es. In our study, symptomatic patients with MVP hadignificantly lower time–domain indices than controls withhe exception of pNN50. Similar findings were reportedreviously.5–10 Furthermore, Frisinghelli et al11 found thathe presence of mitral regurgitation in patients with MVP iselated to increased vagal tone. None of our patients haditral regurgitation, but all were symptomatic. Therefore,e believe the depression in time–domain HRV indices inur study population was caused by heightened sympatheticone.

We found that metoprolol improved depressed HRVarameters in symptomatic patients with MVP. The im-rovement in HRV indices using a � blocker constitutestrong proof that increased sympathetic activity is the causef depressed HRV indices in symptomatic patients withVP. To the best of our knowledge, effects of metoprolol

n HRV indices in patients with MVP were not reportedreviously.

The major limitation in this study is the absence of ansymptomatic MVP population, without which we couldnly speculate that HRV depression is caused by symptomsnd heightened sympathetic tone at the basal evaluation.nother limitation is the relatively short (3 months) dura-

able 4eart rate variability indices of patients with mitral valve prolapse afteretoprolol treatment compared with controls

Patients With MVPAfter MetoprololTherapy (n � 39)


p Value


Abbreviations as in Table 2.

ion of metoprolol therapy, which precludes the applicabil-

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ty of our finding of improvement in HRV indices to long-erm �-blocker therapy in patients with MVP.

1. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP,Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, et al,for American College of Cardiology, American Heart AssociationTask Force on Practice Guidelines (Writing Committee to revise the1998 guidelines for the management of patients with valvular heartdisease), Society of Cardiovascular Anesthesiologists, Society for Car-diovascular Angiography and Interventions, Society of Thoracic Sur-geons. ACC/AHA 2006 guidelines for the management of patientswith valvular heart disease: a report of the American College ofCardiology/American Heart Association Task Force on PracticeGuidelines (writing Committee to Revise the 1998 guidelines for themanagement of patients with valvular heart disease) developed incollaboration with the Society of Cardiovascular Anesthesiologistsendorsed by the Society for Cardiovascular Angiography and Inter-ventions and the Society of Thoracic Surgeons. J Am Coll Cardiol2006;48:e1–e148.

2. Task Force of the European Society of Cardiology and the NorthAmerican Society of Pacing and Electrophysiology. Heart rate vari-ability. Standards of measurement, physiological interpretation, andclinical use. Circulation 1996;93:1043–1065.

3. Han L, Ho TF, Yip WC, Chan KY. Heart rate variability of children
with mitral valve prolapse. J Electrocardiol 2000;33:219–224.
4. Diegos-Hasnier S, Copie X, Paziaud O, Abergel E, Guize L, DieboldB, Jeunemaitre X, Berrebi A, Piot O, Lavergne T, Le Heuzey JY.Abnormalities of ventricular repolarization in mitral valve prolapse.Ann Noninvasive Electrocardiol 2005;10:297–304.

5. Kochiadakis G, Tsagournakis M, Zouridakis M, Parthenakis F,Plaitakis A, Vardas P. Assessment of autonomic function in patientswith mitral valve prolapse. J Neurol Sci 1997;150(suppl 1):S140.

6. Rosano GM, Rillo M, Leonardo F, Pappone C, Chierchia SL. Palpi-tations: what is mechanism, and when should we treat them? Int JFertil Womens Med 1997;42:94–100.

7. Kochiadakis GE, Parthenakis FI, Zuridakis EG, Rombola AT, Chry-sostomakis SI, Vardas PE. Is there increased sympathetic activity inpatients with mitral valve prolapse? Pacing Clin Electrophysiol 1996;19:1872–1876.

8. Pasternac A, Tubau JF, Puddu PE, Krol RB, de Champlain J. Increasedplasma catecholamine levels in patients with symptomatic mitral valveprolapse. Am J Med 1982;73:783–790.

9. Davies AO, Mares A, Pool JL, Taylor AA. Mitral valve prolapse withsymptoms of beta-adrenergic hypersensitivity. Beta 2-adrenergic re-ceptor supercoupling with desensitization on isoproterenol exposure.Am J Med 1987;82:193–201.

0. Boudoulas H, Reynolds JC, Mazzaferri E, Wooley CF. Metabolicstudies in mitral valve prolapse syndrome. A neuroendocrine–cardio-vascular process. Circulation 1980;61:1200–1205.

1. Frisingelli A, Turiel M, Milletich A, Crema C, Malliani A. The role ofmitral regurgitation in the neurovegetative regulation of mitral valve
prolapse. Cardiologia 1992;37:781–783.

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Comparison of Long-Term Outcome After Mitral ValveReplacement or Repeated Balloon Mitral Valvotomy in Patients

With Restenosis After Previous Balloon Valvotomy

Jin-Bae Kim, MD, Jong-Won Ha, MD, PhD*, Jung-Sun Kim, MD, Won-Heum Shim, MD, PhD,Seok-Min Kang, MD, Young-Guk Ko, MD, Donghoon Choi, MD, PhD, Yangsoo Jang, MD, PhD,

Namsik Chung, MD, PhD, Seung-Yun Cho, MD, PhD, and Sung-Soon Kim, MD, PhD

Symptomatic mitral stenosis (MS) develops in 7% to 21% of patients after percutaneousmitral balloon valvotomy (PMV). Treatment options for these patients are surgical mitralvalve replacement (MVR) or repeated PMV. However, no comparisons were made betweenthese 2 procedures regarding long-term outcome. This retrospective study compares thelong-term outcome of 888 patients with symptomatic MS after MVR or repeated PMV whounderwent PMV from April 1988 to December 2003. Thirty-two patients subsequentlyunderwent repeated PMV, and 59 patients underwent MVR for symptomatic MS. Meanfollow-up was 85 � 43 months with a maximum follow-up of 15 years. Patients with MVRhave more unfavorable clinical characteristics, including a higher incidence of atrialfibrillation and severe mitral regurgitation. Event-free survival was similar between the 2groups up to 40 months after the procedure; 3-year event-free survival rates were 96.6% forMVR patients and 90.0% for repeated PMV patients (p � 0.215). However, after 40months, the outcome was more favorable for MVR. Comparing MVR versus PMV, 6-yearevent-free survival rates were 93.0% versus 75.9% (p � 0.036), and 9-year event-freesurvival rates were 90.4% versus 36.0% (p <0.001). In conclusion, the long-term outcomeof patients with symptomatic MS after previous PMV was more favorable after MVRthan after repeated PMV. These data suggest that MVR may be the preferred mode oftherapy in patients with unfavorable valve morphologic characteristics and no co-morbid
disease. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1571–1574)
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ercutaneous mitral balloon valvotomy (PMV) was intro-uced in 1984 by Inoue et al1 and has since evolved as a safend effective procedure in the management of patients withheumatic mitral stenosis (MS).2–6 However, symptomatic

S develops in 7% to 21%2–4 of PMV patients. Surgicalitral valve replacement (MVR) and repeated PMV are

lternative treatment options for these patients. Previoustudies indicated that repeated PMV was feasible with goodmmediate and intermediate outcomes7–9 in patients withestenosis after previous PMV, but no comparisons wereade regarding long-term outcome between the 2 proce-

ures. Therefore, this study compares the long-term out-ome of patients with symptomatic stenosis after repeatedMV or MVR.

ethodsPatients: Eight hundred eighty-eight patients underwent

MV in our institution from April 1988 to December 2003.f these, we identified 32 patients who underwent repeatedMV for symptomatic restenosis (repeated-PMV group)

Cardiology Division, Yonsei Cardiovascular Center and Cardiovascu-ar Research Institute, Yonsei University College of Medicine, Seoul,outh Korea. Manuscript received October 12, 2006; revised manuscripteceived and accepted December 28, 2006.

eE-mail address: [email protected] (J.-W. Ha).

nd 59 patients who underwent MVR (MVR group) duringhe same period. Criteria for choosing MVR or repeatedMV in patients with restenosis were at the discretion of

he attending physician. Clinical outcome (such as re-eated procedure, stroke, readmission for heart failure,nd death) and echocardiographic data for the 2 groupsere compared.

Procedure: PMV was performed using the anterograderansseptal approach with the Inoue balloon technique or dou-le-balloon technique. The effective balloon-dilating area ofhe balloons used was calculated using standard geometricormulas and normalized to body surface area as previouslyescribed.2 A right heart oximetry saturation run was per-ormed before and after PMV to check for left-to-right shunt-ng at the atrial level. Left-to-right shunting through the createdtrial communication was diagnosed if an increase in oxygenaturation �7% was detected between the superior vena cavand pulmonary artery. The procedure was considered effectivehen full expansion of the balloon was accompanied by im-rovement in the mitral pressure gradient without detection ofignificant mitral regurgitation or other mechanical complica-ion. Left ventricular angiograms and aortograms were ob-ained using standard procedures.

Two-dimensional and Doppler echocardiography andolor flow imaging were performed. Baseline anatomic fea-ures of the mitral valve were assessed using the total
chocardiographic score described by Wilkins et al.10 Mitral
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alve area (MVA) was determined using direct planimetryf the mitral orifice in a 2-dimensional short-axis view earlyn diastole11 or the pressure half-time method in patientsith MVR. Mitral regurgitation was detected and semi-uantitatively graded by means of color flow imaging usingolor Doppler echocardiography. Transmitral pressure gra-ients and right ventricular systolic pressures were esti-ated using continuous-wave Doppler echocardiography.

Data collection and follow-up: Demographic, clinical,nd procedural variables were collected retrospectively using aeview of medical records and telephone contact. Results ofepeated PMV were defined as optimal when MVA was �1.5m2 with no regurgitation �2/46,7 and suboptimal for MVA1.5 cm2. Patients were followed up for a mean of 85 � 43onths for up to 15 years after repeated PMV or MVR. End

oints of follow-up were repeated PMV or MVR, stroke,

able 1aseline characteristics

ariables MVR(n � 59)

Repeated PMV(n � 32)

p Value

ge (yrs) 50 � 10 42 � 11 0.001en/women 18/41 (31/70%) 2/30 (6/94%) 0.008

inus rhythm/atrialfibrillation

26 (45%)/32 (55%) 22 (71%)/9 (29%) 0.02

ew York HeartAssociation class

0.19

II 21 (39%) 14 (52%)III 32 (59%) 12 (44%)IV 1 (2%) 1 (4%)

able 2re- and postprocedural echocardiographic parameters

ariables MVR(n � 59)

Repeated PMV(n � 32)

p Value

reprocedureEjection fraction (%) 60 � 10 62 � 9 0.37Mitral valve area (cm2) 1.42 � 1.82 1.03 � 0.2 0.24Left atral dimension

(mm)*60 � 10 51 � 10 �0.001

Mitral regurgitationgrade

0.01

0–2 32 (71%) 29 (100%)3–4 13 (29%) 0 (0%)

Echocardiographic score 9.2 � 2.3 8.4 � 1.0 0.079Mean diastolic pressure

gradient (mm Hg)6.0 � 2.1 6.9 � 3.3 0.21

Right ventricular systolicpressure (mm Hg)

43.6 � 14.4 37.7 � 12.7 0.13

ostproceduralMitral valve area (cm2)

2 dimension 1.52 � 0.28Pressure half-time 2.67 � 0.64 1.53 � 0.26 �0.001

Mean diastolic pressuregradient (mm Hg)

3.41 � 1.38 4.71 � 2.0 0.036

Right ventricular systolicpressure (mm Hg)

35.6 � 15.2 32.2 � 8.52 0.442

* Anteroposterior diameter.

eadmission for heart failure, or death. i

Statistical analysis: Continuous variables are expresseds mean � SD, and categorical variables are expressed asercentages. Unpaired Student’s t test and chi-square anal-sis were used to compare continuous and categorical vari-bles, respectively. Kaplan-Meier estimates were used toetermine overall and event-free survival rates for bothroups. Comparison between groups was performed usingog-rank test. Cox regression hazards analyses were used todentify independent correlates of long-term event-free sur-ival. All analyses were performed using SPSS softwareersion 11.5 (SPSS Inc., Chicago, Illinois).

esultsPre- and postprocedural characteristics of patients:

aseline characteristics of both groups of patients are listedn Table 1. Repeated PMV was performed at 72.7 � 34.3onths after initial PMV and MVR at 57.6 � 35.2 months

fter initial PMV. Patients in the repeated-PMV group wereenerally younger than those in the MVR group (42 � 11 vs0 � 10 years, p � 0.001) and had a lower incidence oftrial fibrillation (29% vs 55%, p � 0.02). Pre- and post-rocedural echocardiographic parameters are listed in Table 2.here was a significant increase in MVA after the procedure

n both groups. However, patients with repeated PMV had aignificantly smaller postprocedural MVA than those withVR (1.52 � 0.28 vs 2.67 � 0.64 cm2, p �0.001). Twenty

atients (62.5%) had results classified as optimal after re-eated PMV, and there was no complication except forrade 3 mitral regurgitation in 1 patient. Of patients withVR, 12 (20.3%) underwent double valve replacement

nd 2 patients (3.4%) underwent bioprosthetic valveeplacement.

Clinical follow-up: In the repeated-PMV group, meanollow-up was 59 � 32 months and 4 patients (12.5%) wereost to follow-up. In the MVR group, mean follow up was8 � 43 months and 5 patients (8.5%) were lost to follow-p. There were no deaths in either group during the fol-ow-up period. Ten patients in the repeated-PMV groupequired an additional procedure (MVR in 8, repeated PMV

igure 1. Comparison of event-free survival curves between MVR andepeated PMV patients.

n 2), whereas no patient in the MVR group required re-

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1573Valvular Heart Disease/Restenosis After Previous PMV

eated surgery. However, 3 patients in the MVR groupxperienced an ischemic stroke and 3 patients requiredeadmission for congestive heart failure. New York Heartssociation functional class at last follow-up was not sig-ificantly different in the groups (16 of 8 vs 42 of 12atients in class I/II, p � 0.47). Using Kaplan-Meier esti-ates, event-free survival was similar between the 2 groups

ntil 40 months after the procedure; 3-year event-free sur-ival rates were 96.6% for MVR patients and 90.0% forepeated PMV patients (p � 0.215). After 40 months, aore favorable outcome was noted for MVR versus re-

eated PMV; 6-year event-free survival rates were 93.0%ersus 75.9% (p � 0.036) and 9-year event-free survivalates were 90.4% versus 36.0% (p �0.001; Figure 1). Long-erm outcome remained better in patients with MVR evenhen only patients with optimal results after repeated PMVere compared with the MVR group (Figure 2). On multi-ariate analysis, type of procedure (repeated PMV or MVR)as a powerful indicator of long-term outcome independentf age, gender, rhythm, echocardiographic score, and ejec-ion fraction (relative risk 0.16, �95% confidence interval.03 to �0.78).

iscussion

he present study compares MVR with repeated PMV inatients with mitral restenosis after previous PMV forhom long-term follow-up �10 years could be analyzed.ata show that MVR is associated with better long-term

vent-free survival and remains superior to repeated PMVor up to 15 years after surgery. These data suggest that

VR may be the preferred mode of therapy for patientsho are expected to benefit during a long period. The

trength of this study is the availability of data for long-termutcome with follow-up extending up to almost 20 years.

The safety of repeated PMV is reflected by the lack ofrocedure-related deaths, cardiac tamponade, or thrombo-mbolic complications in these patients. There was no pro-edural failure and 62.5% of results were classified as op-imal. In addition, the immediate outcome of patients with

igure 2. Comparison of event-free survival curves between MVR andepeated PMV patients with optimal results.

epeated PMV was similar to that of MVR, except that

VA after repeated PMV was smaller. Follow-up showed3-year event-free survival rate of 90.0% in the repeated-MV group, similar to that of the MVR group and previ-usly reported data for initial PMV procedures.5,6

Previous studies showed that both immediate and inter-ediate outcomes were similar between repeated PMV andVR up to 4 years after the procedure. Iung et al7 reportedidterm outcomes of repeated PMV. Compared with the

resent study, patients were younger with a lower incidencef atrial fibrillation and similar valve morphologic charac-eristics. The intervention-free survival rate 5 years afterepeated PMV was 74 � 11%. However, the study did notompare long-term outcome with that of MVR. In a similartudy, Pathan et al8 reported immediate and long-term clin-cal follow-up for 36 patients who underwent repeated PMVor symptomatic mitral restenosis after previous PMV.

ean follow-up was 30 � 33 months with a maximumollow-up of 10 years, shorter than that of the present studymean follow-up 85 � 43 months, maximum 15 years).hey concluded that repeated PMV results in good imme-iate and intermediate outcome in patients with low echo-ardiographic scores and in the absence of co-morbid dis-ases. The present study shows that immediate andntermediate outcomes up to 4 years after the procedureere similar between the repeated-PMV and MVR groups,

onsistent with results of previous studies. However, be-ond 4 years, there was an increased incidence of additionalntervention, mostly MVR or repeated PMV, in patientsho underwent repeated PMV. After 6 years of follow-up,

he MVR group had a significantly more favorable outcome;3.0% of the MVR group was free of clinical events com-ared with 75.9% of patients in the repeated-PMV grouplthough the MVR group included older patients with aigher incidence of atrial fibrillation and more severe mitralegurgitation. Therefore, an increase in clinical events be-ond 10 years of follow-up may negate the initial proce-ural benefit of repeated PMV. However, previous stud-es7–9 focused on only immediate and midterm outcome upo 5 years after repeated PMV.

This is a nonrandomized retrospective study of a smallatient population in a single institution. Comparison ofonrandomized groups of patients undergoing different pro-edures is difficult because of the potential bias in patientelection and different patient groups involved.

1. Inoue K, Okawi T, Nakamura T, Kitamura F, Miyamoto N. Clinicalapplication of transvenous mitral commissurotomy by a new ballooncatheter. J Thorac Cardiovasc Surg 1984;87:394–402.

2. Palacios I, Block PC, Brandi S, Blanco P, Casal H, Pulido JI, Munoz S,Empaire GD, Ortega MA, Jacobs M. Percutaneous balloon valvotomy forpatients with severe mitral stenosis. Circulation 1987;75:778–784.

3. Desideri A, Vanderperren O, Serra A, Barraud P, Petitclerc R, Les-perance J, Dyrda I, Crepeau J, Bonan R. Long term (9 to 33 months)echocardiographic follow-up after successful percutaneous mitralcommissurotomy. Am J Cardiol 1992;69:1602–1606.

4. Iung B, Cormier B, Ducimetiere P, Porte JM, Nallet O, Michel PL,Acar J, Vahanian A. Functional results 5 years after successful percu-taneous mitral commissurotomy in a series of 528 patients and analysisof predictive factors. J Am Coll Cardiol 1996;27:407–414.

5. Hernandez R, Banuelos C, Alfonso F, Goicolea J, Fernandez-Ortiz A,Escaned J, Azcona L, Almeria C, Macaya C. Long-term clinical andechocardiographic follow-up after percutaneous mitral valvuloplasty
with the Inoue balloon. Circulation 1999;99:1580–1586.

1

1


6. Iung B, Garbarz E, Michaud P, Helou S, Farah B, Berdah P, MichelPL, Cormier B, Vahanian A. Late results of percutaneous mitralcommissurotomy in a series of 1024 patients: analysis of late clinicaldeterioration: frequency, anatomic findings and predictive factors. Cir-culation 1999;99:3272–3278.

7. Iung B, Garbarz E, Michaud P, Fondard O, Helou S, Kamblock J,Berdah P, Michel PL, Lionet P, Cormier B, Papouin G, VahanianA. Immediate and mid-term results of repeat percutaneousmitral commissurotomy for restenosis following earlier percu-taneous mitral commissurotomy. Eur Heart J 2000;21:1683–1689.

8. Pathan AZ, Mahdi NA, Leon MN, Lopez-Cuellar J, Simosa H, Block
PC, Harrell L, Palacios IF. Is redo percutaneous mitral balloon valvu-
loplasty (PMV) indicated in patients with post-PMV mitral restenosis?J Am Coll Cardiol 1999;34:49–54.

9. Turgeman Y, Atar S, Suleiman K, Feldman A, Bloch L, Jabaren M,Rosenfeld T. Feasibility, safety, and morphologic predictors of out-come of repeat percutaneous balloon mitral commissurotomy. Am JCardiol 2005;95:989–991.

0. Wilkins GT, Weyman AE, Abascal VM, Block PC, Palacios IF.Percutaneous balloon dilation of the mitral valve: an analysis of echo-cardiographic variables related to outcome and mechanisms of dila-tion. Br Heart J 1988;60:229–308.

1. Palacios IF. What is the gold standard to measure mitral valve areapost mitral balloon valvuloplasty? Cathet Cardiovasc Diagn 1994;33:
315–316.

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Usefulness and Safety of Transcatheter Ablation of AtrialFibrillation in Patients With Hypertrophic Cardiomyopathy

Fiorenzo Gaita, MDa,*, Paolo Di Donna, MDa, Iacopo Olivotto, MDb, Marco Scaglione, MDa,Ivana Ferrero, MDa, Antonio Montefusco, MDa, Domenico Caponi, MDa, Maria Rosa Conte, MDc,

Stefano Nistri, MDb, and Franco Cecchi, MDb

Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HC) andpredicts adverse outcome. Radiofrequency catheter ablation (RFCA) represents a poten-tially advantageous alternative to lifelong pharmacologic treatment. However, its efficacyin patients with HC is not established. In the present study, the feasibility, safety, andefficacy of RFCA of AF in patients with HC were evaluated. Twenty-six patients with HCwith paroxysmal (n � 13) or permanent (n � 13) AF refractory to antiarrhythmic therapy(age 58 � 11 years, time from AF onset 7.3 � 6.2 years, left atrial volume 170 � 48 ml)underwent RFCA. A schema with pulmonary vein isolation plus linear lesions was used.No major periprocedural complication occurred. One patient died from a hemorrhagicstroke 4 weeks after RFCA while in sinus rhythm. During a 19 � 10-month follow-up, 9of the remaining 25 patients (36%) experienced recurrence of AF (despite repeated RFCAin 3) and were considered failures, whereas 16 remained in sinus rhythm (i.e., 64% overallsuccess rate). Ten of these 16 patients were off antiarrhythmic drug therapy at finalevaluation. RFCA was highly successful in patients with paroxysmal AF (77% success ratecompared with 50% in the subgroup with permanent AF). Patients with restoration of sinusrhythm showed marked symptomatic improvement (final New York Heart Associationfunctional class 1.2 � 0.5 vs 1.7 � 0.7 before the procedure, p � 0.003). Conversely,patients for whom RFCA failed showed no change (final functional class 1.9 � 0.8 vs 1.7 �0.9 before the procedure, p � 0.59). In conclusion, in most studied patients with HC, RFCAproved a safe and effective therapeutic option for AF, improved functional status, and wasable to reduce or postpone the need for long-term pharmacologic treatment. © 2007
Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1575–1581)
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trial fibrillation (AF) is the most common arrhythmia inatients with hypertrophic cardiomyopathy (HC)1 and rep-esents an important complication in the clinical course ofhe disease, with adverse long-term consequences on func-ional status and outcome.2–6 Maintenance of sinus rhythms highly desirable in patients with HC, particularly whenhe onset of the arrhythmia is at a young age. Nevertheless,harmacologic prevention of AF recurrence is challengingecause of the limited long-term efficacy and potentiallyazardous side effects of available treatment options.7,8

During the last decade, transcatheter techniques for ab-ation of AF were successfully introduced in clinical prac-ice.9–11 However, the feasibility and efficacy of these tech-iques in patients with genetically determined myocardialisease, such as HC, is largely unknown.12,13 Thus, the aimf the present study is to evaluate the feasibility, safety, andfficacy of radiofrequency catheter ablation (RFCA) in aelected cohort of patients with HC with severely symptom-tic AF refractory to pharmacologic antiarrhythmic therapy.

aOspedale Civile Cardinal Massaia, Asti; bAzienda Ospedaliero-Uni-ersitaria Careggi, Florence; and cOspedale degli Infermi, Rivoli, Italy.anuscript received October 18, 2006; revised manuscript received and

ccepted December 28, 2006.*Corresponding author: Tel: 39-01-4148-7121; fax: 39-01-4148-7134.

tE-mail address: [email protected] (F. Gaita).


n ablation schema characterized by pulmonary vein (PV)solation and linear lesions at the roof and mitral isthmusas chosen by virtue of its proven efficacy in patients withalvular heart disease associated with extensive left atrialemodeling and dilatation.14

ethods

he study group included 26 patients with HC from 3eferral institutions (Asti, Florence, and Turin, Italy) with aistory of AF dating back �12 months for whom medicalntiarrhythmic therapy (including amiodarone) proved in-ffective. Of these, 13 patients had a history of paroxysmalF and were included because of frequent (�2 times/yr)

nd markedly symptomatic recurrences that caused severeuality-of-life impairment and potential hemodynamic com-romise. Of the remaining 13 patients, all with permanentF, 9 were included because of new onset or worsening ofeart failure symptoms after perpetuation of AF (�1 Nework Heart Association functional class), 3 because of poorharmacologic control of ventricular rate and subsequentisk of tachycardiomyopathy and 1 because of marked in-rinsic QT interval prolongation (�500 ms) preventingong-term use of antiarrhythmic agents for maintenance ofinus rhythm.7

Paroxysmal AF is defined as the occurrence of self-
erminating AF episodes lasting �7 days. Permanent AF is
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efined as recurrent stable AF after cardioversion.7 Theiagnosis of HC was based on 2-dimensional echocardio-raphic evidence of a hypertrophied nondilated left ventri-le (maximum wall thickness �15 mm in sporadic cases,13 mm in patients with a documented family history ofC) in the absence of another cardiac or systemic disease

apable of producing the magnitude of hypertrophy evi-ent.15,16 Documentation of AF was based on electrocardio-raphic recordings obtained either after acute onset ofymptoms or during routine examination.

Results obtained in our HC cohort were compared with 2ontrol groups, 1 with “lone” (idiopathic) AF and 1 withtructural heart disease other than HC (secondary AF). Tohis aim, we consecutively assessed all patients who under-ent RFCA for idiopathic AF at our institution during the

ame period and using the same technique. Each of the 26atients with HC was matched with the first encounterederson of the same age (�1 year), gender, and type of AFparoxysmal or permanent). The same approach was used todentify controls with secondary AF, although matching forender was not possible for 1 patient in this group. Patientsith secondary AF had underlying diagnoses of dilated

ardiomyopathy (n � 6), coronary artery disease (n � 10),nd valvular heart disease (n � 10).

All procedures were performed consecutively from Jan-ary 2002 to June 2005 after obtaining informed consent.ransesophageal echocardiography was performed to ruleut atrial thrombi. An octapolar electrode catheter (Bostoncientific) was positioned in the coronary sinus for pacingnd recording. The left atrium was accessed using transsep-al puncture or through a patent foramen ovale, whenresent. The transseptal sheath was continuously perfusedith a heparinized 5% dextrose and water solution. Sys-

emic anticoagulation was achieved using intravenous hep-rin during the procedure. PVs were identified using selec-ive venography through the transseptal sheath. A-dimensional shell representing the left atrium and PVstia was constructed using an electroanatomic mappingystem (Carto, Biosense-Webster). PVs were mapped usingdecapolar ring catheter (Orbiter PV Bard and Lasso Bio-

ense-Webster) to evaluate basal electrical activity.The ablation schema was characterized by complete

lectrical isolation of PVs and creation of linear lesionsnterconnecting the upper PV ostia (roof line) and left in-erior PV down to the mitral annulus.14 An irrigated 4-mmip catheter was used (Navistar Thermocool, Biosense Web-ter) with a 0.9% saline solution flow rate titrated to achievehe desired power (through an irrigation pump, Biosense

ebster) with temperature limited to 43°C. Radiofrequencynergy, with power limited to 35 W, was delivered l to 2 cmrom the PV ostia to encircle both the left and right PVs.inear ablations between the mitral ring and inferior left PVnd between the left and right PVs were performed withower varying from 35 to 45 W. Electrical isolation of PVsas considered complete if no or dissociated PV potentialsere recorded.10 Creation of an effective mitral isthmus

inear lesion was assessed by mapping the activation detoururing pacing from either side of the lesion.17 If a completelock was not achieved, adjacent lines were added to slowonduction to an interval of the local double potential �80
s. Double separated atrial potentials were considered ev- R
dence of an effective local lesion on the left atrial roof linesonnecting the left and right PVs.18 Finally, all patientsnderwent radiofrequency ablation of the cavotricuspidsthmus, with demonstration of complete bidirectional blockt the end of the procedure.

After RFCA, the electrocardiogram was continuouslyonitored, and a standard heparin infusion was maintained

or 24 hours. Low-molecular-weight heparin and warfarinherapy were instituted on the next day. Heparin treatmentas stopped when the international normalized ratio was in

he therapeutic range of 2 to 3. Antiarrhythmic therapy wasiscontinued after 3 months unless there were other indica-ions (usually repeated runs of nonsustained ventricularachycardia on the Holter electrocardiogram). After hospitalischarge, patients were followed up with clinical evalua-ion, 12-lead electrocardiogram, echocardiography, and 24-our Holter monitoring at 1, 3, 6, and 12 months and everymonths thereafter. In addition, patients were instructed to

eek medical attention �12 hours after the onset of newymptoms.

The end-point of the study was any documented recur-ence of AF based on electrocardiogram recordings ob-ained either after the acute onset of symptoms or in theourse of scheduled follow-up visits. However, becausepisodes of AF occurring within the first few weeks after

able 1emographic and clinical features of 26 patients with hypertrophic

ardiomyopathy (HC)

ariable

ge (yrs) 58 � 11 (range 25–82)omen 8 (31%)ears since first diagnosis of HC 15 � 8amily history of HC 10 (38%)ew York Heart Association functionalclass

1.7 � 0.7

I 11 (42%)II 10 (38%)III 5 (19%)aseline echocardiographic measurementsMaximum LV thickness (mm) 23 � 4Basal LV outflow gradient �30 mm Hg 6 (23%)Left atrial diameter (mm) 52 � 6Left atrial volume (ml) 170 � 48Smoke effect in the left atrium 9 (35%)Mitral regurgitation

None 5 (19%)Mild 18 (69%)Moderate 3 (12%)

Ejection fraction (%) 57 � 4revious interventionsAlcohol septal ablation 4 (15%)Surgical septal myectomy and mitral valvereplacement

1 (4%)

Dual-chamber implantable cardioverter-defibrillator for primary prevention ofsudden death*

5 (19%)

* According to current guidelines for management of HC.1 The reasonor implantation was not related to clinical manifestations or consequencesf AF.LV � left ventricular.

FCA are common, usually transient, and show poor cor-

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1577Cardiomyopathy/Transcatheter Ablation of AF in HC

elation with outcome, a 30-day blanking period was al-owed, defined as a period immediately after RFCA duringhich episodes of AF were considered a nonspecific re-

ponse elicited by the procedure, rather than true recurrencef the arrhythmia.19 After 4 weeks, any AF recurrence wasonsidered a failure of RFCA.

Data are expressed as mean � SD. Student’s t test ornalysis of variance, as appropriate, was used for compar-son of normally distributed data. Chi-square or Fisher’sxact test was used, as appropriate, to compare noncontin-ous variables expressed as proportions.

esults

f 26 study patients, 13 had permanent AF and 13 hadaroxysmal AF refractory to antiarrhythmic therapy (Tablesand 2). Average time from the onset of AF was 7.3 � 6.2

ears. Patients with paroxysmal AF had experienced anverage of 12 � 7 documented episodes of the arrhythmiauring 9.3 � 7.4 years. In patients with permanent AF, timerom AF onset was 5.9 � 5.5 years, and duration of theurrent episode was 2.6 � 1.4 years. A mean of 2.3 � 1.4ntiarrhythmic drugs had been unsuccessfully tested in eachatient, with amiodarone used in all, sotalol in 66%,

able 2linical features of 26 patients with hypertrophic cardiomyopathy (HC) (

atiento.

Age(yrs)/Sex

FamilyHistoryof HC

NYHAFunctional

Class atEnrollment

Type of AF

1 25/F No III Paroxysmal2 40/M No III Paroxysmal3 43/M Yes I Permanent4 40/M Yes II Permanent5 52/M No II Paroxysmal6 54/M Yes I Permanent7 54/M Yes I Paroxysmal8 55/F No II Permanent9 56/M No I Paroxysmal0 57/M Yes II Permanent1 57/M Yes I Paroxysmal2 57/F No II Permanent3 57/M No II Paroxysmal4 58/F No II Paroxysmal5 59/M No I Permanent6 60/M Yes II Permanent7 61/M No I Permanent

8 61/M Yes I Paroxysmal9 64/F No III Permanent0 65/M No II Permanent1 65/M No III Permanent2 65/F Yes II Permanent3 66/F No I Paroxysmal4 72/M No I Paroxysmal5 74/M No I Paroxysmal6 82/F Yes III Paroxysmal

EF � LV ejection fraction; LA � left atrial; LV � left ventricular; LVOT

ropafenone in 37%, flecainide in 23%, and quinidine in d

%. Average left atrial size was markedly increased (Tablesand 2).Total procedural time was 108 � 25 minutes, and fluo-

oscopy time was 36 � 13 minutes. Average hospital stayas 3 days. PVs were successfully disconnected usingFCA in all patients. Complete mitral isthmus block wasbtained in 9 patients (35%; Figure 1). In the remaining 17atients (65%), acute conduction slowing along the mitralsthmus was observed, with a mean atrial electrogram in-erval of 110 � 18 ms during coronary sinus pacing. Noajor periprocedural complication occurred; 5 patients de-

eloped mild pericardial effusion.Of 13 patients with paroxysmal AF, 8 remained in sinus

hythm throughout the procedure, whereas 5 developed AF,ncluding 2 with spontaneous restoration of sinus rhythmnd 3 requiring electrical cardioversion. The 13 patientsith permanent AF required cardioversion. All patientsere in sinus rhythm at the end of the procedure, althoughhad arrhythmic recurrences during the hospital stay: a

7-year old man with a history of amiodarone-induced hy-erthyroidism who experienced left atrial tachycardia and a0-year old man with a 3-year history of permanent AF whoxperienced recurrence of AF. Therefore, 24 of 26 studyatients (92%) were in sinus rhythm at the time of hospital

ed on next page)

ofcaletF

RedoProcedure

FinalResult

Final Status

4 Yes Successful Stable SR3 Yes Failed Permanent AF3 0 Failed Paroxysmal AF9 0 Successful Stable SR0 0 Successful Stable SR0 0 Successful Stable SR1 0 Successful Stable SR2 0 Failed Parox AF5 0 Successful Stable SR1 Yes Failed Chronic left atrial tachycardia0 0 Successful Stable SR2 0 Failed Paroxysmal AF1 0 Successful Stable SR9 0 Successful Stable SR5 0 Successful Stable SR0 Yes Failed Permanent AF4 0 Early death Died in stable SR, CAM

hemorragic stroke2 0 Successful Stable SR5 0 Successful Stable SR4 0 Successful Stable SR8 0 Failed Paroxysmal AF4 0 Successful Stable SR3 0 Failed Paroxysmal AF2 0 Failed Paroxysmal AF0 0 Successful Stable SR4 Yes Successful Stable SR

outflow tract; NYHA � New York Heart Association; SR � sinus rhythm.

continu

YearCliniOnsof A

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After discharge, a 61-year-old man in the permanent-AFroup died from hemorrhagic stroke at the end of the-week blanking period while in sinus rhythm. In the ab-ence of other systemic or intracranial causes, the event wasonsidered a complication of oral anticoagulant treatmentespite an international normalized ratio in the appropriateherapeutic range. The other 25 patients were followed upor a mean of 19 � 10 months (range 6 to 46). Of these, 14atients (56%) remained in stable sinus rhythm (Figure 2).he remaining 11 patients (44%) experienced recurrence ofaroxysmal AF (n � 9), permanent AF (n � 1), or left atrialachycardia (n � 1), including the 2 men who experiencedrrhythmic recurrences during the hospital admission. Timeo recurrence of AF was 2 days to 12 months (average 4.6 �.2 months). Five of these 11 patients underwent a repeatedrocedure 1 to 12 months after the first ablation that suc-essfully restored stable sinus rhythm in 2 patients (Table 2nd Figure 2). Therefore, at the end of follow-up, 16 of 25atients were in stable sinus rhythm, corresponding to a4% overall success rate (Table 3). Specifically, RFCAroved highly effective in patients with a history of parox-smal AF (10 of 13 [77%] compared with 6 of 12 [50%] inhe subgroup with permanent AF). The success rate ofFCA in our HC cohort was similar to that achieved inontrol groups with idiopathic and secondary AF despite

able 2continued)

Echo Data EF(%)

LAiameter(mm)

LAVolume

(ml)

MaximumLV Wallthickness

LVOTGradient

� 30mm Hg

MitralRegurgitation

SmokeEffect inthe LA

54 148 21 No Mild 53 No55 253 20 No Mild 58 No44 122 18 No Mild 60 No48 140 25 No 0 58 No46 120 23 No 0 60 No49 124 13 No 0 54 Yes47 126 22 No 0 55 No52 144 22 No Mild 60 Yes46 156 28 No Mild 55 No58 194 36 Yes Mild 60 Yes60 220 23 No Mild 60 No53 129 27 No Mild 55 No58 271 22 Yes Mild 63 No49 145 30 No Mild 50 Yes54 213 25 Yes Mild 60 Yes49 190 24 No Mild 50 No50 206 19 No Mild 52 Yes

44 190 22 Yes Mild 62 No65 134 23 Yes Moderate 60 No51 232 23 No Moderate 60 No59 168 24 No Mild 60 Yes58 164 24 No Mild 55 Yes50 121 23 No Mild 60 Yes63 227 19 No Moderate 60 No43 124 20 No Mild 55 No46 125 21 Yes 0 60 No

arger left atrial size in patients with HC (Table 3). fl

On average, the 16 patients with successful restoration ofinus rhythm had marked improvement in functional statusNew York Heart Association functional class at final eval-ation 1.2 � 0.5 compared with 1.7 � 0.7 before therocedures, p � 0.003), including 2 patients who improvedrom class III to I and II and 5 patients who improved fromlass II to I (Table 2). The remaining 9 patients with AFecurrence, considered failures, showed no change in symp-oms (functional class at final evaluation 1.9 � 0.8 vs 1.7 �.9 before RFCA, p � 0.59). Nevertheless, 2 of these 9atients reported subjective improvement and decreased fre-uency and duration of AF recurrences, and only 2 hadermanent AF (or atrial tachycardia) at the end of follow-upTable 2). With regard to antiarrhythmic therapy, 10 of 16atients with successful RFCA were off drug therapy at thend of follow-up (62%), including 8 of 10 with previousaroxysmal AF and 2 of 6 with previous permanent AF.onversely, 6 patients were maintained on amiodarone

n � 3) or sotalol (n � 3) treatment after the end of thelanking period because of nonsustained ventricular ar-hythmias. Of note, 4 of 5 patients �55 years of age wereff drug therapy at the end of follow-up.

Overall, 5 repeated RFCAs were performed in patientsith HC, of which 2 were successful, in a 25-year-oldoman for whom the repeated procedure showed left atrial

rocedural Data Final Evaluation

Durationocedure

in)

Fluoroscopy(min)

Mitralmus

block

Follow-up NYHAFunctional

Class

MaintainanceAntiarrhythmic

Treatment

90 24 No 11 I 020 41 No 21 II Botolal20 60 No 14 I 007 32 Yes 53 I 018 36 Yes 36 I 077 28 No 18 I Amiodarone12 29 Yes 36 I 060 31 No 11 I Amiodarone34 43 No 21 I Sotalol83 67 No 18 III 000 42 No 11 I 090 31 No 11 I Sotalol10 21 No 20 I 056 59 Yes 12 II Sotalol90 37 No 12 I Amiodarone86 40 No 15 II Amiodarone90 57 Yes NA I Amiodarone

15 22 No 16 I 085 31 No 15 II Sotalol95 26 Yes 11 I Amiodarone10 49 No 11 III Amiodarone06 26 No 23 I 067 30 Yes 14 I Sotalol05 32 Yes 16 I Amiodarone15 27 Yes 17 I 030 23 No 23 III 0

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utter around the right PV, which was ablated; and an

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2-year-old woman for whom conduction recovery in theeft PV common trunk in the right inferior PV was identifiednd isolated. In the other 3 patients, the arrhythmia recurred

igure 1. Echocardiographic and RFCA procedural data in a 25-year-old woenes (A86fs/27[delC] and R869H, respectively), with diastolic dysfunctiopatient 1, Table 2). The patient required a repeated procedure because of lherapy. (A) Echocardiographic parasternal long-axis view shows asymransmitral pulse-wave Doppler image shows a restrictive left ventricular fioronary sinus pacing of double atrial (A) potential along the isthmus lineoronary sinus pacing represents the left atrium and PV ostia. (E) Electroalus linear lesions (LL) (red dots). Color-coded activation shows compctivation, purple zones represent sites of late activation. I-II � electrocarS � coronary sinus; d � distal; LI � left inferior. LS � left superior;S � right superior.

igure 2. Outcome of 26 patients with HC who underwent RFCA of AF.he final success rate of RFCA for the study group was 64% and wasigher in patients with a history of paroxysmal AF (10 of 13, 77%)ompared with those with previous permanent AF (6 of 12, 50%; see text).

hortly after the repeated procedure. One patient with both u

F and left atrial flutter recurrences showed conductionecovery of all PVs and persistence of isthmus conduction;F recurred despite PV isolation and a second left isthmus

ine that failed to obtain complete block. Another patientith recurrence of left atrial tachycardia showed radiation

rom the discrete site of earliest activation located at theoof of the left atrium, with a range of activation time lesshan the tachycardia cycle length. Radiofrequency was de-ivered at the site of earliest atrial bipolar activity withoutodification of the cycle length or interruption of the ar-

hythmia. The third patient showed partial conduction re-overy in the left superior and right inferior PVs and alonghe roof line. AF recurred despite isolation of PVs andlimination of the conduction gap.

iscussion

ur findings suggest that RFCA is safe and effective inestoring stable sinus rhythm in patients with HC, evenhen a long-standing history of permanent AF has led to

xtensive atrial remodeling. In the present cohort, averageuration of AF was �7 years, and average left atrial volumeas 170 ml. Despite these unfavorable features and the

ith HC caused by a double mutation of the cardiac troponin I and � myosintrial dilatation, and paroxysmal AF refractory to antiarrhythmic treatmentl flutter around the right PVs and is currently in sinus rhythm and off drughypertrophy of the left ventricle and marked left atrial dilatation. (B)ttern. (C) Endocavitary recordings on the ablation catheter during proximalwide delay of 150 ms. (D) Three-dimensional shell activation map duringc re-map shows the activation pattern after creation of PV isolation (PVI)duction block along mitral isthmus. Red zones represent sites of earlysurface leads; A � atrial potential recordings; ABL � ablation catheter;

roximal; PA � posteroanterior; PV � superior PV; RI � right inferior;

man wn, left aeft atriametriclling pawith anatomilete condiogram

p � p

nique genetic substrate of HC, successful restoration of

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inus rhythm was achieved in 64% of patients after anverage follow-up of 19 months. Of note, RFCA was highlyffective in patients with HC with paroxysmal AF, with auccess rate as high as 77%. However, only 50% of patientsith permanent AF were treated successfully. Such discrep-

ncy is not surprising and reflects the greater degree of lefttrial remodeling associated with permanent AF, represent-ng a particularly adverse substrate for ablation proce-ures.20

After RFCA, restoration of stable sinus rhythm was as-ociated with general and marked improvement in conges-ive symptoms in our patients. Moreover, long-term antiar-hythmic therapy could be discontinued in the majority ofatients with successful procedures (10 of 16), including 4f 5 patients �55 years of age. In the remaining patients,ithdrawal of class III antiarrhythmic agents was not pos-

ible because of other arrhythmic problems related to thenderlying cardiomyopathic process (mainly nonsustainedentricular tachycardia). We acknowledge that this mayave enhanced the efficacy of RFCA in the present cohort.owever, this is unavoidable because patients with HCften have AF in the context of a heterogeneous arrhythmicrofile and a scarcely predictable clinical course. Thus, it isot always possible or prudent to withdraw antiarrhythmicherapy although AF has been successfully controlled.21

The present findings agree with the limited existing ex-erience. In a previous report of a small series of surgicalatients with HC, the Maze III procedure was satisfactorilysed, usually in association with septal myotomy-myectomy.22

sing RFCA, Liu et al12 reported no recurrence of AF in amall group of 4 patients with HC with paroxysmal AFollowed up for up for �6 months after circumferential PVadiofrequency ablation. Recently, a more sizeable series of7 patients with HC showed a 70% success rate approxi-ately 1 year after PV antrum isolation.13 All patients were

ff drug therapy at final evaluation. However, patients withermanent AF were rare in this cohort (15% vs 50% in theresent study).

Of note, no major complications occurred during RFCAn our patients. Nevertheless, the issue of periproceduralisk needs to be addressed further in patients with a disease,uch as HC, characterized by electrically vulnerable myo-

able 3linical features and results of radiofrequency catheter ablation (RFCA) iontrols with idiopathic or secondary atrial fibrillation (AF)

ariable HC(n � 26)

ge (yrs) 58 � 11omen 8 (31%)

ime since AF onset (yrs) 7.3 � 6.2aroxysmal AF 13 (50%)ermanent AF 13 (50%)eft atrial volume (ml) 170 � 48ollow-up after RFCA (mo) 19 � 10epeated procedures 5 (19%)uccessful RFCA 16 (64%, 95% CI 42–82)

* One patient who died at the end of the blanking period was not cons† AF in the context of coronary artery disease (n � 10), valvular (n �CI � confidence interval; NA � not applicable.

ardium and elevated risk of cardioembolic events.2,3,5 In a

ecent survey of �8,700 patients without HC undergoingF ablation, the procedure-related mortality rate was as low

s 0.05%. However, the prevalence of major complications,anging from cardiac tamponade to PV stenosis and cardio-mbolic stroke, was not negligible (6%).23 Whether similarates should be applied to patients with HC or an added riskpecifically related to the disease exists remains to be de-ermined. In any case, safety should represent a major con-ern influencing the selection of appropriate candidates andethods for RFCA.23

In the present study, the success rate of RFCA in patientsith HC was similar to that achieved in matched subjects

rom our institutions with structural heart conditions otherhan HC, as well as previous reports by other groups as-essing RFCA for secondary AF. In the report by Hsu etl,24 78% of 58 patients with AF in the context of heartailure and left ventricular dysfunction were in sinushythm 1 year after the procedure. In a cohort of 26atients with mitral valve prostheses and AF, 73% weren sinus rhythm and off drug therapy 1 year afterFCA.25 All these comparisons are based on small num-ers of patients because of the rarity of potential candi-ates with HC for RFCA and warrant further investiga-ion. Nevertheless, these encouraging results suggest thathe efficacy of catheter AF ablation may be similar inatients with a variety of structural heart diseases, whichlso include genetic cardiomyopathies.

1. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ,Seidman CE, Shah PM, Spencer WH III, Spirito P, Ten Cate FJ, WigleED, for the Task Force on Clinical Expert Consensus Documents.American College of Cardiology, Committee for Practice Guidelines,European Society of Cardiology, American College of Cardiology/European Society of Cardiology clinical expert consensus documenton hypertrophic cardiomyopathy. A report of the American College ofCardiology Foundation Task Force on Clinical Expert ConsensusDocuments and the European Society of Cardiology Committee forPractice Guidelines. J Am Coll Cardiol 2003;42:1687–1713.

2. Maron BJ, Olivotto I, Bellone P, Conte MR, Cecchi F, Flygenring BP,Casey SA, Gohman TE, Bongioanni S, Spirito P. Clinical profile ofstroke in 900 patients with hypertrophic cardiomyopathy. J Am CollCardiol 2002;39:301–307.

3. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ.Impact of atrial fibrillation on the clinical course of hypertrophic

dy patients with hypertrophic cardiomyopathy (HC) compared with

Secondary†

(n � 26)Idiopathic AF

(n � 26)p Value

59 � 11 59 � 8 NS9 (35%) 8 (31%) NS

5.8 � 3.8 5.1 � 3.7 NS13 (50%) 13 (50%) NA13 (50%) 13 (50%)

147 � 35 115 � 28 �0.00116 � 8 20 � 4 NS5 (19%) 7 (27%) NS

%, 95% CI 44–83) 20 (77%, 95% CI 56–91) 0.455

n calculating the success rate.d dilated cardiomyopathy (n � 6).

n 26 stu

17 (65

idered i10), an

cardiomyopathy. Circulation 2001;104:2517–2522.

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2


4. Glancy DL, O’Brien KP, Gold HK, Epstein SE. Atrial fibrillation inpatients with idiopathic hypertrophic subaortic stenosis. Br Heart J1970;32:652–659.

5. Stafford WJ, Trohman RG, Bilsker M, Zaman L, Castellanos A,Myerburg RJ. Cardiac arrest in an adolescent with atrial fibrillationand hypertrophic cardiomyopathy. J Am Coll Cardiol 1986;7:701–704.

6. Furlan AJ, Craciun AR, Raju NR, Hart N. Cerebrovascular complica-tions associated with idiopathic hypertrophic subaortic stenosis. Stroke1984;15:282–284.

7. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijins HJ, Frye RL,Halperin JL, Kay GN, Klein WW, Levy S, et al. American College ofCardiology/American Heart Association Task Force on PracticeGuidelines; European Society of Cardiology Committee for PracticeGuidelines and Policy Conferences (Committee to Develop Guidelinesfor the Management of Patients With Atrial Fibrillation); North Amer-ican Society of Pacing and Electrophysiology. Circulation 2001;104:2118–2150.

8. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y,Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, CorleySD, for the Atrial Fibrillation Follow-up Investigation of RhythmManagement (AFFIRM) Investigators: a comparison of rate controland rhythm control in patients with atrial fibrillation. N Engl J Med2002;347:1825–1833.

9. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G,Garrigue S. Spontaneous initiation of atrial fibrillation by ectopic beatsoriginating in the pulmonary veins. N Engl J Med 1998;339:659–666.

0. Haissaguerre M, Jais P, Shah DC, Garrigue S, Takahashi A, LavergneT, Hocini M, Peng JT, Roudaut R, Clementy J, et al. Electrophysio-logical end point for catheter ablation of atrial fibrillation initiatedfrom multiple pulmonary venous foci. Circulation 2000;101:1409–1417.

1. Oral H, Scharf C, Chugh A, Hall B, Cheung P, Good E, Veerareddy S,Pelosi F Jr, Morady F. Catheter ablation for paroxysmal atrial fibril-lation: segmental pulmonary vein ostial ablation versus left atrialablation. Circulation 2003;108:2355–2360.

2. Liu X, Ouyang F, Mavrakis H, Ma C, Dong J, Ernst S, Bansch D, AntzM, Kuck KH. Complete pulmonary vein isolation guided by three-dimensional electroanatomical mapping for the treatment of paroxys-mal atrial fibrillation in patients with hypertrophic obstructive cardio-myopathy. Europace 2005;7:421–427.

3. Kilicaslan F, Verma A, Saad E, Themistoclakis S, Bonso A, Raviele A,Bozbas H, Andrews MW, Beheiry S, Hao S, et al. Efficacy of catheterablation of atrial fibrillation in patients with hypertrophic obstructivecardiomyopathy. Heart Rhythm 2006;3:275–280.

4. Gaita F, Riccardi R, Caponi D, Shah D, Garberoglio L, Vivalda L,Dulio A, Chiecchio A, Manasse E, Gallotti R. Linear cryoablation of
the left atrium versus pulmonary vein cryoisolation in patients with
permanent atrial fibrillation and valvular heart disease: correlation ofelectroanatomic mapping and long-term clinical results. Circulation2005;111:136–142.

5. Klues HG, Schiffers A, Maron BJ. Phenotypic spectrum and patternsof left ventricular hypertrophy in hypertrophic cardiomyopathy: mor-phologic observations and significance as assessed by two-dimen-sional echocardiography in 600 patients. J Am Coll Cardiol 1995;26:1699–1708.

6. McKenna WJ, Spirito P, Desnos M, Dubourg O, Komajda M. Expe-rience from clinical genetics in hypertrophic cardiomyopathy: pro-posal for new diagnostic criteria in adult members of affected families.Heart 1997;77:130–132.

7. Jais P, Hocini M, Hsu LF, Sanders P, Scavee C, Weerasooriya R,Macle L, Raybaud F, Garrigue S, Shah DC, et al. Technique andresults of linear ablation at the mitral isthmus. Circulation 2004;110:2996–3002.

8. Hocini M, Jais P, Sanders P, Takahashi Y, Rotter M, Rostock T, HsuLF, Sacher F, Reuter S, Clementy J, Haissaguerre M. Techniques,evaluation and consequences of linear block at the left atrial roof inparoxysmal atrial fibrillation. A prospective randomized study. Circu-lation 2005;112:3688–3696.

9. Oral H, Knight P, Ozaydin M, Tada H, Chugh A, Hassan S, Scharf C,Lai SWK, Greenstein R, Pelosi F, Strickberger A, Morady F. Clinicalsignificance of early recurrences of atrial fibrillation after pulmonaryvein isolation. J Am Coll Cardiol 2002;40:100–104.

0. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillationbegets atrial fibrillation. A study in awake chronically instrumentedgoats. Circulation 1995;92:1954–1968.

1. Cecchi F, Olivotto I, Montereggi A, Santoro G, Dolara A, Maron BJ.Hypertrophic cardiomyopathy in Tuscany: clinical course and out-come in an unselected population. J Am Coll Cardiol 1995;26:1529–1536.

2. Chen MS, McCarthy PM, Lever HM, Smedira NG, Lytle BL. Effec-tiveness of atrial fibrillation surgery in patients with hypertrophiccardiomyopathy. Am J Cardiol 2004;93:373–375.

3. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, KimYH, Klein G, Packer D, Skanes A. Worldwide survey on the methods,efficacy, and safety of catheter ablation for human atrial fibrillation.Circulation 2005;111:1100–1105.

4. Hsu LF, Jais P, Sanders P, Garrigue S, Hocini M, Sacher F,Takahashi Y, Rotter M, Pasquie JL, Scavee C, et al. Catheterablation for atrial fibrillation in congestive heart failure. N Engl J Med2004;351:2373–2383.

5. Lang CC, Santinelli V, Augello G, Ferro A, Gugliotta F, Gulletta S,Vicedomini G, Mesas C, Paglino G, Sala S, et al. Transcatheterradiofrequency ablation of atrial fibrillation in patients with mitralvalve prostheses and enlarged atria: safety, feasibility, and efficacy.
J Am Coll Cardiol 2005;45:868–872.

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Effect of Chronic Afterload Increase on Left VentricularMyocardial Function in Patients With Congenital Left-Sided

Obstructive Lesions

Yat-Yin Lam, MBBS, MRCPa,d,*, Mehmet G. Kaya, MDa, Wei Li, MD, PhDa,b,c,Michael A. Gatzoulis, MD, PhDa,c, and Michael Y. Henein, MD, PhDa,b,c

The effect of pressure-overloading distance on left ventricular (LV) function in patientswith congenital aortic coarctation and aortic stenosis (AS) was investigated. LV long-axismotions were recorded using M-mode and tissue Doppler imaging (TDI) techniques in 46consecutive patients with severe LV outflow tract obstruction (23 coarctation and 23 AS),and results were compared with those of 23 controls. TDI lateral and septal long-axissystolic velocities, early diastolic velocities, and M-mode systolic amplitudes were lower inpatients with coarctation and AS than controls (lateral site long-axis systolic velocity 7.1 �1.7 and 6.4 � 1.6 vs 9.7 � 1.7 cm/s, septal site long-axis systolic velocity 6.3 � 1.3 and5.4 � 1.1 vs 7.7 � 1.3 cm/s; lateral site early diastolic velocity 10.5 � 2.2 and 8.2 � 2.6 vs13.1 � 2.5 cm/s, septal site early diastolic velocity 7.4 � 1.9 and 6.0 � 1.8 vs 10.8 � 1.6cm/s, lateral site M-mode systolic amplitude 1.4 � 0.2 and 1.3 � 0.2 vs 1.6 � 0.2 cm, septalsite M-mode systolic amplitude 1.2 � 0.2 and 1.1 � 0.2 vs 1.4 � 0.2 cm, p <0.01 for all).Compared with patients with coarctation, those with AS had lower TDI velocities,higher early LV filling velocity/long-axis diastolic velocity ratios, and a higher preva-lence of long-axis incoordination (p <0.05 for all) despite similar LV mass index,ejection fraction, and systolic wall stress. In conclusion, LV long-axis function isimpaired in patients with a chronic increase in afterload. Worse deterioration in LVfunction and higher prevalence of long-axis incoordination independent of LV outflowresistance is seen in patients with proximally increased LV afterload (AS) comparedwith distal disease (aortic coarctation). © 2007 Elsevier Inc. All rights reserved. (Am
J Cardiol 2007;99:1582–1587)
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dult patients with severe aortic stenosis (AS) more oftenevelop angina and/or heart failure symptoms than patientsith aortic coarctation despite a similar degree of left ven-

ricular (LV) systolic hypertension.1,2 We previously re-orted a reversible and inverse relation between the distancef arterial clamping (aortic or iliac artery level) and degreef LV long-axis impairment in patients with combined cor-nary artery and peripheral vascular disease.3 Whether suchelations could be applied to the 2 chronic conditions re-ains unknown. The selective sensitivity of LV long-axis

unction to unveil LV dysfunction was documented in pa-ients with AS.4,5 In addition, LV long-axis incoordinationefined as long-axis shortening after end-ejection (after sys-olic shortening) was reported as a sign of subendocardialschemia that normalizes after percutaneous coronary inter-

aAdult Congenital Heart Unit and bDepartment of Echocardiography,oyal Brompton Hospital; cNational Heart and Lung Institute, Imperialollege, London, United Kingdom; dDivision of Cardiology, SH Ho Car-iovascular and Stroke Centre, Department of Medicine and Therapeutics,rince of Wales Hospital, The Chinese University of Hong Kong, Hongong. Manuscript received November 10, 2006; revised manuscript re-

eived and accepted January 10, 2007.Dr. Lam was supported by the Hong Kong Hospital Authority, Hong

ong.*Corresponding author: Tel.: 852-2632-3131; fax: 852-2632-4590.

wE-mail address: [email protected] (Y.-Y. Lam).


ention,6 as well as an objective end point for inducibleschemic dysfunction during diagnostic stress echocardiog-aphy in patients without intraventricular conduction abnor-alities.7,8 We therefore studied LV long-axis function in

atients with a chronic increase in LV outflow tract resis-ance at the aortic valve level (AS) and descending aortaevel (aortic coarctation) to understand the impact of differ-ntial pressure-overloading distances on LV function.

ethods

e retrospectively studied 46 consecutive patients withoderate to severe AS and coarctation followed up in an

dult congenital heart disease clinic who underwent trans-horacic echocardiography at the Royal Brompton HospitalLondon, United Kingdom) from 2003 to 2005. Patientlood pressure was measured while supine using a standardercury sphygmomanometer at the same time. Patientsere defined as hypertensive if they had blood pressure

eadings �140/90 mm Hg at rest during previous clinicisits. A history of antihypertensive use was recorded ando change in medications was allowed 6 months before thechocardiographic examination. Significant AS is defined ast least a fivefold increase in transvalvular velocity withespect to subvalvular velocity, aortic valvular area �1.0m2, and mean transvalvular gradient �40 mm Hg. Patients
ith significant aortic coarctation had decreased femoral
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1583Congenital Heart Disease/LV Function and Congenital LVOTO

ulses and continuous-wave Doppler-derived early diastolicail velocity (measured at the end of the T wave on thelectrocardiogram tracing) �193 cm/s.9 Their findings wereompared with 23 age- and gender-matched controls. Pa-ients with suboptimal echocardiographic windows, pace-akers, atrial fibrillation, mitral annular calcifications,

ranch bundle block, and/or other hemodynamically signif-cant cardiac lesions were excluded from the study.

Echocardiograms were obtained using a Hewlett-Pack-rd Sonos 2500 and 5500 system (Hewlett Packard, Palolto, California), and images were obtained according touidelines of the American Society of Echocardiography.10

t least 3 consecutive beats in sinus rhythm were recorded,nd average values were obtained.

Peak and mean pressure gradients across the aortic valvend coarctation site were derived from continuous waveoppler recordings at an apical 5-chamber and suprasternaliew, respectively. LV end-diastolic and end-systolic di-ensions, and interventricular septal and posterior wall

hicknesses were measured from M-mode recordings of theV cavity with the cursor by the tip of the mitral valve

eaflets in the parasternal long-axis view, and LV ejectionraction was calculated using Simpson’s volume estimates.V mass index was derived using the Devereux formula.11

V end-systolic meridional wall stress was calculated from-mode and systolic blood pressure data using the follow-

ng formula12,13: LV end-systolic meridional wall stress �.334 � P � LVESD/(LPWs � [1 � LPWs/LVESD]),here P � (systolic blood pressure) and P � (systolic bloodressure � peak systolic pressure gradient across aorticalve) in patients with coarctation and AS, respectively;VESD � LV end-systolic dimension, and LPWs � LVnd-systolic posterior wall thickness.

A 2-mm sample volume of pulse-wave Doppler waslaced at the tip of the mitral leaflets to record transmitraloppler velocities. Peak early LV filling velocity (E), peak

trial filling velocity (A), E/A ratio, E wave decelerationime, and isovolumic relaxation time were measured fromV filling recordings. Total LV isovolumic time was cal-

able 1atient characteristics

ariables Control(n � 23)

ge (yrs) 35 � 8en/women 11/12eart rate (beats/min) 67 � 11icuspid valve 0/23ypertension 0/23se of �-blocker 0/23lood pressure (mm Hg)Systolic 122 � 9Diastolic 70 � 10eak pressure gradient (mm Hg) 4.6 � 2.4ean pressure gradient (mm Hg)ortic valvular area (cm2)V end-systolic wall stress (102 dynes/cm2) 56 � 13

* p �0.01 versus control.† p �0.05 coarctation versus AS.‡ p �0.05 versus control.

ulated as the sum of total filling and ejection times sub- m

racted from the RR interval.14 LV myocardial performancendex was calculated as total LV isovolumic time divided byjection time.15

Segmental myocardial function was assessed by record-ng LV long-axis motions from lateral and septal angles ofhe atrioventricular junction with M-mode and pulsed-waveissue Doppler imaging (TDI) techniques as previously de-cribed.4 The presence of long-axis segmental incoordina-ion (prolonged shortening after end-ejection) was alsoecorded.7,16 Inter- and intraobserver variabilities were as-essed in 15 randomly chosen patients. Variability wasalculated as percentage of error, derived as the absoluteifference between 2 sets of measurements divided by the

Coarctation(n � 23)

AS(n � 23)

35 � 10 36 � 1212/11 11/12

68 � 14 70 � 1312/23 52%* 16/23 70%*13/23 57%* 3/23* 13%*†

3/23 13%* 2/23 9%*

140 � 19‡ 132 � 16‡

80 � 12‡ 76 � 10‡

53.7 � 7.8* 62.3 � 8.7*†

45.9 � 4.80.8 � 0.1

96 � 16* 100 � 18*

able 2lobal left ventricular (LV) structure and function

ariables Control(n � 23)

Coarctation(n � 23)

AS(n � 23)

V end-diastolicdiameter (mm)

48.8 � 6.1 50.6 � 6.9 50.1 � 6.1

V end-systolicdiameter (mm)

29.7 � 4.6 29.6 � 5.8 27.3 � 5.0

nterventricular septumdiameter (mm)

8.8 � 1.6 12.3 � 2.8* 11.7 � 2.6*

V posterior walldiameter (mm)

8.6 � 1.1 10.8 � 2.8* 12.6 � 3.4*

V mass index (g/m2) 87 � 15 151 � 30* 157 � 26*V ejection fraction (%) 68 � 7 65 � 8 66 � 8V myocardialperformance index

0.29 � 0.08 0.31 � 0.14 0.30 � 0.08

V total isovolumictime (s/min)

8.5 � 0.8 10.1 � 1.2 9.8 � 1.4

(cm/s) 80 � 15 84 � 22 86 � 26(cm/s) 49 � 11 58 � 16 59 � 19

/A ratio 1.7 � 0.4 1.6 � 0.4 1.6 � 0.6eceleration time (ms) 204 � 21 213 � 41 213 � 39

sovolumic relaxationtime (ms)

65 � 16 63 � 13 69 � 9

* p �0.01 versus control.

0%0%0%

ean of the observations.

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Statistical analysis was performed using designated soft-are (SPSS 13, SPSS Inc., Chicago, Illinois). Parametricariables are expressed as mean � SD. Differences betweenarametric variables among the 3 groups were evaluatedsing 1-way analysis of variance. When analysis of varianceas significant, continuous variables between groups were

ompared using 2-tailed unpaired Student’s t test or Mann-hitney U test as appropriate. Categorical variables are

resented as absolute values and percentages, and compar-sons were tested using chi-square test. Pearson’s methodas used to calculate correlation coefficients between TDI

ong-axis velocities and estimated wall stress. p Values0.05 (2 tailed) and �0.01 are considered statistically sig-

ificant and highly significant, respectively.

esults

able 1 lists clinical data for all patients. There were noignificant differences between patients and controls withespect to age, gender, and heart rate. The 23 patients withortic coarctation (14 native coarctation and 9 recoarctationeveloped 20 � 7 years after previous surgical repair) hadmean age of 35 years, and those with AS had a mean agef 36 years. Fifty-two percent of patients with coarctationnd 70% of patients with AS had bicuspid valves (p �.23). Percentages of �-blocker use were similar in 2 groups13% vs 9%, p � 0.64). Systemic hypertension was morerevalent in patients with coarctation than those with AS57% vs 13%, p �0.01). Mean systolic and diastolic bloodressures were not statistically different at the time of studyetween the 2 patient groups because we recruited onlyatients with good blood pressure control in the previous 6onths. Compared with patients with coarctation, thoseith AS had similar degrees of LV outflow resistance in-icated by comparable LV end-systolic wall stress (96 � 16s 100 � 18 102 dynes/cm2, p � 0.24).

With respect to controls, patients had no significant dif-erences in LV dimensions, but had thicker interventricular

able 3egmental myocardial function

ariables Group 1Control

(n � 23)

GrCoa

(n

ateral M-mode systolic amplitude (cm) 1.6 � 0.2 1.ateral TDISm (cm/s) 9.7 � 1.7 7.Em (cm/s) 13.1 � 2.5 10.Am (cm/s) 7.4 � 2.4 6.E/Em 5.6 � 1.5 8.eptal M-mode systolic amplitude (cm) 1.4 � 0.2 1.eptal TDISm (cm/s) 7.7 � 1.3 6.Em (cm/s) 10.8 � 1.6 7.Am (cm/s) 6.7 � 2.4 6.E/Em 6.7 � 1.4 13.ong-axis incoordinationLateral site 1Septal site 4

Am � TDI long-axis late diastolic velocity.

eptal and posterior walls (p �0.01) and consequently a

igher LV mass indexes (p �0.01; Table 2). No significantifference was observed among the 3 groups with regard toV ejection fraction, other global LV functional indices

myocardial performance index, total isovolumic time), andonventional LV filling measurements (E, A, E/A ratio,eceleration time, and isovolumic relaxation time).

Table 3 lists LV segmental function for all subjects. LVateral and septal M-mode long-axis systolic amplitudesere decreased in 2 patient groups compared with controls

p �0.01 for all). Patients also had significantly lower TDIong-axis systolic and early diastolic velocities and E/long-xis diastolic velocity (Em) ratios at both the lateral andeptal sites than controls (p �0.01 for all).

Patients with AS had lower lateral and septal long-axisystolic (p �0.05) and early diastolic velocities (p �0.01)nd higher E/Em ratios (p �0.01) compared with patientsith aortic coarcation (Figure 1). This difference in LVyocardial function was independent of LV end-systoliceridional wall stress and global LV functional indexes,

uch as LV ejection fraction, myocardial performance in-ex, and total isovolumic time. Furthermore, LV long-axisncoordination was more frequently seen in patients withS than coarctation (lateral 26% vs 4%, septal 52% vs 17%,�0.05 for both). A nonsignificant inverse relation was

ound between TDI long-axis systolic velocity (Sm) and Emnd estimated LV meridional wall stress in both patientroups (patients with coarctation: lateral Sm vs wall stress� �0.08; lateral Em vs wall stress r � �0.21; septal Sms wall stress r � �0.35; septal Em vs wall stress r �0.13; patients with AS: lateral Sm vs wall stress r �0.22; lateral Em vs wall stress r � �0.16; septal Sm vsall stress r � �0.28; and septal Em vs wall stress r �0.20; p �0.10 for all correlations).Intra- and interobserver variability for conventional

oppler and TDI-derived variables (deceleration time, Sm,nd Em) ranged from 1% to 7%. Reproducibility of long-

Group 3AS

(n � 23)

p Values

(1 vs 2) (1 vs 3) (2 vs 3)

1.3 � 0.2 0.002 0.001 0.225

6.4 � 1.6 0.001 0.001 0.0368.2 � 2.6 0.002 0.001 0.0076.6 � 2.7 0.148 0.106 0.898

12.0 � 2.8 0.001 0.001 0.0091.1 � 0.2 0.004 0.001 0.124

5.4 � 1.1 0.002 0.001 0.0486.0 � 1.8 0.001 0.001 0.0036.3 � 1.4 0.026 0.071 0.695

16.0 � 4.3 0.001 0.001 0.005

6 (26%) 0.04012 (52%) 0.013

oup 2rctation� 23)

4 � 0.2

1 � 1.75 � 2.21 � 1.49 � 2.12 � 0.2

3 � 1.34 � 1.98 � 2.20 � 3.6

(4%)(17%)

xis measurements was previously published.17

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iscussion

ur study is the first to show the impairment in long-axisystolic and diastolic function in patients with significantortic coarctation compared with age- and gender-matchedormal controls. Our data show a significant decrease in LVong-axis amplitude of movement, as well as its TDI sys-olic and diastolic velocities, in the 2 patient groups withimilar blood pressures compared with controls. These find-ngs contrast with the equivocal minor axis conventionaleasurements and traditional LV filling parameters thatere similar in the 2 patient groups. Thus our data confirm

he selective sensitivity of LV long-axis function previouslyeported in patients with AS4,5 and hypertension18 in unveil-ng myocardial dysfunction in patients with aortic coarcta-ion, as well. Such findings likely represent subclinical myo-

igure 1. TDI long-axis (A, B) systolic and (C, D) diastolic velocities and (ersus control; ‡p �0.01 patients with coarctation versus aortic stenosis; §patio at lateral and septal sites, respectively; LSm and LEm � TDI lateral site systolic and early diastolic velocity, respectively.

ardial dysfunction in these patients in view of the relative t

oad independence of long-axis TDI velocities and the es-ablished accuracy of E/Em ratio in predicting LV fillingressure in patients with aortic stenosis.5 The lack of atrong and significant inverse relation between TDI long-xis velocities and estimated wall stress (an indication forutflow resistance) suggest factors other than afterload in-rease itself were involved in myocardial damage.

Compared with patients with coarctation, patients withS had significantly lower Sm and Em and higher E/Em

atios (Figure 1). They also had a significantly higher prev-lence of long-axis incoordination. These findings highlighthe important influence of afterload distance on LV func-ion, with proximal having a more profound effect com-ared with distal. These findings are in line with our previousbservations during arterial clamping,3 although chronicity of

/Em ratios at the LV lateral and septal sites in 3 patient groups. *p �0.01atients with coarctation versus aortic stenosis. LE/Em and SE/Em � E/Emlic and early diastolic velocity, respectively; SSm and SEm � TDI septal

E, F) E�0.05 pite systo

he 2 study conditions is different. The generally accepted

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ore frequently occurring LV dysfunction in patients withS than coarctation supports the differences we found be-

ween the 2 patient groups with a similar degree of increasen LV outflow resistance.

Furthermore, we show a significantly higher prevalencef LV long-axis incoordination, which is a very sensitivearker of coronary ischemia19 in patients with AS without

bnormal ventricular activation pattern. This finding sug-ests a higher frequency of subclinical subendocardial isch-mia in patients with AS than their coarctation counterparts.his is supported by the positron emission tomographicnding of severe impairment of coronary flow reserve in theubendocardium in patients with LV hypertrophy attribut-ble to severe AS.20 Recent elegant cardiac magnetic reso-ance imaging data also showed perfusion abnormalities indult patients with aortic coarctation.21 In patients with AS,he combination of decreased long-axis relaxation velocitiesnd incoordination may result in increased early diastolicegmental tension, compromised blood flow to the suben-ocardium, and hence the development of subendocardialschemia, which may explain the angina-like symptoms inhese patients,1,22,23 even in the absence of epicardial coro-ary artery disease. Recovery of this degree of disturbedyocardial oxygen supply and demand after aortic valve

eplacement surgery results in the disappearance of anginaymptoms,23 regression of LV mass,23 and improvement inoronary flow reserve24 and LV function.25 Unlike patientsith AS, an early study reported an increase in coronarylood flow in patients with coarctation.26 This finding isupported by the presence of a higher proportion of capil-ary angiogenesis, histologically shown in patients withoarctation than their AS counterparts.27 A lesser degree ofisturbed myocardial oxygen supply and demand in patientsith coarctation therefore could explain the lower preva-

ence of long-axis incoordination than in patients with AS.Our data suggest that the closer the pressure overload to

he left ventricle, the higher the diastolic dysfunction. Al-hough the reflected waves recently confirmed in animaltudies28 may have had a role during acute aortic clamping,hronic conditions with different pressure-overload dis-ances could affect LV function by alteration in coronarylood flow. This hypothesis was shown in a similar fashionn animal studies that showed subendocardial ischemia orltered patterns of coronary blood flow as a result of acutehange in aortic compliance.29,30

Our study has potential limitations. Most of them arenherent to the small sample size and retrospective design.

oreover, we did not have invasive data to validate esti-ated LV end-systolic meridional stress. Finally, we only

tudied a prespecified group of patients, and the applicabil-ty of results to other patients with poorly controlled hyper-ension; atrial fibrillation, and aortic or mitral valvular dis-ase are considered inappropriate.

cknowledgment: We are grateful for the support receivedrom adult patients with congenital heart disease and staff athe Royal Brompton Hospital.

1. Hess OM, Villari B, Krayenbuehl HP. Diastolic dysfunction in aorticstenosis. Circulation 1993;87(suppl IV):SIV73–SIV76.

2. Gatzoulis MA, Webb GD, Daubeney PE. Textbook of Diagnosisand Management of Adult Congenital Heart Disease. New York:Churchill Livingstone, 2003:Chapter 30:253–264.

3. Henein MY, Das Saroj K, O’Sullivan C, Kakkar VV, Gillbe CE,Gibson DG. Effect of acute alteration in afterload on left ventricularfunction in patients with combined coronary artery and peripheralvascular disease. Heart 1996;75:151–158.

4. Lam YY, Kaya MG, Goktekin O, Gatzoulis MA, Henein MY, Li W.“Isolated” diastolic dysfunction in left ventricular outflow tract ob-struction. Am J Cardiol 2006;98:509–514.

5. Bruch C, Stypmann J, Grude M, Gradaus R, Breithardt G, Wichter T.Tissue Doppler imaging in patients with moderate to severe aorticvalve stenosis: clinical usefulness and diagnostic accuracy. Am Heart J2004;148:696–702.

6. Henein MY, Priestley K, Davarashvili T, Buller N, Gibson DG. Earlychange in left ventricular subendocardial function after successfulcoronary angioplasty. Br Heart J 1993;69:501–506.

7. Duncan AM, O’Sullivan CA, Carr-White GS, Gibson DG, HeneinMY. Long axis electromechanics during dobutamine stress in patientswith coronary artery disease and left ventricular dysfunction. Heart2001;86:397–404.

8. Duncan AM, Francis DP, Gibson DG, Henein MY. Differentiation ofischemic from non-ischemic cardiomyopathy during dobutaminestress by left ventricular long axis function: additional effect of LBBB.Circulation 2003;108:1214–1220.

9. Tan JL, Babu-Narayan SV, Henein MY, Mullen M, Li W. Dopplerechocardiographic profile and indexes in the evaluation of aortic co-arctation in patients before and after stenting. J Am Coll Cardiol2005;46:1045–1053.

0. Schiller NB. Two-dimensional echocardiographic determination of leftventricular volume, systolic function, and mass. Summary and discus-sion of the 1989 recommendations of the American Society of Echo-cardiography. Circulation 1991;84(suppl I):SI280–SI287.

1. Devereux RB. Detection of left ventricular hypertrophy by M-modeechocardiography: anatomical validation, standardization, and com-parison to other methods. Hypertension 1987;9(suppl II):SII19–SII26.

2. Reichek N, Wilson J, St John Sutton M, Plappert TA, Goldberg S,Hirshfeld JW. Noninvasive determination of left ventricular end-sys-tolic stress: validation of the method and initial application. Circula-tion 1982;65:99–108.

3. Douglas PS, Reichek N, Plappert T, Muhammad A, St John SuttonMG. Comparison of echocardiographic methods for assessment of leftventricular shortening and wall stress. J Am Coll Cardiol 1987;9:945–951.

4. Duncan AM, Francis DP, Henein MY, Gibson DG. Limitation ofcardiac output by total isovolumic time during pharmacologic stress inpatients with dilated cardiomyopathy: activation-mediated effects ofleft bundle branch block and coronary artery disease. J Am CollCardiol 2003;41:121–128.

5. Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, TajikAJ, Seward JB. New index of combined systolic and diastolic myo-cardial performance: a simple and reproducible measure of cardiacfunction—a study in normals and dilated cardiomyopathy. J Cardiol1995;26:357–366.

6. Li W, Hornung TS, Francis DP, O’Sullivan C, Duncan A, GatzoulisM, Henein M. Relation of biventricular function quantified by stressechocardiography to cardiopulmonary exercise capacity in adults withMustard (atrial switch) procedure for transposition of the great arteries.Circulation 2004;110:1380–1386.

7. Chen QM, Li W, O’Sullivan C, Francis DP, Gibson D, Henein MY.Clinical in vivo calibration of pulse wave tissue Doppler velocities inthe assessment of ventricular wall motion. A comparison study withM-mode echocardiography. Int J Cardiol 2004;97:289–295.

8. Wang M, Yip GW, Wang AY, Zhang Y, Ho PY, Tse MK, Yu CM,Sanderson JE. Tissue Doppler imaging provides incremental prognos-tic value in patients with systemic hypertension and left ventricularhypertrophy. J Hypertens 2005;23:183–191.

9. Henein MY, Gibson DG. Long axis function in disease. Heart 1999;81:229–231.

0. Rajapppan K, Rimoldi OE, Dutka DP, Ariff B, Pannell DJ, SheridanDJ, Camici PG. Mechanisms of coronary microcirculatory dysfunctionin patients with aortic stenosis and angiographically normal coronary
arteries. Circulation 2002;105:470–476.

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1. Cook SC, Roman SV. Subendocardial ischaemia in adults with re-paired coarctation: a potential mechanism for early ischaemic events.Circulation 2006;114(suppl II):18:pt ii–408.

2. Julius BK, Spillmann M, Vassalli G, Villari B, Eberli FR, Hess OM.Angina pectoris in patients with aortic stenosis and normal coronaryarteries: mechanisms and pathophysiological concepts. Circulation1997;95:892–898.

3. Rajappan K, Rimoldi OE, Camici PG, Bellenger NG, Pannell DJ,Sheridan DJ. Functional changes in coronary microcirculation aftervalve replacement in patients with aortic stenosis. Circulation 2003;107:3170–3175.

4. Hildick-Smith DJ, Shapiro LM. Coronary flow reserve improvesafter aortic valve replacement for aortic stenosis: an adenosinetransthoracic echocardiography study. J Am Coll Cardiol 2000;36:1889 –1896.

5. Beyerbacht HP, Lamb HJ, van Der Laarse A, Vliegen HW, LeujesF, Hazekamp MG, de Roos A, van Der Wall E. Aortic valve
replacement in patients with aortic valve stenosis improves myo-
cardial metabolism and diastolic function. Radiology 2001;219:637– 643.

6. Bing RJ, Hammond MM, Handelsman JC, Powers SR, Spencer F,Eckenhoff JE, Goodale WT, Hafkenschiel J, Kety SS. The measure-ment of coronary blood flow, oxygen consumption, and efficiency ofthe left ventricle in man. Am Heart J 1949;38:1–24.

7. Rakusan K, Flanagan MF, Geva T, Southern J, Van Praagh R. Mor-phometry of human coronary capillaries during normal growth and theeffect of age in left ventricular pressure-overload hypertrophy. Circu-lation 1992;86:38–46.

8. Khir AW, Parker AH. Wave intensity in the ascending aorta: effects ofarterial occlusion. J Biomech 2005;38:647–655.

9. Watanabe H, Ohitsuka S, Kakihana M, Sugishita Y. Decreased aorticcompliance aggravates subendocardial ischemia in dogs with stenosedcoronary artery. Cardiovasc Res 1992;26:1212–1218.

0. Watanabe H, Ohitsuka S, Kakihana M, Sugishita Y. Coronary circu-lation in dogs with an experimental decrease in aortic compliance.
J Am Coll Cardiol 1993;21:1497–1506.

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Frequency of Development of Aortic Cuspal Prolapse and AorticRegurgitation in Patients With Subaortic Ventricular Septal Defect

Diagnosed at <1 Year of Age

Susan F. Saleeb, MDa,*, David E. Solowiejczyk, MDb, Julie S. Glickstein, MDb,Rosalind Korsin, RNb, Welton M. Gersony, MDb, and Daphne T. Hsu, MDb

The natural history of aortic cuspal prolapse and aortic regurgitation (AR), studied mostcommonly in subpulmonic ventricular septal defect (VSD), has not been well defined inisolated, unrepaired VSD diagnosed during infancy. This study aimed to define theincidence and progression of aortic cuspal prolapse and AR in patients with subaorticVSDs diagnosed at <1 year of age who had no aortic cuspal prolapse or AR at presentationand did not require surgery within the first year of life. Patients had yearly follow-up, anddata regarding clinical course, physical examination, and echocardiography were obtained.Comparisons were made between patients who developed aortic cuspal prolapse and ARand those who did not. One hundred patients, with a mean age at VSD diagnosis of 0.1 �0.5 years, followed for a mean of 7.1 � 10.1 years, were studied. Aortic cuspal prolapsedeveloped in 14 patients (14%) at a mean age of 7.1 � 6 years (range 0.4 to 18.4). ARmurmurs were heard in 6 patients (6%) at a mean age of 5.1 � 3.1 years, all of whom hadaortic cuspal prolapse and underwent VSD closure and aortic valvuloplasty. In conclusion,aortic cuspal prolapse and clinical AR are not uncommon in patients with subaortic VSDs.Long-term follow-up of patients with subaortic VSDs should include the serial evaluationof aortic valve anatomy and function. © 2007 Elsevier Inc. All rights reserved. (Am J
Cardiol 2007;99:1588–1592)
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ortic cuspal prolapse and aortic regurgitation (AR) arenown to be associated with ventricular septal defectsVSDs), with prevalences of 4% to 9% and 2% to 6%,espectively.1–8 Subpulmonic VSD has a reported incidencef aortic cuspal prolapse of up to 73%, with progression ofR in 52% to 78% of patients, most typical in Asianopulations.9–14 Eroglu et al1,2 published the prevalences ofortic cuspal prolapse and AR in subaortic VSD to be 12%nd 7%, respectively, in their study. When aortic cuspalrolapse is present in subaortic VSD, the incidence of echo-ardiographic AR is reported to be 62%. Similarly, 77% to0% of patients with subaortic VSDs and AR have associ-ted aortic cuspal prolapse.15,16 The natural history andlinical significance of the development of aortic cuspalrolapse and/or AR in patients with subaortic VSDs has noteen fully determined.2,5,7,8,16–18 This study was designed tovaluate the incidence and progression of aortic cuspalrolapse and AR in patients with subaortic VSDs whoresented in infancy, did not require surgical repair withinhe first year of life, and had no evidence of aortic cuspalrolapse or insufficiency at the time of presentation.

aDepartment of Cardiology, Children’s Hospital of Boston, Boston,assachusetts; and bDivision of Pediatric Cardiology, Department of Pe-

iatrics, Morgan Stanley Children’s Hospital of New York–Presbyterian,ew York, New York. Manuscript received August 4, 2006; revisedanuscript received and accepted January 10, 2007.

*Corresponding author: Tel: 617-355-8539; fax: 617-739-6282. (S.F.aleeb).

cE-mail address: [email protected]


ethods

he medical records of all patients who underwent echo-ardiography at Children’s Hospital of New York fromanuary 1996 to July 2001 were reviewed, and patients who1) were diagnosed at �1 year of age with subaortic VSDsy 2-dimensional echocardiography, (2) had no aortic cus-al prolapse or AR present at the time of VSD diagnosis, (3)ere followed annually and had a minimum of 2 echocar-iograms and follow-up visits available for review, and (4)ere followed for �1 year without surgical interventionere included for study. Patients with bicuspid aortic valves

nd coarctation of the aorta were included in the studyopulation. Patients were excluded if significant associatedesions were present (e.g., tetralogy of Fallot, transpositionf the great vessels, double-outlet right ventricle, or hypo-lastic left-heart syndrome). All patients who were ex-luded from the study because surgical closure of the VSDas performed within the first year of life had significant

ongestive heart failure; none of the patients had aorticuspal prolapse. This study was approved by the New Yorkresbyterian Hospital Institutional Review Board.

Data collection: Serial data were collected in the fol-owing categories: (1) clinic chart: age, gender, height per-entile, weight percentile, grade of AR murmur, evidence ofongestive heart failure, and use of digoxin, diuretics, orngiotensin-converting enzyme inhibitors; (2) echocardiog-aphy: VSD size and location, AR color grade, aortic cuspalrolapse, left ventricular end-diastolic volume, left ventric-lar end-systolic volume, VSD pressure gradient, and asso-
iated lesions; (3) catheterization: VSD size, pulmonary
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1589Congenital Heart Disease/Aortic Prolapse and Insufficiency in VSD

ow/systemic flow ratio (Qp/Qs), pulmonary arterial pres-ure, AR grade, and aortic systolic and diastolic pressures;nd (4) intraoperative data: VSD size, aortic cuspal pro-apse, associated anatomic findings, transesophageal echo-ardiographic findings, and type of surgical repair.

Echocardiographic analysis: Subaortic VSD locationas determined by 2-dimensional and color Doppler echo-

ardiography to be bordered superiorly by the right andoncoronary cusps of the aortic valve and to the right by theeptal leaflet of the tricuspid valve. The findings were con-rmed at the time of surgery for all patients who subse-uently underwent repair. VSD size was defined by echo-ardiography as small for lesions �5 mm in diameter,oderate for lesions 5 to 7 mm in diameter with restrictive

ressure gradients across the VSDs, and large for lesions7 mm in diameter with no significant pressure gradients

cross the VSDs. Aortic cuspal prolapse was defined asrotrusion of the right or noncoronary aortic valve leaflet,ith or without the associated sinus, into the VSD in the

pical anterior and/or parasternal view, as shown in Figure. Color Doppler echocardiographic AR severity was esti-ated on the basis of the ratio of the width of the regurgitant

et at the origin of the left ventricular outflow tract to theiameter of the left ventricular outflow tract in the paraster-al long-axis view. A regurgitant jet/left ventricular outflowract ratio �20% was considered mild, 20% to 80% mod-rate, and �80% severe.19

Statistical analysis: Results are expressed as mean �D. Comparisons were made among the following groups:1) patients who did and did not develop aortic cuspalrolapse and (2) patients who did and did not develop ARusing StatView, Abacus Concepts, Berkeley, California).ontinuous variables were compared using Student’s t test,nd categorical variables were compared using chi-squarenalysis. The development of aortic cuspal prolapse with

LVOT

LA

Aortic cuspalprolapse

A

igure 1. Echocardiographic demonstration of subaortic VSD and aortic cuhe aortic valve (AoV) (arrow). (B) Parasternal short-axis view demonstratento the VSD (short arrow). LA � left atrium; LVOT � left ventricular

ge was analyzed by Kaplan-Meier actuarial analysis. f

esults

tudy population: The study population consisted of 100atients: 67 males and 33 females. The mean age at VSDiagnosis was 0.1 � 0.5 years (median 0.3), and the meanotal number of follow-up visits and echocardiograms was0.2 � 5.7 per patient (range 2 to 30, median 9). Follow-upime was a mean of 7.1 � 5.1 years per patient (range 1 to4, median 5.6) and was considered as the last visit innoperated patients, until spontaneous VSD closure, or untilurgical closure of the VSD.

Initial VSD sizes at diagnosis by echocardiography weremall in 38 patients, moderate in 50 patients, and large in 12atients. Tricuspid valve aneurysms partially closing theSDs were present in 64% of patients. Twenty-three pa-

ients underwent cardiac catheterization. The mean Qp/Qsas 2.5:1, with a range of 1.2:1 to 7.9:1. The mean pulmo-ary arterial pressure was 16.5 mm Hg, with a range of 7 to6 mm Hg. Coarctation of the aorta was present in 7 pa-ients, all repaired in infancy. Bicuspid aortic valve wasoted in 4 patients, 2 of whom had associated coarctations.chocardiographic gradients �20 mm Hg (range 23 to 55)easured across the left ventricular outflow tract associatedith subaortic membranes were noted in 5 patients aged 4 to0 years.

During the follow-up period, the VSDs closed spontane-usly in 4 patients at a mean age of 6.0 � 4.5 years (range.4 to 12.7); initial VSD sizes were small in 3 patients andoderate in 1 patient. A single patient with no evidence ofR developed endocarditis. No deaths were reported.Aortic cuspal prolapse: Aortic cuspal prolapse devel-

ped in 14 of 100 patients (14%), at a mean age of 7.1 � 6ears (range 0.4 to 18.4, median 7.8), as listed in Table 1.y echocardiography, prolapse of the right coronary cuspccurred in all 14 patients. In 2 of these patients (patients 1nd 3), surgical inspection demonstrated that the right cor-nary cusp and noncoronary cusp were prolapsed, with

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olapse. (A) Parasternal long-axis view demonstrates prolapse of a cusp ofbaortic VSD (long arrow) and prolapse of the right cusp of the aortic valvetract.

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usion of the 2 cusps. A comparison of patients who did and

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id not develop aortic cuspal prolapse is listed in Table 2.he development of aortic cuspal prolapse was not associ-ted with age at VSD presentation, initial VSD size, gender,istory of a failure to thrive, or length of follow-up. Theaplan-Meier curve demonstrating freedom from aortic

uspal prolapse by age is shown in Figure 2. The incidencef aortic cuspal prolapse was 6.3% at 5 years and 14.9% at0 years.

Echocardiographic AR: Color Doppler evidence of AReveloped in 25 of the 100 patients (25%), at a mean age of.7 � 4.8 years. Echocardiographic AR occurred in 10 of 14atients (71%) with aortic cuspal prolapse and in 15 of 86atients (17%) with no aortic cuspal prolapse (p �0.01).atients who did and did not develop echocardiographic ARre compared in Table 3. Echocardiographic AR developedore frequently in patients with large VSDs at presentation

ut did not vary with age at VSD presentation, gender,istory of a failure to thrive, or length of follow-up. Of thepatients with bicuspid aortic valves, 1 developed mild

chocardiographic AR, which did not progress.In the 10 patients who developed echocardiographic AR

nd aortic cuspal prolapse, the AR was initially mild. Dur-

able 1atients who developed aortic cuspal prolapse

atient Age AorticCuspal

ProlapseDiagnosed

(yrs)

AgeEchocardiographic

AR Diagnosed(yrs)

Age AMurmHea(yrs

0.4 0.4 3.20.6 0.6 2.50.9 0.5 2.41.5 1.5 4.81.7 0 02.3 0 07.4 7.4 08.2 5.6 8.28.7 8.7 0

0 9.5 5.0 9.51 10.9 0 02 13.8 5.8 03 15.3 8.0 04 18.4 0 0

* Surgery refers to VSD closure and aortic valvuloplasty.† Patient scheduled for surgery at time of data completion.

able 2omparison of patients who did and did not develop aortic cuspal prolap

ariable

Yes (n � 14, 1

ean age (yrs) at VSD diagnosis 0.1 � 0.2nitial VSD sizeLarge 2Moderate 5Small 6ale/female 9/5istory of failure to thrive 0ean yrs of follow-up 7.4 � 5.1

ng the follow-up period (mean 3.4 years, range 0.6 to 7.8), m
patients continued to have mild AR, 3 progressed to
InitialEchocardiographic

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FinalEchocardiographic

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Age atSurgery(yrs)*

�Mild Moderate 4.2�Mild Moderate 0†

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0 0 00 0 0

�Mild �Mild 0�Mild �Mild 8.4�Mild �Mild 0�Mild �Mild 9.7

0 0 0�Mild �Mild 0�Mild �Mild 0

0 0 0

rtic Cuspal Prolapse p Value

No (n � 86, 86%)

0.1 � 0.2 0.92

10 0.884032

58/28 0.8210 0.18

6.7 � 5.0 0.61

igure 2. Kaplan-Meier curve demonstrating freedom from aortic cuspalrolapse compared with age.

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oderate AR, and 1 progressed to severe echocardiographic

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1591Congenital Heart Disease/Aortic Prolapse and Insufficiency in VSD

R. In the 15 patients who developed echocardiographicR and had no evidence of aortic cuspal prolapse, the initialrade of AR was mild or less in all patients and remainedild or less in all patients over a mean follow-up period of

.3 � 3.1 years (range 0 to 10.1).AR murmur: In the patients who developed echocar-

iographic AR, diastolic AR murmurs were heard only inatients who had also developed aortic cuspal prolapse. ARurmurs were heard in 6 of the 14 patients (43%) who

eveloped aortic cuspal prolapse (Table 1) and in none of 86atients without aortic cuspal prolapse (p �0.01). In the 6atients who developed aortic cuspal prolapse and clinicalR, murmurs were heard at the time of diagnosis of aortic

uspal prolapse in 2 patients and developed up to 3 yearsfter prolapse was diagnosed in 4 others. AR murmur de-eloped at a mean age of 5.1 � 3.1 years. No AR murmuras audible at a mean follow-up of 2.7 � 3.7 years in 8 of4 patients who developed aortic cuspal prolapse. Patientsho did and did not develop audible AR murmurs are

ompared in Table 4.Surgical intervention: A total of 11 patients in this

tudy underwent surgical intervention. In 5 patients, all ofhom had developed aortic cuspal prolapse and audibleR, the primary indication for surgery was AR. The sixthatient (patient 2) with aortic cuspal prolapse and audibleR was scheduled for surgery at the time data collection

nded. In the operated patients with aortic cuspal prolapse,SD closure and aortic valvuloplasty were performed at aean age of 5.9 � 3.0 years (range 2.5 to 9.7) (Table 1).ne patient (patient 10) also underwent resection of a sub-

ortic membrane. At last follow-up (mean 2.3 � 1.8 yearsfter surgery), all 5 operated patients with aortic cuspalrolapse had mild echocardiographic AR, and 3 had persis-ent audible AR murmurs. Patient 4 required 2 repeat sur-

able 3omparison of patients who did and did not develop echocardiographic a

ariable

Yes (n � 25, 2

nitial VSD size � large 6ean age (yrs) at VSD diagnosis 0.2 � 0.3ale/female 20/5istory of failure to thrive 4ean yrs of follow-up 8.3 � 5.1

able 4omparison of patients who did and did not develop aortic regurgitation

ariable

Yes (n � 6, 6

ean age (yrs) at VSD diagnosis 0.2 � 0.3nitial VSD sizeLarge 2Moderate 2Small 2ale/female 4/2istory of failure to thrive 0ean years of follow-up 4.8 � 3.0

ical valvuloplasties for recurrent aortic cuspal prolapse m

econdary to valve leaflet dehiscence. Patient 1 required aoss procedure after initial aortic valvuloplasty for persis-

ent aortic cuspal prolapse and insufficiency. A total of 6atients underwent surgery for indications other than AR; 1atient with mild AR underwent surgery for progressiveubaortic stenosis, and 5 patients who had no evidence ofortic cuspal prolapse or AR underwent VSD closure forailure to thrive.

iscussion

ew studies have focused on the occurrence and outcome ofortic cuspal prolapse and/or AR in association with aubaortic VSD. Eroglu et al1,2 reported a prevalence ofortic cuspal prolapse in patients with subaortic VSDs of2%. Trivial or mild AR was detected by echocardiographyn 62% of these patients. These studies do not providenformation regarding the age at onset of echocardiographicR or information on clinical AR. Tomita et al20 describedsubset of patients with subaortic VSDs and right coronary

usp prolapse and reported that the addition of noncoronaryusp prolapse is a risk factor for developing AR.

In the current study of patients who presented in infancyith subaortic VSDs and no evidence of aortic cuspal pro-

apse, 6% of patients had developed aortic cuspal prolapsey 5 years of age, and similar to the data of Eroglu et al,1,2

4% had developed echocardiographic evidence of prolapsey 10 years of age. In the patients who developed aorticuspal prolapse, 71% (10 of 14) had trivial to mild ARetected by color flow Doppler at the time of the diagnosisf prolapse or within 3 years, and 43% (6 of 14) developedurmurs of AR. All patients with aortic cuspal prolapse and

linical AR were deemed to require surgical interventionhat included aortic valve repair. After surgical intervention,

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raphic or clinical evidence of AR did not occur during theollow-up period in 29% of patients (4 of 14) with aorticuspal prolapse. Overall, 6% of patients (6 of 100) in thistudy with subaortic VSDs developed significant AR inssociation with aortic cuspal prolapse during a mean fol-ow-up period of 7.1 years.

In the 86 patients with no evidence of aortic cuspalrolapse, trivial or mild echocardiographic AR developed in7%. During a mean follow-up period of 4.3 years after theevelopment of echocardiographic AR, none of the 86 pa-ients developed signs of aortic cuspal prolapse or clinicalR, and the echocardiographic AR did not progress beyondild in any patient.The long-term follow-up of patients with unrepaired sub-

ortic VSDs should include the evaluation of aortic valveunction by clinical examination and echocardiography. Onhe basis of data from published research and the results ofhis study, it is possible to make the following recommen-ations regarding indications for surgical intervention byhe presence or absence of aortic cuspal prolapse, the pres-nce or absence of clinical AR on physical examination, andhe degree of echocardiographic AR. (1) At 1 extreme,atients with no aortic cuspal prolapse and no AR by clin-cal exam or echocardiography should continue to be mon-tored without surgical intervention. (2) On the other side ofhe spectrum, most patients with aortic cuspal prolapse andignificant AR by clinical exam and echocardiographyhould undergo surgical intervention to close their VSDsnd repair their aortic valves. It should be noted that someegree of postoperative AR is expected. (3) In the subset ofatients with clinically mild AR, surgical intervention maye deferred if a patient is closely followed, because the ARay remain mild for several years. (4) Patients with pro-

apse of the aortic valve with no evidence of AR by clinicalxam or echocardiography should be watched closely forhe development of AR; “prophylactic” surgery has notroved to change the clinical course in this group, becauseany of these patients may not develop AR. (5) Patientsith prolapse of the aortic valve, no AR murmurs, and onlyild echocardiographic AR also should be monitored

losely for the progression of AR. (6) Last, patients with ARhat is mild or less by echocardiography and no evidence ofortic cuspal prolapse or audible AR do not warrant surgery,ecause this appears to be a benign echocardiographic find-ng that does not progress. We anticipate that these guide-ines will provide a rational basis for serial monitoring andurgical intervention for patients with subaortic VSDs vis--vis aortic valve issues.

1. Eroglu AG, Oztunc F, Saltik L, Bakari S, Dedeoglu S, Ahunbay G.
Evolution of ventricular septal defect with special reference to spon-
taneous closure rate, subaortic ridge and aortic valve prolapse. PediatrCardiol 2003;24:31–35.

2. Eroglu AG, Oztunc F, Saltik L, Dedeoglu S, Bakari S, Ahunbay G.Aortic valve prolapse and aortic regurgitation in patients with ventric-ular septal defect. Pediatr Cardiol 2003;24:36–39.

3. Glenn S, Burns J, Bloomfield P. Prevalence and development ofadditional cardiac abnormalities in 1448 patients with congenital ven-tricular septal defects. Heart 2004;90:1321–1325.

4. Van Praagh R, McNamara JJ. Anatomic types of ventricular septaldefect with aortic insufficiency. Diagnostic and surgical consider-ations. Am Heart J 1968;75:604–619.

5. Keane JF, Plauth WH, Nadas AS. Ventricular septal defect with aorticregurgitation. Circulation 1977;56(suppl):72–77.

6. Corone P, Doyon F, Gaudeau S, Guerin F, Vernant P, Ducam H,Rumeau-Rouquette C, Gaudeul P. Natural history of ventricular septaldefect. A study involving 790 cases. Circulation 1977;55:908–915.

7. Nadas AS, Thilenius OG, LaFarge CG, Hauck AJ. Ventricular septaldefect with aortic regurgitation. Medical and pathological aspects.J Thorac Cardiovasc Surg 1964;29:862–873.

8. Karpawich PP, Duff DF, Mullins CE, Cooley DA, McNamara DG.Ventricular septal defect with associated aortic valve insufficiency.Progression of insufficiency and operative results in young children.J Thorac Cardiovasc Surg 1981;82:182–189.

9. Ando M, Takao A. Pathological anatomy of ventricular septal defectassociated with aortic valve prolapse and regurgitation. Heart Vessels1986;2:117–126.

0. Tohyama K, Satomi G, Momma K. Aortic valve prolapse and aorticregurgitation associated with subpulmonic ventricular septal defect.Am J Cardiol 1997;79:1285–1289.

1. Lun K, Li H, Leung MP, Chau AK, Yung T, Chiu CS, Cheung Y.Analysis of indications for surgical closure of subarterial ventricularseptal defect without associated aortic cusp prolapse and aortic regur-gitation. Am J Cardiol 2001;87:1266–1270.

2. Leu HC, Sung TC, Hou SH, Wu MH, Cheng SJ, Chu SH, Hung CR.Ventricular septal defect in Chinese with aortic valve prolapse andaortic regurgitation. Heart Vessels 1986;2:111–116.

3. Momma K, Toyama K, Takao A, Ando M, Nakazawa M, Hirosawa K,Imai Y. Natural history of subarterial infundibular ventricular septaldefect. Am Heart J 1984;108:1312–1317.

4. Tatsuno K, Konno S, Sakakibara S. Ventricular septal defect withaortic insufficiency. Angiocardiographic aspects and a new classifica-tion. Am Heart J 1973;85:13–21.

5. Eapen RS, Lemler MS, Scott WA, Ramaciotti C. Echocardiographiccharacteristics of perimembranous ventricular septal defects associatedwith aortic regurgitation. J Am Soc Echocardiogr 2003;16:209–213.

6. Rhodes LA, Keane JF, Keane JP, Fellows KE, Jonas RA, CastanedaAR, Nadas AS. Long follow-up (to 43 years) of ventricular septaldefect with audible aortic regurgitation. Am J Cardiol 1990;66:340–345.

7. Sanfellipo PM, DuShane JW, McGoon DC, Danielson GK. Ventric-ular septal defect and aortic insufficiency. Surgical considerations andresults of operation. Ann Thorac Surg 1974;17:213–222.

8. Leung MP, Beerman LB, Siewers RD, Bahnson HT, Zuberbuhler JR.Long-term follow-up after aortic valvuloplasty and defect closure inventricular septal defect with aortic regurgitation. Am J Cardiol 1987;60:890–894.

9. Perry GJ, Helmcke F, Nanda NC, Byard C, Soto B. Evaluation ofaortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol1987;9:952–959.

0. Tomita H, Arakaki Y, Ono Y, Yamada O, Yagihara T, Echigo S.Impact of noncoronary cusp prolapse in addition to right coronary cuspprolapse in patients with a perimembranous ventricular septal defect.
Int J Cardiol 2005;101:279–283.

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Comparison of Echocardiographic and Cardiac MagneticResonance Imaging for Assessing Right Ventricular Function

in Adults With Repaired Tetralogy of Fallot

Markus Schwerzmann, MDa, Ahmed M. Samman, MDa, Omid Salehian, MD, MSca,Johan Holm, MDa, Yves Provost, MDa,b, Gary D. Webb, MDa, Judith Therrien, MDa,

Samuel C. Siu, MD, SMa, and Candice K. Silversides, MD, SMa,*

Adults with repaired tetralogy of Fallot and significant chronic pulmonary regurgitationare at risk for progressive right ventricular (RV) dilatation and dysfunction. The assess-ment of RV function is important in the management in these patients. There is still a lackof an adequate geometric model to quantify RV function by echocardiography. Themyocardial performance index (MPI) is a nonvolumetric method to quantify global ven-tricular function. In this study, the accuracy of MPI obtained by echocardiography toquantify RV function was assessed in 57 adults with repaired tetralogy of Fallot. The MPImeasurement was compared with the RV ejection fraction (EF) derived by cardiac mag-netic resonance imaging. There was a negative linear correlation between the MPI and theRVEF (r � 0.73, p <0.001). A MPI cutoff of >0.40 had a sensitivity of 81% and a specificityof 85% to diagnose a RVEF <35%. A MPI cutoff of <0.25 had a sensitivity of 70% and aspecificity of 89% to identify patients with RVEFs >0.50. In a multivariate regressionmodel, the MPI was not affected by the degree of pulmonary regurgitation, the presence oftricuspid regurgitation, or the QRS duration. In conclusion, the Doppler-derived MPI is asimple and reliable method for the evaluation of RV systolic function in adults withrepaired tetralogy of Fallot. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;
99:1593–1597)
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dults with repaired tetralogy of Fallot and severe pulmo-ary regurgitation are at risk for progressive right ventric-lar (RV) dilatation and dysfunction.1–3 The assessment ofV function is important for management in these patients.lthough cardiac magnetic resonance imaging (MRI) al-

ows the accurate assessment of RV size and function,4hese studies are costly, and centers with the expertise re-uired to acquire and interpret the data are few. Further-ore, patients with pacemakers or defibrillators cannot un-

ergo MRI. Because of the complex crescentic RV shape,here is no ideal geometric model to calculate RV volumesnd derive ejection fractions (EFs) from standard echocar-iographic windows. However, ventricular function can beuantified by other means, including the myocardial perfor-ance index (MPI). This measure of global ventricular

unction is derived from time intervals5 and has initiallyeen used in the assessment of left ventricular function.6–8

he present study evaluated the utility of the MPI to assessV function in adults with repaired tetralogy of Fallot.

aDivision of Cardiology, Toronto Congenital Cardiac Centre fordults; and bMedical Imaging Department, University Health Network,oronto General Hospital, Toronto, Ontario, Canada. Manuscript receivedovember 17, 2006; revised manuscript received and accepted January 10,007.

Dr. Schwerzmann is supported by a grant from the Swiss National Scienceoundation, Bern, Switzerland. Dr. Silversides is supported by a grant from

he Heart and Stroke Foundation of Ontario, Toronto, Ontario, Canada.*Corresponding author: Tel: 416-340-3146; fax: 416-340-5014.

aE-mail address: [email protected] (C.K. Silversides).


ethods

fter approval from the university research ethics board,dult patients (aged �18 years) with repaired tetralogy ofallot followed at the Toronto Congenital Cardiac Centreor Adults were identified from our database. Routine careor patients with tetralogy of Fallot at our centre includesardiac MRI approximately every 3 years and annual clin-cal evaluation, including transthoracic echocardiography.atients were included in the study if (1) the last cardiacagnetic resonance scan was performed after January 2003,

2) the echocardiographic assessment was made within 6onths of the MRI, and (3) they were clinically stable, in

inus rhythm, and had native and unrepaired tricuspidalves. The patients’ medical records were reviewed toollect demographic information, electrocardiographic data,nd medical histories, including previous surgical historiesnd current clinical status.

Echocardiographic measurements: Transthoracic echo-ardiography was performed with commercially availableachines. All studies were stored digitally and available

or off-line analysis with commercially available softwareEncompass; Heartlab, Westerly, Rhode Island). Dopplereasurements across the tricuspid valve were made from

he apical 4-chamber view. Pulmonary outflow Dopplereasurements were made from a parasternal short-axis

iew with the pulse-wave sample volume placed just abovehe pulmonary valve. Three consecutive cardiac cycles were
veraged to correct for heart rate variation and measurement
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rrors. The time interval “a” denotes the duration of thericuspid regurgitation Doppler signal. The time interval “b”enotes pulmonary ejection time (Figure 1). The MPI wasalculated from the average values using the formulaPI � (a � b)/b, as previously described.9 The severity

f tricuspid and pulmonary regurgitation was gradedualitatively according to the guidelines of the Americanociety of Echocardiography.10 Pulmonary regurgitationas graded as severe if the pulmonary regurgitation pres-

ure halftime was �100 ms11 and if the density of theegurgitant jet on continuous-wave Doppler was similar tohe jet density of the anterograde flow.10

Our group recently reported an intraobserver variabilityor RV MPI measurements of 3% to 4% and an interob-erver variability of 6% in patients with complete transpo-ition of the great arteries and patients with atrial septalefects.9,12

MRI measurements: Magnetic resonance scans wereerformed using a 1.5-T CV/I magnetic resonance imagerSigna; GE Medical Systems, Waukesha, Wisconsin) and aedicated 4-channel phased-array cardiac coil. Electrocar-iographically gated cine magnetic resonance images werecquired in the axial and short-axis oblique planes throughhe heart using a steady-state free precession cine sequencefast imaging using steady-state acquisition; repetitionime ranged from 3.5 to 4.6 ms and echo time from 1.4 to.6 ms). Contiguous images of 10 mm were obtained in bothlanes at the end of expiration to maximize consistency. The

igure 1. (A) Continuous-wave Doppler recordings of tricuspid regurgito its cessation. (B) Pulse-wave Doppler recordings of pulmonary outflohe ratio (a � b)/b.

ndocardial surfaces were carefully traced manually to ob- a

ain RV end-diastolic and end-systolic volumes from im-ges in the axial plane. The RV end-diastolic image wasdentified by selecting the largest ventricular surface at theidventricular level, whereas the end-systolic image was

dentified by selecting the smallest ventricular surface. Cal-ulations of RV end-diastolic and end-systolic volumesere done using an Advantage Windows workstation

Rev 4.0P; GE, Buc, France) and Mass Analysis softwareMEDIS Medical Imaging Systems, Leiden, The Nether-ands). The RVEF was calculated using the equation EF �end-diastolic volume � end-systolic volume)/end-diastolicolume, with inter- and intraobserver variabilities of 5%.elocity-mapping cardiac MRI, performed in a double-blique plane perpendicular to the main pulmonary arteryust below the bifurcation, was used to quantify pulmonaryegurgitant volumes and calculate the pulmonary regurgi-ant fraction.11

Statistical analysis: Data are expressed as mean � SDor normally distributed variables and as medians with in-erquartile ranges (IQRs) for non-normal data. Between-roup comparisons of continuous variables were performedsing Student’s t test or the Mann-Whitney test for normallynd non-normally distributed data, respectively. Between-roup comparisons of categorical data were performed us-ng Pearson’s chi-square test or Fisher’s exact test as ap-ropriate. The Kruskal-Wallis test was used for multipleomparisons. Linear regression analysis was used to calcu-ate the correlation between the RVEF determined by MRI

ime interval “a” represents the interval from the onset of regurgitatione interval “b” represents RV ejection time. The MPI was calculated as

ation: tw: tim

nd the RV MPI. Pulmonary regurgitant fraction, the sever-

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1595Congenital Heart Disease/Echocardiographic Follow-Up in Tetralogy of Fallot

ty of tricuspid regurgitation, and QRS duration were con-idered to be clinically important determinants of RV func-ion and were included in a multivariate linear regressionnalysis. MPI cut-off values for discrimination between aVEF �35% or �35% and for discrimination between aVEF � or �50% were calculated using a receiver-perating characteristic plot.13 A p value �0.05 wasonsidered statistically significant. Data were analyzedsing Stata version 8.2 statistical software (StataCorp LP,ollege Station, Texas).

esultsPatient characteristics: Demographic and clinical data

f adults with repaired tetralogy of Fallot are listed inable 1. Transannular patch repair was part of the initialurgical repair in 61% of the patients (22 of 36) withouturther surgery, and pulmonary valvotomies were per-ormed in 11 patients (31%). Twenty-one patients had ad-itional surgery after total repair, consisting of pulmonaryalve (n � 19) or conduit (n � 2) replacement, at a mediange of 33.0 years (IQR 15.2 to 44.4). Overall, the averageime between last surgery and echocardiography was 19.4 �1.7 years (median 18.2, IQR 3.0 to 37.1). Thirty-five pa-ients (61%) were in New York Heart Association func-ional class I, 16 patients (28%) were in functional class II,nd 6 patients (11%) were in functional class III.

In all patients, electrocardiography at last follow-uphowed sinus rhythm and complete right bundle branchlock. The mean QRS duration was 150 � 26 ms. Eightatients had QRS durations �180 ms, 3 of whom had severeulmonary regurgitation.

MRI parameters: The median time interval betweenardiac magnetic resonance scans and echocardiographyas 2.5 months (IQR 0 to 4.9). The mean RV end-diastolicolume corrected for body surface area was 136 �8 ml/m2, and mean left ventricular end-diastolic volumeas 75 � 16 ml/m2. In 20 patients, the RV end-diastolicolume corrected for body surface area was �150 ml/m2,nd 15 of these (75%) had severe pulmonary regurgitation.verall, the mean RVEF was 41 � 10%, and the mean leftentricular EF was 49 � 16%. The mean pulmonary regur-

able 1atient characteristics (n � 57)

haracteristic Value

omen 26 (46%)ge (yrs) 36.6 � 11.8edian age at total repair (yrs) 6.6 (IQR2.1–19.9)edian age at last surgery (yrs) 11.0 (IQR2.1–44.2)ody surface area (m2) 1.8 � 0.3ystolic blood pressure (mm Hg) 115 � 15iastolic blood pressure (mm Hg) 68 � 10eart rate (beats/minute) 70 � 12evere pulmonary regurgitation 29 (51%)V outflow tract aneurysm 14 (25%)eft or right pulmonary artery stenosis 16 (28%)ore than mild tricuspid regurgitation 12 (21%)

Continuous variables are expressed as mean � SD or median valuesith IQRs.

itant fraction in patients with severe pulmonary regurgita- d

ion was 38 � 12%. Patients with severe pulmonary regur-itation had larger RV end-diastolic volumes (155 � 33 vs16 � 33 ml/m2, p �0.001), with a trend toward smaller leftentricular end-diastolic volumes (71 � 14 vs 79 �6 ml/m2, p � 0.06), better RVEFs (43 � 8% vs 38 � 11%,� 0.07), and lower left ventricular EFs (46 � 17% vs

2 � 15%, p � 0.19) compared with those patients with-ut severe pulmonary regurgitation. Patients with QRSurations �180 ms had lower RVEFs (35 � 6% vs 42 �0%, p � 0.02) compared with those with QRS durations180 ms.

Echocardiographic parameters: The mean peak in-tantaneous RV to pulmonary artery gradient was 23 �4 mm Hg, with a mean gradient of 12 � 7 mm Hg.oderate tricuspid insufficiency was reported in 12 patients

21%); no patient had severe tricuspid regurgitation. Pa-ients with QRS durations �180 ms had higher MPIs com-ared with those with QRS durations �180 ms (0.43 � 0.13s 0.33 � 0.14, p � 0.07).

Comparison between echocardiography and cardiacRI: Table 2 lists echocardiographic parameters for pa-

ients with normal and impaired RV systolic function aseasured by MRI. There was an inverse linear correlation

etween echocardiographically based RV MPI and RVEFn cardiac magnetic resonance scans (r � 0.73, p �0.001;igure 2). The mean MPI in patients with severe pulmonaryegurgitation was lower than the mean MPI in those withoutevere pulmonary regurgitation (0.30 � 0.13 vs 0.39 �.14, p � 0.02), because the sum of the isovolumetric timentervals was significantly longer in the latter patients121 � 36 vs 96 � 38 ms, p � 0.01). Patients with none orild tricuspid regurgitation had similar RVEFs on cardiacRI (41 � 10% vs 41 � 9%, respectively, p � 0.96) and

imilar MPIs on echocardiography (0.35 � 0.12 vs 0.32 �.20, respectively, p � 0.63) compared with patients withoderate tricuspid regurgitation.In the multivariate regression model, the inverse relation

etween the MPI and the RVEF remained significant (� �0.42, p �0.001), but the MPI was not correlated with

ulmonary regurgitant fraction (� � 0.0008, p � 0.99),oderate or more tricuspid regurgitation (� � �0.01, p �

.50), or the QRS duration (� � �0.007, p � 0.10).A MPI cutoff of �0.40 had a sensitivity of 81% and a

pecificity of 85% to diagnose a RVEF �35%. With thisutoff, 84% of cases were correctly classified. A MPI cutofff �0.25 had a sensitivity of 70% and a specificity of 89%o identify patients with RVEFs �0.50.

iscussion

he Doppler-derived RV MPI measurement correlates withhe MRI-derived RVEF and is a simple and reliable methodor the evaluation of RV function in adults with repairedetralogy of Fallot.

Many adults with corrected tetralogy of Fallot underwentepair at a time when the complete relief of RV outflow tractbstruction was the aim. This often resulted in a disruptionf the integrity of the pulmonary valve, severe pulmonaryegurgitation,14 and varying degrees of RV dilatation and
ysfunction. Recent data suggest that the recovery of RV

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unction after pulmonary valve replacement is unlikely ifV end-diastolic volume corrected for body surface area is170 ml/m2.15 Similarly, patients with RVEFs �40% on

adionuclide angiography before surgery have a low likeli-ood of maintaining adequate RV contractility after pulmo-ary valve replacement.16 Hence, quantitative measure-ents of RV size and function are important parameters for

etermining the timing of pulmonary valve replacement.MPI values obtained in patients with normal RV function

ave varied among studies. In adult patients without cardiacisease, a RV MPI of 0.28 � 0.04 has been reported toepresent normal RV function.17,18 Similarly, in patientsith complete transposition of the great arteries and atrial

witch repair, a RV MPI of 0.30 � 0.1 was found in thoseith normal systemic EFs.9 The RV MPI of 0.21 � 0.10 inur study in adults with repaired tetralogy of Fallot andormal RV function on MRI was slightly lower than ex-ected but similar to that obtained in a study by Abd Elahman et al,19 who examined children and adolescentsith repaired tetralogy of Fallot approximately 10 years

fter surgery. A possible explanation for the observed lowerean MPI values in our study comes from the observation

f Gatzoulis et al,20 who demonstrated that �50% of adult

igure 2. Correlation between the RVEF by MRI and the MPI by echo-ardiography (y � �0.48 � x � 0.58, r � 0.73, p �0.001).

able 2atient findings in relation to right ventricular function

ariable RVEF �50%(n � 13)

evere pulmonary regurgitation 7 (54%)eak RV to pulmonary artery gradient (mm Hg) 26 � 16V end-diastolic volume corrected for bodysurface area (ml/m2)

113 � 30†

RS duration (ms) 125 � 26*†

sovolumetric time interval (ms) 68 � 28*†

ulmonic ejection time (ms) 338 � 46PI 0.21 � 0.10

Continuous variabels are expressed as mean � SD and categorial varia* p �0.05 for RVEF �50% versus RVEF 35 to 49%.† p �0.05 for RVEF �50% versus RVEF �35%.‡ p �0.05 for RVEF 35 to 49% versus RVEF �35%.

atients with tetralogy of Fallot had signs of restrictive RV

hysiology. Patients with restrictive physiology have clini-al features of high RV filling pressures, independent of RVystolic function,21 and similar to patients with left ventric-lar restriction,22 relaxation time is shortened. Hence, thePI may be lowered.23

Although patients with severe chronic pulmonary regur-itation had a lower MPIs in univariate analysis comparedith patients with relatively competent valves, the pulmo-ary regurgitant fraction was not an independent predictorf the MPI in the multivariate model. As shown, our pa-ients with severe pulmonary regurgitation tended to haveetter RV function on MRI (43 � 8% vs 38 � 11%, p �.07). This is not surprising, because our group aims toeplace a severely regurgitant pulmonary valve before sig-ificant RV dysfunction occurs. Because all patients in thistudy were clinically stable, these findings only pertain toatients with chronic severe pulmonary regurgitation, andPI measurement relations may vary in patients with acute

evere pulmonary regurgitation.Vogel et al24 found that QRS duration was positively

orrelated with regional RV wall motion abnormalities inatients with tetralogy of Fallot.24 In our study, patientsith QRS complexes �180 ms had a trend for higherPIs than those with QRS durations �180 ms. Ventric-

lar dyssynchrony has been shown to prolong isovolu-etric relaxation time25,26 and shorten ejection time.27

ence, this nonuniformity in ventricular contraction isxpected to increase the MPI.

All measurements in this report were averaged over 3eats, but respiratory cycles were not specifically recorded.espiratory variations of preload and their effects on echo-ardiographic measurements were not assessed and mayotentially influence the relation of MPI to cardiac magneticesonance measured RV function.

The length of time between the MRI and echocardio-raphic studies in our cohort may have biased the diagnosticccuracy of the MPI. By including only clinically stableatients, we attempted to minimize its confounding effects.

1. Redington AN, Oldershaw PJ, Shinebourne EA, Rigby ML. A newtechnique for the assessment of pulmonary regurgitation and its ap-plication to the assessment of right ventricular function before and

RVEF 35%–49%(n � 28)

RVEF �35%(n � 16)

p Value

17 (61%) 5 (31%) 0.1721 � 13 24 � 15 0.69

134 � 35‡ 158 � 39 0.006

150 � 22‡ 170 � 15 �0.001105 � 27‡ 146 � 26 �0.001321 � 27 310 � 30 0.240.33 � 0.09‡ 0.48 � 0.12 �0.001

percentages.

*†

bles as

after repair of tetralogy of Fallot. Br Heart J 1988;60:57–65.

1

1

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2

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1597Congenital Heart Disease/Echocardiographic Follow-Up in Tetralogy of Fallot

2. Bouzas B, Kilner PJ, Gatzoulis MA. Pulmonary regurgitation: not abenign lesion. Eur Heart J 2005;26:433–439.

3. Geva T, Sandweiss BM, Gauvreau K, Lock JE, Powell AJ. Factorsassociated with impaired clinical status in long-term survivors oftetralogy of Fallot repair evaluated by magnetic resonance imaging.J Am Coll Cardiol 2004;43:1068–1074.

4. Niezen RA, Helbing WA, van der Wall EE, van der Geest RJ, Reber-gen SA, de Roos A. Biventricular systolic function and mass studiedwith MR imaging in children with pulmonary regurgitation after repairfor tetralogy of Fallot. Radiology 1996;201:135–140.

5. Tei C. New non-invasive index for combined systolic and diastolicventricular function. J Cardiol 1995;26:135–136.

6. Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, TajikAJ, Seward JB. New index of combined systolic and diastolic myo-cardial performance: a simple and reproducible measure of cardiacfunction—a study in normals and dilated cardiomyopathy. J Cardiol1995;26:357–366.

7. Dujardin KS, Tei C, Yeo TC, Hodge DO, Rossi A, Seward JB.Prognostic value of a Doppler index combining systolic and diastolicperformance in idiopathic-dilated cardiomyopathy. Am J Cardiol1998;82:1071–1076.

8. Bruch C, Schmermund A, Marin D, Katz M, Bartel T, Schaar J, ErbelR. Tei-index in patients with mild-to-moderate congestive heart fail-ure. Eur Heart J 2000;21:1888–1895.

9. Salehian O, Schwerzmann M, Merchant N, Webb GD, Siu SC, Ther-rien J. Assessment of systemic right ventricular function in patientswith transposition of the great arteries using the myocardial perfor-mance index: comparison with cardiac magnetic resonance imaging.Circulation 2004;110:3229–3233.

0. Zoghbi WA, Enriquez-Sarano M, Foster E, Graybrun PA, Kraft CD,Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, RakowskoH, et al. Recommendations for evaluation of the severity of nativevalvular regurgitation with two-dimensional and Doppler echocardi-ography. J Am Soc Echocardiogr 2003;16:777–802.

1. Silversides CK, Veldtman GR, Crossin J, Merchant N, Webb GD,McCrindle BW, Siu SC, Therrien J. Pressure half-time predicts hemo-dynamically significant pulmonary regurgitation in adult patients withrepaired tetralogy of Fallot. J Am Soc Echocardiogr 2003;16:1057–1062.

2. Salehian O, Horlick E, Schwerzmann M, Haberer K, McLaughlin P,Siu SC, Webb G, Therrien J. Improvements in cardiac form andfunction after transcatheter closure of secundum atrial septal defects.J Am Coll Cardiol 2005;45:499–504.

3. Zweig MH, Campbell G. Receiver-operating characteristic (ROC)plots: a fundamental evaluation tool in clinical medicine. Clin Chem1993;39:561–577.

4. Lillehei CW, Cohen M, Warden HE, Read RC, Aust JB, Dewall RA,Varco RL. Direct vision intracardiac surgical correction of the tetral-ogy of Fallot, pentalogy of Fallot, and pulmonary atresia defects;
report of first ten cases. Ann Surg 1955;142:418–442.
5. Therrien J, Provost Y, Merchant N, Williams W, Colman J, Webb G.Optimal timing for pulmonary valve replacement in adults after tetral-ogy of Fallot repair. Am J Cardiol 2005;95:779–782.

6. Therrien J, Siu SC, McLaughlin PR, Liu PP, Williams WG, Webb GD.Pulmonary valve replacement in adults late after repair of tetralogy ofFallot: are we operating too late? J Am Coll Cardiol 2000;36:1670–1675.

7. Eidem BW, O’Leary PW, Tei C, Seward JB. Usefulness of the myo-cardial performance index for assessing right ventricular function incongenital heart disease. Am J Cardiol 2000;86:654–658.

8. Ishii M, Eto G, Tei C, Tsutsumi T, Hashino K, Sugahara Y, HimenoW, Muta H, Furuj J, Akagi T, et al. Quantitation of the global rightventricular function in children with normal heart and congenital heartdisease: a right ventricular myocardial performance index. PediatrCardiol 2000;21:416–421.

9. Abd El Rahman MY, Abdul-Khaliq H, Vogel M, Alexi-MeskischviliV, Gutberlet M, Hetzer R, Lange PE. Value of the new Doppler-derived myocardial performance index for the evaluation of right andleft ventricular function following repair of tetralogy of Fallot. PediatrCardiol 2002;23:502–507.

0. Gatzoulis MA, Clark AL, Cullen S, Newman CG, Redington AN.Right ventricular diastolic function 15 to 35 years after repair oftetralogy of Fallot. Restrictive physiology predicts superior exerciseperformance. Circulation 1995;91:1775–1781.

1. Cullen S, Shore D, Redington A. Characterization of right ventriculardiastolic performance after complete repair of tetralogy of Fallot:restrictive physiology predicts slow postoperative recovery. Circula-tion 1995;91:1782–1789.

2. Mulvagh S, Quinones MA, Kleiman NS, Cheirif J, Zoghbi WA.Estimation of left ventricular end-diastolic pressure from Dopplertransmitral flow velocity in cardiac patients independent of systolicperformance. J Am Coll Cardiol 1992;20:112–119.

3. Sachdev MS, Bhagyavathy A, Varghese R, Coelho R, Kumar RS.Right ventricular diastolic function after repair of tetralogy of Fallot.Pediatr Cardiol 2006;27:250–255.

4. Vogel M, Sponring J, Cullen S, Deanfield JE, Redington AN. Regionalwall motion and abnormalities of electrical depolarization and repo-larization in patients after surgical repair of tetralogy of Fallot. Cir-culation 2001;103:1669–1673.

5. Bonow RO, Vitale DF, Bacharach SL, Frederick TM, Kent KM, GreenMV. Asynchronous left ventricular regional function and impairedglobal diastolic filling in patients with coronary artery disease: reversalafter coronary angioplasty. Circulation 1985;71:297–307.

6. Betocchi S, Piscione F, Villari B, Pace L, Ciarmiello A, Perrone-Filardi P, Salvatore C, Salvatore M, Chiariello M. Effects of inducedasynchrony on left ventricular diastolic function in patients with cor-onary artery disease. J Am Coll Cardiol 1993;21:1124–1131.

7. Vignon P, Weinert L, Mor-Avi V, Spencer KT, Bednarz J, Lang RM.Quantitative assessment of regional right ventricular function with
color kinesis. Am J Respir Crit Care Med 1999;159:1949–1959.

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Association of Multiple Inflammatory Markers with CarotidIntimal Medial Thickness and Stenosis (from the

Framingham Heart Study)Avni H. Thakore, MD, MSa,b, Chao-Yu Guo, PhDa,e, Martin G. Larson, ScDa,c,e, Diane Corey, BAa,

Thomas J. Wang, MDa,f, Ramachandran S. Vasan, MDa,b,c, Ralph B. D’Agostino, Sr., PhDa,e,Izabella Lipinska, PhDd, John F. Keaney, Jr., MDb,d, Emelia J. Benjamin, MD, ScMa,b,c,d,

and Christopher J. O’Donnell, MD, MPHa,f,g,*

Inflammatory markers, particularly C-reactive protein (CRP), predict incident cardiovas-cular disease and are associated with the presence of subclinical atherosclerosis. Therelations between multiple inflammatory markers and direct measures of atherosclerosisare less well established. Participants in the Offspring Cohort of the Framingham HeartStudy (n � 2,885, 53% women, mean age 59 years) received routine assessments of commoncarotid artery intima-media thickness (CCA-IMT), internal carotid artery intima-mediathickness (ICA-IMT), and the presence or absence of >25% carotid stenosis by ultrasonog-raphy. Circulating inflammatory markers assessed from an examination 4 years laterincluded CRP, interleukin-6 (IL-6), intercellular adhesion molecule-1, monocyte chemoat-tractant protein-1, P-selectin, and CD40 ligand. Assessed as a group, inflammatory mark-ers were significantly associated with ICA-IMT (p � 0.01), marginally with carotid stenosis(p � 0.08), but not with CCA-IMT. Individually, with an increase from the 25th to 75thpercentile in IL-6, there were significant increases in ICA-IMT and carotid stenosis (forICA-IMT, estimated fold increase 1.04, 95% confidence interval 1.03 to 1.06, p � 0.0004;for carotid stenosis, odds ratio 1.25, 95% confidence interval 1.06 to 1.47, p � 0.007) afteradjustment for age, gender, and established risk factors for atherosclerosis. There was asimilar significant multivariate-adjusted association of CRP with ICA-IMT but not withcarotid stenosis. Smoking appeared to modify the associations of ICA-IMT with CRP (p �0.009) and with IL-6 (p � 0.006); the association was more pronounced in current (vsformer or never) smokers. In conclusion, there were modest associations of inflammatorymarkers, particularly IL-6, with carotid atherosclerosis. This association appears morepronounced in current smokers than in former smokers and nonsmokers. © 2007 Elsevier
Inc. All rights reserved. (Am J Cardiol 2007;99:1598–1602)
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everal noninvasive measures of subclinical atherosclerosisave received intense attention as clinical and researchools.1 Of these, measurements of carotid plaque, such asarotid stenosis, and intima-media thickness (IMT) by high-

aNational Heart, Lung, and Blood Institute’s Framingham Heart Study,ramingham, Massachusetts; bEvans Memorial Department of Medicine,Department of Preventive Medicine, dWhitaker Cardiovascular In-titute, Boston University School of Medicine, and eDepartment of Math-matics, Boston University; fCardiology Division, Massachusetts Generalospital, Harvard Medical School, Boston, Massachusetts; and gNationaleart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript re-

eived September 13, 2006; revised manuscript received and acceptedanuary 10, 2007.

This study was supported by Contract N01-HC-25195 from the Na-ional Heart, Lung, and Blood Institute, Bethesda, Maryland. Dr. Benjaminas supported by Grants HL64753 and 1 RO1 HL076784, Dr. Keaney byrants DK55656 and HL60886, Dr. Vasan by Grant HL70139, and Dr.ang by Grant HL074077 from the National Institutes of Health, Be-

hesda, Maryland. Dr. Vasan is the recipient of Research Career AwardL04334 from the National Institutes of Health.

dE-mail address: [email protected] (E.J. Benjamin).

esolution B-mode carotid ultrasound have been shown toorrelate with prevalent cardiovascular disease (CVD)2,3

nd with incident myocardial infarction and stroke.2,4 In thevailable prospective studies, internal carotid artery IMTICA-IMT) and common carotid artery IMT (CCA-IMT)redict increased risk for myocardial infarction and stroke.4,5

revious studies revealed a modest graded association between-reactive protein (CRP) and carotid plaque and IMT in adultsnd children.2,6,7 However, previous studies focused on carotidarkers and only CRP.8–10 We hypothesized that vascular

nflammation is a local and a systemic process and that a panelf inflammatory markers would be related to carotid athero-clerotic measures. As a secondary aim, we sought to under-tand the relations of specific markers with carotid atheroscle-osis. To test these hypotheses, we examined the associationsf a panel of 6 circulating inflammatory markers simulta-eously and individually with measures of carotid atheroscle-osis, carotid IMT and stenosis, in the community-based Fra-ingham Heart Study.

ethodsParticipants and covariates: The selection criteria and

esign of the Framingham Heart Study have been detailed.11

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1599Miscellaneous/Inflammation and Carotid Ultrasound Measures

articipants attending the sixth (1996 to 1998) and seventh1998 to 2001) examination cycles were eligible for thisnvestigation. There were 3,532 participants in the Off-pring Cohort study at examination cycle 6, of whom 3,40796%) underwent B-mode carotid ultrasonography. Amonghose with carotid ultrasonography, 2,885 men and womenlso had serum inflammatory markers (CRP, interleukin-6IL-6], intercellular cell adhesion molecule-1, monocytehemoattractant protein-1, CD40 ligand, and P-selectin)easured about 4 years later at examination cycle 7.The medical histories, physical examinations, and labo-

atory tests (other than for the inflammatory markers) con-ucted during the sixth examination cycle were the sourcef the cardiovascular risk factor data. Subjects were classi-ed as current cigarette smokers if they reported havingmoked during the previous year, former smokers if theyad ever smoked before the previous year, or nonsmokers.ystolic and diastolic blood pressure values were the meansf 2 physician-obtained measurements. Subjects were clas-ified into 3 categories on the basis of their fasting bloodlucose: �110 mg/dl, 110 to 125 mg/dl (impaired fastinglucose), and �126 mg/dl or receiving insulin or hypogly-emic medications (diabetes). The protocol was approvedy the Boston Medical Center Institutional Review Board,nd all participants provided written informed consent.

Inflammatory markers: Inflammatory markers wereeasured at the seventh examination cycle. Participantsere instructed not to eat or drink anything except water orecaffeinated black coffee or tea after 8 P.M. the previousvening. Blood samples were collected from an antecubitalein from 8 to 9 A.M. and were stored at �80°C. Fornalysis, samples were thawed at room temperature andortexed vigorously. Markers were measured in duplicatend averaged with commercially available enzyme-linkedmmunosorbent assay kits (R&D Systems, Minneapolis,

innesota, for serum IL-6, intercellular cell adhesion mol-cule-1, monocyte chemoattractant protein-1, and plasma-selectin; BenderMed System, Burlingame, California, forerum and plasma CD40 ligand). Quality control proceduresave been previously described elsewhere.12 The medianntra-assay coefficients of variation were 2.8%, 3.6%, 3.0%,.0%, 4.2%, and 4.6%, respectively. CRP was measurednce using a high-sensitivity assay (BN100 nephelometer;ade Behring, Deerfield, Illinois); the median interassay coef-cient of variation was 3.2% on 139 phantom replicates.

Carotid ultrasonography: Ultrasound studies were ac-uired and images analyzed according to a standard proto-ol by a single trained sonographer.13,14 Imaging was con-ucted using a high-resolution 7.5-MHz transducer for theommon carotid artery and a 5.0-MHz for the carotid bulbnd internal carotid artery (Toshiba Medical Systems, Tus-in, California).

A single trained sonographer who was blinded to clinicalnformation made measurements, which were overread by 1f the investigators. Carotid IMT measurements were maderom 2 gated diastolic images on the right and left carotidrteries at each of the 3 sites: the level of the distal commonarotid artery, the carotid artery bulb, and the proximal 2 cm
f the internal carotid artery. The maximal IMT at each site p
as defined as the mean of the maximal IMT measured athe near and far walls of the vessel. Maximal IMT has beenhown to correlate well with CVD risk in other studies.3 TheCA-IMT was the mean of the maximal IMT measurementsor the carotid artery bulb and the internal carotid artery onhe right and left sides. The CCA-IMT was the mean of theaximal IMT measurement for the right and left common

arotid artery. We previously reported good reproducibilityor our protocol, with intraclass correlation coefficients forean ICA-IMT and mean CCA-IMT of 0.74 and 0.86,

espectively.13 For the present investigation, we definedarotid stenosis as present if the sonographer estimated thenternal carotid artery narrowing as �25%, on the basis ofhe more diseased of the 2 arteries measured in eacharticipant.

Statistical analysis: Carotid IMT measures and inflam-atory marker levels, which had skewed distributions, were

og transformed. We used multivariate regression to assesshether markers of inflammation were associated with mea-

ures of carotid IMT (linear models) and stenosis (logisticodels).15–17 To reduce multiple testing, we limited the

nitial analyses to a single robust multivariate model forach carotid phenotype. There was no evidence of an inter-ction by gender for any of the markers, so we pooled mennd women in all our models. In addition to gender, allodels included the following covariates classified at ex-

mination 6: age, body mass index, systolic blood pressure,he ratio of total to high-density lipoprotein cholesterol,riglycerides, menopausal status, hormone replacement ther-py, smoking status, fasting glucose category, lipid-lower-ng therapy, antihypertensive therapy, and CVD prevalence.or each carotid measure, we specified an omnibus nullypothesis that none of the 6 markers would be related tohe dependent carotid variable. We fitted a model that in-luded risk factors plus all 6 inflammatory markers, and weested the markers as a group using a test statistic with 6egrees of freedom. We used a partial F test for linearodels and a likelihood ratio test for logistic models to

ssess the significance of adding 6 inflammatory markers ton existing multivariate model. We also tested associationsf individual markers with each carotid measure.

Given the 4-year time interval between carotid measure-ents at exam 6 and inflammatory marker measurements at

xam 7, secondary analyses were performed in which wexcluded subjects with interim CVD between examinationsand 7. Three hundred ninety-seven patients were excluded

t exam 7 because of interim CVD. On the basis of the sameet of covariates used in the primary analysis, secondarynalyses were also performed to test for 5 interaction effectsage and body mass index as continuous variables andender, smoking status, and CVD as categorical variables,hosen on the basis of the results of the primary analysis) onhe association between ICA-IMT and 2 markers (CRP andL-6) using linear models and the association between ca-otid stenosis and IL-6 using logistic models.

SAS (SAS Institute Inc., Cary, North Carolina) was usedor all statistical analyses.17 All statistical tests were 2 sided;p value �0.01 was considered statistically significant for

rimary and secondary analyses.

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he mean age of the 2,885 eligible participants (53%omen) was 59 years at examination cycle 6, when the

arotid measures were assessed. Additional clinical charac-eristics as well as distributions of carotid measures andnflammatory markers are listed in Table 1.

In the multimarker model, we found that the 6 inflam-atory markers as a group were significantly associatedith ICA-IMT (p � 0.01; Table 2), although they accountednly for an additional 0.5% of the variability in ICA-IMT.he 6 markers as a group were marginally associated witharotid stenosis (p � 0.08) and were not significantly asso-

able 1linical, carotid, and inflammatory marker characteristics in 2,885 mennd women

ariable Value

omen 53%ge (yrs) 59 � 10ody mass index (kg/m2) 28.0 � 5.1ystolic blood pressure (mm Hg) 128 � 18otal cholesterol/high-density lipoproteincholesterol ratio

4.4 � 1.5

riglycerides (mg/dl) 139 � 93mokers (current/former) 14%/51%iabetes mellitus (blood glucose �126 mg/dlor prescription 110–125 mg/dl)

10%/11%

ipid-lowering treatment 13%ntihypertensive treatment 28%revalent CVD 10%CA-IMT (mm) 0.70 (0.63, 0.80)*

CA-IMT (mm) 0.60 (0.49, 0.86)*25% carotid stenosis (%) 18%RP (mg/L) 2.2 (1.0, 5.2)*

L-6 (pg/ml) 2.7 (1.8, 4.3)*ntercellular adhesion molecule-1 (ng/ml) 241 (210, 283)*

onocyte chemoattractant protein-1 (pg/ml) 315 (255, 385)*-selectin (ng/ml) 36 (29, 46)*D40 ligand (ng/ml) 3.0 (1.1, 5.7)*

Values are expressed as mean � SD or percentages of patients.* CCA-IMT, ICA-IMT, and all inflammatory markers are expressed asedian (25th percentile, 75th percentile).

able 2elations of a panel of multiple inflammatory markers as a group witharotid intima-media thickness and stenosis

ariable R2 p Value

Without Markers With Markers

CA-IMT 0.322 0.322 0.86CA-IMT 0.217 0.222 0.01arotid stenosis 0.276 0.281 0.08

Markers in the panel included CRP, IL-6, soluble intercellular adhesionolecule-1, monocyte chemoattractant protein-1, CD40 ligand, and P-

electin. Model adjusted for age, gender, body mass index, systolic bloodressure, total/high-density lipoprotein cholesterol, triglycerides, meno-ausal status, use of hormone replacement therapy, smoking status, fastinglucose category, lipid-lowering therapy, antihypertensive therapy, andrevalence of CVD.

iated with CCA-IMT (p � 0.86). t

Examining the associations between each individual in-ammatory marker and the different carotid measures (Ta-le 3), we observed significant positive relations of CRP andL-6 with ICA-IMT. The estimated fold increases in ICA-MT between the 25th and 75th percentiles for CRP andL-6 were 1.04 (95% confidence interval [CI] 1.03 to 1.06)nd 1.04 (95% CI 1.03 to 1.05), respectively. We observedsignificant positive association of IL-6 with carotid steno-

is (odds ratio 1.25, 95% CI 1.06 to 1.47). No significantssociation was observed between inflammatory markersnd CCA-IMT.

After excluding subjects with prevalent CVD by exam 7defined as present at the time of the ultrasound study), thereontinued to be significant multivariate-adjusted associa-ions of IL-6 with ICA-IMT (p � 0.01) and carotid stenosisodds ratio 1.21, 95% CI 1.01 to 1.46; data for other in-ammatory markers not shown).

In secondary analyses, we analyzed whether key covari-tes associated with individual inflammatory markers (in-luding age, body mass index, gender, smoking, and prev-lent CVD) modified the relation of the markers with thearotid phenotypes. For ICA-IMT, smoking had a signifi-ant interaction with CRP and with IL-6 (p � 0.009 and� 0.006, respectively; Figure 1), such that the relations of

CA-IMT with CRP and IL-6 were more pronounced inurrent compared with never smokers. Using a threshold of�0.01, we did not observe any other significant interac-

ions (i.e., no p �0.01) between the inflammatory markersnd age, body mass index, gender, or prevalent CVD. Inecondary models, we also examined plasma CD40 ligand,nd the results were similar to those for serum CD40 ligand;lasma CD40 ligand concentrations were unrelated to thearotid measures tested.

iscussion

n our large community-based cohort, we examined theelations of a panel of 6 inflammatory markers with mea-ures of carotid atherosclerosis. In the multivariate-adjustedultimarker model, inflammatory markers as a group were

ound to be associated with ICA-IMT. Further examinationf individual markers revealed that CRP and IL-6 wereositively related to ICA-IMT, and IL-6 was positivelyssociated with carotid stenosis.

Our findings confirm and extend our previous report of aignificant association of carotid IMT with a somewhat lessensitive CRP assay measured 4 years before the carotidMT test.6 Several recent consensus panels have suggestedhat there may be a role for the use of CRP testing in thelinical setting for risk stratification.18,19 Whereas CRP ishe most intensively studied inflammatory marker to date,ts incremental predictive value over and above traditionalisk factors remains controversial.20,21

In the current study, IL-6 was found to be as stronglyorrelated with ICA-IMT and carotid stenosis as CRP.any previous studies have shown IL-6 and CRP to be 2 of

he inflammatory markers most consistently elevated inVD.21–23 The apparent coupling of CRP and IL-6 may bexplained by multiple studies that revealed IL-6 to be anmportant stimulus for hepatic CRP production.23–25 Thus,
hese 2 markers may be closely linked in the inflammatory

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1601Miscellaneous/Inflammation and Carotid Ultrasound Measures

ascade. Whereas the overall associations between inflam-atory markers and carotid measures were statistically sig-

ificant, the strength of the associations was modest.An additional interesting finding that emerged from our

econdary analyses was that cigarette smoking may modifyhe association of inflammation with carotid atherosclerosis.he association of internal carotid IMT with CRP and IL-6as more pronounced in current smokers than in never

mokers (Figure 1). The suggestion that inflammation pro-otes more atherosclerotic progression in smokers than in

onsmokers deserves further study.As epidemiologic studies seek to examine the potential

igure 1. Interaction effect of smoking on the association between CRP andCA-IMT and IL-6 and ICA-IMT.

able 3ncreases in common carotid artery intima-media thickness and internal crom 25th to 75th percentile in individual inflammatory markers

ariable CCA-IMT

Fold Increase (95% CI) p Value

RP 1.005 (0.999–1.010) 0.36L-6 1.040 (1.029–1.052) 0.34ntercellular adhesion

molecule-10.999 (0.995–1.003) 0.92

onocyte chemoattractantprotein-1

1.000 (0.996–1.004) 0.97

erum P-selectin 1.003 (0.999–1.008) 0.39D40 ligand 1.004 (0.999–1.008) 0.42

Gender-pooled samples: CCA-IMT and markers, n � 2,823; ICA-IMTModel adjusted for age, gender, body mass index, systolic blood pressur

f hormone replacement therapy, smoking status, diabetes mellitus, lipid-

ole of multiple biomarkers in subclinical and clinical n

therosclerosis, a potential limitation is the risk for false-ositive results due to the conduct of multiple testing. Weought a priori to address this risk by restricting the initialnalyses to a single robust multivariate model for eacharotid measure, taking into account all of the inflammatoryarkers and potential covariates. Subsequent examination

f the associations of individual markers with ICA-IMT andarotid stenosis provided consistency of evidence for theontribution of IL-6 and CRP to these associations. Further-ore, the interaction analyses are considered secondary

nalyses, which are susceptible to false-positive results,lthough we did restrict these analyses to prespecified in-eraction terms.

Another potential limitation is the 4-year interval be-ween the carotid measurements and the inflammatoryarker assays. Our results may be viewed as “cross-

ectional” associations, in particular because rates of ca-otid IMT progression in untreated arms of randomizedrials have been reported to be on the order of 0.01 mm/yearnd are likely to be even slower in general community–welling men and women. However, we acknowledge thatlaque progression may have occurred during the intervaletween the carotid ultrasound (exam 6) and the measure-ent of inflammatory markers (exam 7). The impact of

arotid and/or inflammation marker progression is likely toias any association toward the null. However, to addresshe possibility that progression to clinical CVD may haveonfounded this association, we conducted secondary anal-ses restricted to the subjects who did not develop intercur-ent CVD between the 2 examination cycles, and our resultsere similar. In addition, although we adjusted for medica-

ions, because we examined an ambulatory cohort, the usef cardiac medications may have confounded our findings.ur findings from the carotid measures may not reflect the

ole of inflammation in other vascular territories, such as theoronary arteries, aorta, and lower extremity arteries. Therogression of atherosclerotic disease may occur at differentates and as a result of different risk factors in other vasculareds, so it may not be appropriate to generalize our resultso atherosclerosis in other vascular beds. The Framinghamohort was white and middle aged to elderly; the general-zability of our findings to younger subjects or other eth-

rtery intima-media thickness and carotid stenosis (�25%) with increase

ICA-IMT Carotid Stenosis

Increase (95% CI) p Value Odds Ratio (95% CI) p Value

1 (1.027–1.056) 0.003 1.09 (0.98–1.21) 0.130 (1.029–1.052) 0.0004 1.25 (1.06–1.47) 0.0075 (1.004–1.025) 0.15 1.49 (0.97–2.29) 0.07

2 (1.001–1.022) 0.28 1.13 (0.81–1.57) 0.48

5 (0.994–1.0162) 0.62 1.38 (1.02–1.86) 0.049 (0.987–1.010) 0.87 1.01 (0.92–1.10) 0.87

rkers, n � 2,613; carotid stenosis and markers, n � 2,825./high-density lipoprotein cholesterol, triglycerides, menopausal status, useg therapy, antihypertensive therapy, and prevalence of CVD.

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1. Taylor AJ, Merz CN, Udelson JE. 34th Bethesda Conference: Exec-utive summary—can atherosclerosis imaging techniques improve thedetection of patients at risk for ischemic heart disease? J Am CollCardiol 2003;41:1860–1862.

2. Burke GL, Evans GW, Riley WA, Sharrett AR, Howard G, BarnesRW, Rosamond W, Crow RS, Rautaharju PM, Heiss G. Arterial wallthickness is associated with prevalent cardiovascular disease in mid-dle-aged adults. The Atherosclerosis Risk in Communities (ARIC)study. Stroke 1995;26:386–391.

3. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolf-son SK Jr. Carotid-artery intima and media thickness as a risk factorfor myocardial infarction and stroke in older adults. CardiovascularHealth Study Collaborative Research Group. N Engl J Med 1999;340:14–22.

4. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Commoncarotid intima-media thickness and risk of stroke and myocardialinfarction: the Rotterdam Study. Circulation 1997;96:1432–1437.

5. Schillinger M, Exner M, Mlekusch W, Sabeti S, Amighi J, NikowitschR, Timmel E, Kickinger B, Minar C, Pones M, et al. Inflammation andCarotid Artery—Risk for Atherosclerosis Study (ICARAS). Circula-tion 2005;111:2203–2209.

6. Jarvisalo MJ, Harmoinen A, Hakanen M, Paakkunainen U, Viikari J,Hartiala J, Lehtimaki T, Simell O, Raitakari OT. Elevated serumC-reactive protein levels and early arterial changes in healthy children.Arterioscler Thromb Vasc Biol 2002;22:1323–1328.

7. Wang TJ, Nam BH, Wilson PW, Wolf PA, Levy D, Polak JF,D’Agostino RB, O’Donnell CJ. Association of C-reactive protein withcarotid atherosclerosis in men and women: the Framingham HeartStudy. Arterioscler Thromb Vasc Biol 2002;22:1662–1667.

8. Cao JJ, Thach C, Manolio TA, Psaty BM, Kuller LH, Chaves PH,Polak JF, Sutton-Tyrrell K, Herrington DM, Price TR, Cushman M.C-reactive protein, carotid intima-media thickness, and incidence ofischemic stroke in the elderly: the Cardiovascular Health Study. Cir-culation 2003;108:166–170.

9. Makita S, Nakamra M, Hiramori K. The association of C-reactiveprotein levels with carotid intima-media complex thickness and plaqueformation in the general population. Stroke 2005;36:2138–2142.

0. Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M,Meilahn EN, Kuller LH. Relationship of C-reactive protien to risk ofcardiovascular disease in the elderly. Arterioscler Thromb Vasc Biol1997;17:1121–1127.

1. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP.An investigation of coronary heart disease in families. The Framing-ham offspring study. Am J Epidemiol 1979;110:281–290.

2. Keaney JF Jr, Larson MG, Vasan RS, Wilson PW, Lipinska I, CoreyD, Massaro JM, Sutherland P, Vita JA, Benjamin EJ. Obesity andsystemic oxidative stress: clinical correlates of oxidative stress in the
Framingham study. Arterioscler Thromb Vasc Biol 2003;23:434–439.
3. Fox CS, Cupples LA, Chazaro I, Polak JF, Wolf PA, D’Agostino RB,Ordovas JM, O’Donnell CJ. Genomewide linkage analysis for internalcarotid artery intimal medial thickness: evidence for linkage to chro-mosome 12. Am J Hum Genet 2004;74:253–261.

4. O’Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG, WolfsonSK Jr, Bommer W, Price TR, Gardin JM, Savage PJ. Distribution andcorrelates of sonographically detected carotid artery disease in theCardiovascular Health Study. The CHS Collaborative Research Group.Stroke 1992;23:1752–1760.

5. Hosmer DW, Lemeshow S. Applied Logistic Regression. New York,New York: John Wiley, 1989.

6. Kleinbaum DG, Kupper LL, Muller KE. Applied Regression Analysisand Other Multivariable Methods. Boston, Massachusetts: PWS-Kent,1988.

7. SAS Institute. SAS/STAT User’s Guide Version 8. Cary, North Caro-lina: SAS Institute, 1999.

8. Myers GL, Rifai N, Tracy RP, Roberts WL, Alexander RW, BiasucciLM, Catravas JD, Cole TG, Cooper GR, Khan BV, et al. CDC/AHAWorkshop on Markers of Inflammation and Cardiovascular Disease:application to clinical and public health practice: report from thelaboratory science discussion group. Circulation 2004;110:e545–e549.

9. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon ROIII, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, et al.Markers of inflammation and cardiovascular disease: application toclinical and public health practice: a statement for healthcare profes-sionals from the Centers for Disease Control and Prevention and theAmerican Heart Association. Circulation 2003;107:499–511.

0. Wilson PF, Nam BH, D’Agostion RB, Benjamin EJ, O’Donnell CJ.C-reactive protein and risk of cardiovascular disease in men andwomen. Arch Int Med 2005;165:1–6.

1. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, RumleyA, Lowe GD, Pepys MB, Gudnason V. C-reactive protein and othercirculating markers of inflammation in the prediction of coronary heartdisease. N Engl J Med 2004;350:1387–1397.

2. Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ,Sutton-Tyrrell K, Rubin SM, Ding J, Simonsick EM, Harris TB, PahorM. Inflammatory markers and onset of cardiovascular events: resultsfrom the Health ABC study. Circulation 2003;108:2317–2322.

3. Luc G, Bard JM, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P,Arveiler D, Fruchart JC, Ducimetiere P. C-reactive protein, interleu-kin-6, and fibrinogen as predictors of coronary heart disease: thePRIME Study. Arterioscler Thromb Vasc Biol 2003;23:1255–1261.

4. Wigmore SJ, Walsh TS, Lee A, Ross JA. Pro-inflammatory cytokinerelease and mediation of the acute phase protein response in fulminanthepatic failure. Intensive Care Med 1998;24:224–229.

5. Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflamma-tion, obesity, stress and coronary heart disease: is interleukin-6 the
link? Atherosclerosis 2000;148:209–214.

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Changes in Coronary Anatomy and PhysiologyAfter Heart Transplantation

Atsushi Hirohata, MD, Mamoo Nakamura, MD, Katsuhisa Waseda, MD, Yasuhiro Honda, MD,David P. Lee, MD, Randall H. Vagelos, MD, Sharon A. Hunt, MD, Hannah A. Valantine, MD,

Paul G. Yock, MD, Peter J. Fitzgerald, MD, PhD, Alan C. Yeung, MD, and William F. Fearon, MD*

Cardiac allograft vasculopathy (CAV) is a progressive process involving the epicardial andmicrovascular coronary systems. The timing of the development of abnormalities in these2 compartments and the correlation between changes in physiology and anatomy areundefined. The invasive evaluation of coronary artery anatomy and physiology withintravascular ultrasound, fractional flow reserve, coronary flow reserve, and the index ofmicrocirculatory resistance (IMR) was performed in the left anterior descending coronaryartery during 151 angiographic evaluations of asymptomatic heart transplant recipientsfrom 0 to >5 years after heart transplantation (HT). There was no angiographic evidenceof significant CAV, but during the first year after HT, fractional flow reserve decreasedsignificantly (0.89 � 0.06 vs 0.85 � 0.07, p � 0.001), and percentage plaque volume derivedby intravascular ultrasound increased significantly (15.6 � 7.7% to 22.5 � 12.3%, p �0.0002), resulting in a significant inverse correlation between epicardial physiology andanatomy (r � �0.58, p <0.0001). The IMR was lower in these patients compared withthose >2 years after HT (24.1 � 14.3 vs 29.4 � 18.8 units, p � 0.05), suggesting later spreadof CAV to the microvasculature. As the IMR increased, fractional flow reserve increased(0.86 � 0.06 to 0.90 � 0.06, p � 0.0035 comparing recipients with IMRs <20 to those withIMRs >40), despite no difference in percentage plaque volume (21.0 � 11.2% vs 20.5 �10.5%, p � NS). In conclusion, early after HT, anatomic and physiologic evidence ofepicardial CAV was found. Later after HT, the physiologic effect of epicardial CAV maybe less, because of increased microvascular dysfunction. © 2007 Elsevier Inc. All rights
reserved. (Am J Cardiol 2007;99:1603–1607)
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t is now possible to independently assess epicardial coro-ary artery physiology by measuring myocardial fractionalow reserve (FFR) and microvascular physiology by mea-uring the index of microcirculatory resistance (IMR) rela-ively easily and simultaneously with a single coronaryuidewire.1–3 The purpose of this study was to investigatehanges over time in epicardial coronary artery anatomynd physiology after heart transplantation (HT), as deter-ined by intravascular ultrasound (IVUS) and FFR. By alsoeasuring IMR, we hoped to better understand the timing of

he development of cardiac allograft vasculopathy in theicrovasculature and its relation to the anatomic and phys-

ologic changes in the epicardial arteries of these patients.

ethods

table heart transplant recipients who underwent coronaryngiography were eligible for this study. The protocol was

Center for Research in Cardiovascular Interventions, Division of Car-iovascular Medicine, Stanford University Medical Center, Stanford, Cal-fornia. Manuscript received November 22, 2006; revised manuscript re-eived and accepted January 10, 2007.

Dr. Fearon was supported by Grant 1 K23 HL072808-01A1 and Dr.alantine by Grant 1 PO1-AI50153 from the National Heart, Lung, andlood Institute, National Institutes of Health, Bethesda, Maryland.

tE-mail address: [email protected] (W.F. Fearon).

pproved by Stanford University’s Administrative Panel onuman Subjects, and each patient provided informed writ-

en consent. After routine right-sided cardiac catheterizationnd right ventricular endomyocardial biopsy, coronary an-iography was performed in the usual fashion.

Each patient then received intravenous heparin 3,000 to,000 U and intracoronary nitroglycerin 100 to 200 �g via6Fr left coronary guiding catheter. A 0.014-inch coronaryressure wire was calibrated outside of the body and thendvanced into the left anterior descending artery so that theressure sensor, which is 3 cm from the tip of the wire, wasocated at the ostium of the guiding catheter, where equalressure readings from the catheter and wire were con-rmed. The wire was then advanced to the mid to distalegment of the left anterior descending artery.

With commercially available software, the shaft of theressure wire can act as a proximal thermistor, and theressure sensor can act as a distal thermistor; the transit timef an injectate can be determined using a validated ther-odilution technique.4,5 The mean transit time at rest of

aline down the left anterior descending artery was calcu-ated by rapidly injecting 3 ml of room-temperature salinento the left main coronary artery 3 times and averaging theesults. Either intravenous adenosine (140 �g/kgmin) orntracoronary papaverine (15 mg) was then administered tonduce maximal hyperemia. The hyperemic mean transit
ime was then calculated in a similar fashion to the mean
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ransit time at rest. Distal coronary and aortic phasic andean pressures were recorded simultaneously.Coronary flow reserve (CFR) was defined as the mean

ransit time at rest divided by the hyperemic mean transitime.4,5 FFR was measured by dividing the mean distaloronary pressure (measured with the wire) by the meanortic pressure (measured with the catheter) during peakyperemia. The IMR was calculated by dividing the meanistal pressure by the inverse of the hyperemic mean transitime or, more simply, by multiplying the mean distal pres-ure by the hyperemic mean transit time.1 An example ofimultaneous FFR, CFR, and IMR measurements is shownn Figure 1.

A 40-MHz IVUS catheter was then advanced over theressure wire to the mid to distal left anterior descendingrtery. An automated pullback of the catheter at 0.5 mm/sas performed, and the IVUS images were recorded. Off-

ine, the IVUS images were digitized, and 2-dimensionalnalysis of cross sections taken every 0.5 mm was per-ormed. Measurements included maximum and minimumessel and luminal diameters and areas, maximum percent-ge cross-sectional narrowing, plaque area, and maximalntimal thickness. Three-dimensional volumetric analysisas performed using Simpson’s method (Echo Plaque; In-ec Systems, Inc., Santa Clara, California). Measurementsncluded the average vessel, lumen, and plaque area of thentire imaged left anterior descending segment. To stan-ardize for varying degrees of pull-back length and for

IMR = Distal Pressure / Flow during peak hyperemia

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HyperemiaResting

igure 1. Example of FFR, CFR, and IMR measurements. In this examplef a patient 1 year after HT, FFR in the left anterior descending artery isery abnormal at 0.77 (distal pressure 58 mm Hg divided by aortic pressure6 mm Hg, rounded up), despite an angiographically normal appearingessel. IVUS revealed moderate diffuse intimal thickening, with a percent-ge plaque volume of 33%. CFR is calculated by dividing the mean transitime at rest (0.55 seconds) by the hyperemic mean transit time (0.13econds), which are derived from averaging 3 transit times calculated fromhe thermodilution curves created by saline injection. The CFR was 4.3rounded up), which would usually be considered normal, but the low FFRuggests that the normal CFR in this patient was likely once higher. TheMR is calculated as described in the figure by multiplying the hyperemicistal pressure (58 mm Hg) by the hyperemic mean transit time (0.13econds) and was very low at 8 units, suggesting normal microvascularunction.

essel size, the percentage plaque volume, defined as the n

laque volume divided by the vessel volume, was calcu-ated. Plaque morphology was graded as soft, fibrofatty,ixed, or calcific, as previously described.6The Stanford Quantitative Coronary Angiography Core

aboratory, blinded to the physiologic and IVUS results,erformed quantitative coronary angiography on the proxi-al, mid, and distal left anterior descending coronary artery

rom angiograms with cranial angulation and minimal pan-ing of the table. Using the guiding catheter for calibrationnd an edge detection system (Sanders Data Systems, Palolto, California), the reference diameters and minimum

uminal diameter for the 3 sites were calculated and thereatest percentage diameter stenosis recorded.

Data are expressed as mean � SD. The mean FFR, IMR,FR, and IVUS parameters at various time periods after HTere compared using the unpaired Student’s t test. Linear

egression was applied to determine correlations betweenhysiologic and IVUS parameters. Patients were groupedn the basis of the time after HT, from baseline (�2 monthsfter HT) to 1, 2, 3 to 5, and �5 years after HT. Analysis ofariance was used to compare changes in physiologic andVUS parameters over time. A p value �0.05 was consid-red statistically significant. Statistical analysis was per-ormed using StatView 5.0 (SAS Institute Inc., Cary, Northarolina).

esults

atient characteristics are listed in Table 1. A total of 151ases (92 patients) were included in the study. Quantitativeoronary angiography demonstrated no stenosis in the leftnterior descending artery �40% in any patient. Data from6 of these patients have been reported in a previous pub-ication.7

FFR decreased significantly in patients at baseline com-ared with 1 year after HT (0.89 � 0.06 to 0.85 � 0.07, p

0.001; Figure 2). Beyond the first year, FFR graduallyncreased in a nonsignificant fashion (0.85 � 0.07 at year 1o 0.89 � 0.06 at �5 years after HT, p � 0.29). The IMRid not change significantly during the 5 time periods (24.7

13.5 vs 23.6 � 15.1 vs 28.2 � 21.1 vs 31.0 � 18.3 vs8.9 � 16.7, p � 0.35). However, when comparing patients2 years with those �2 years after HT, the IMR increased

24.1 � 14.3 vs 29.4 � 18.8 U, p � 0.05). There was a

able 1linical characteristics (n � 92)

haracteristic Value

onor age (yrs) 34 � 13ecipient age (yrs) 53 � 11ecipient gender male 79%retransplantation hypertension 14%retransplantation diabetes 13%retransplantation smoking 19%schemic time (min) 208 � 51schemic cardiomyopathy 57%ecipient cytomegalovirus positive 65%ytomegalovirus mismatch (donor positive, recipientnegative)

12%

onsignificant increase in the hyperemic mean transit time

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1605Miscellaneous/Coronary Anatomy and Physiology After HT

0.36 � 0.20 vs 0.40 � 0.22 seconds, p � 0.32) and aignificant increase in distal coronary pressure (67 � 12.5s 72.7 � 14.8 mm Hg, p �0.01) in those patients �2 yearsompared with those �2 years after HT. CFR did nothange significantly during the 5 time periods after HT (3.0

1.5 vs 3.4 � 1.9 vs 3.2 � 1.8 vs 2.9 � 1.1 vs 3.3 � 1.4,� 0.72), nor was there a significant difference in CFRhen comparing patients �2 years with those �2 years

fter HT (3.19 vs 3.09, p � 0.70).On average, the IVUS pullback began 66.5 � 14.3 mm

istal to the left anterior descending ostium. Volumetric andross-sectional IVUS findings are listed in Table 2. Averageuminal area decreased significantly over time (11.1 � 2.7s 9.3 � 2.7 vs 9.4 � 1.8 vs 9.0 � 2.1 vs 7.0 � 1.2 mm2,�0.0001), and percentage plaque volume increased sig-

ificantly over time (15.6 � 7.7% vs 22.5 � 12.3% vs 22.711.4% vs 24.1 � 10.6% vs 26.1 � 10.7%, p � 0.002).FFR correlated inversely with percentage plaque volume

nd maximum percentage cross-sectional narrowing in pa-ients �2 years after HT (r � �0.58, p �0.0001, and r �

0.57, p �0.0001, respectively), patients in whom on av-rage the IMR was lower. FFR did not correlate with theseVUS parameters in patients �2 years after HT (r � �0.14,� 0.27, and r � �0.22, p � 0.08, respectively), patients

n whom the IMR on average was higher. In patients inhom the IMR was �20, FFR was significantly lower

ompared with those in whom the IMR was �40, despitequivalent IVUS findings (Table 3). CFR did not correlateith percentage plaque volume (r � 0.13, p � 0.11), max-

mum percentage cross-sectional narrowing (r � 0.11, p �.18), or FFR (r � 0.06, p � 0.49) but did correlate signif-cantly with the IMR (r � 0.51, p �0.0001).

iscussion

he major finding in this study is the interplay between thehysiologic changes in the coronary microvasculature andhe epicardial coronary artery over time in heart transplantecipients and the effect this interplay has on the correlationetween epicardial artery physiology and anatomy. Earlyfter HT, anatomic changes in the epicardial artery as as-essed by IVUS correlate with significant changes in epi-ardial artery physiology as assessed by FFR. On average,icrovascular resistance (IMR) is lower during the first 2

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Figure 2. Change in FFR on the basis of time from transplantation.

ears after HT compared with later after HT, presumably m

ecause of late involvement of the microvasculature byardiac allograft vasculopathy. Late after HT, the increasen microvascular resistance results in a decrease in theaximum achievable flow down the epicardial vessel and

essens the physiologic impact of structural abnormalities inhe epicardial artery. For this reason, FFR may not providegood representation of epicardial artery plaque burden latefter HT, unless microvascular resistance (IMR) is found toe low.

In patients who have not undergone HT but have micro-ascular dysfunction from another cause (e.g., myocardialnfarction), a similar disconnect between the anatomic find-ngs and the physiologic implications may be present. Thisoes not imply that FFR is inaccurate in these patients. TheFR result continues to provide information about the per-entage of maximum achievable myocardial flow in theresence of an epicardial stenosis. In the setting of micro-ascular dysfunction, the maximum achievable flow islunted, the impact of an epicardial stenosis lessened, andhe expected physiologic benefit from stenting lessened.

Cardiac allograft vasculopathy is a progressive processnvolving the epicardial as well as microvascular systems.he changes in physiology and anatomy over time in thesecompartments are poorly defined, and changes in one may

ignificantly affect the assessment of the other. The standardechnique for detecting epicardial cardiac allograft vascu-opathy is IVUS, which has been shown to be more sensitivehan angiography and to be predictive of long-term adverseutcomes.8–10 IVUS is limited, however, because it pro-ides anatomic information only and does not interrogatehe microvasculature.

The standard technique for evaluating coronary physiol-gy in heart transplant recipients has been to use a Dopplerire to measure CFR.11 CFR interrogates the entire coro-ary circulation and is unable to distinguish abnormal epi-ardial physiology from microvascular physiology.12 Addi-ionally, CFR is limited by poor reproducibility.13,14 Theseactors may explain why some previous studies have shown

significant decrease in CFR over time after HT15 andthers a significant increase.16

FFR is an index that provides information about theegree to which epicardial artery disease is affecting myo-ardial perfusion.17 It is unique compared with CFR in thatt is specific for the epicardial artery and is extremelyeproducible.13,14,18 FFR has been well validated in theon-HT population but not well studied in heart transplantecipients. We have previously published a study evaluatingFR at a single time point in heart transplant recipients,redominantly early after HT, and found a strong correla-ion between FFR and the IVUS-determined epicardial per-entage plaque volume.7

IMR is a new index that we recently proposed as aethod for interrogating the status of the coronary micro-

irculation, independent of the epicardial artery.1–3 We haveound that it correlates well with an accepted experimentalechnique for determining microvascular resistance1 andhat it is more reproducible than CFR.14 The ability to assessasily and accurately the epicardial artery and the micro-asculature simultaneously by measuring FFR and IMRith a single wire is a potential advantage over the standard
ethods of using IVUS and a Doppler velocity wire.

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In this study, we found that early after HT (�2 years),here was a significant inverse correlation between epicar-ial artery physiology as measured with FFR and epicardialrtery anatomy as measured with IVUS. During the firstear after HT, FFR decreased significantly while plaqueolume increased significantly. On average, the minimumchievable microvascular resistance, as measured withMR, was low early (during the first 2 years) after HTompared with later. Because of the low microvascularesistance, the peak epicardial flow, as estimated by theyperemic mean transit time, was higher (shorter hyperemicean transit time). The higher flow results in a greater

ressure gradient (lower distal pressure and FFR) across anpicardial stenosis and likely explains the strong correlationetween FFR and IVUS findings.

Later after HT (�2 years), IMR increased, suggestinghat cardiac allograft vasculopathy involves the microvas-ulature later than it does the epicardial artery. Changes inyogenic tone that occur in the microvasculature after HT

nd may initially lower resistance could result in microvas-ular edema, which eventually leads to increased resis-ance.19 During the later time periods (2 to �5 years afterT), there was little change in plaque volume and a more

ignificant late decrease in vessel volume. FFR graduallyncreased during this time, coinciding with the increase inMR (Table 3).

A major limitation of this study is the lack of serialnalyses, meaning that late patients may not have been wellatched with early patients. For example, in a subset of

atients in this study in whom IMR was measured at theime of HT and then 1 year later, we have previouslyeported that IMR was significantly higher at baseline, pre-

able 2ntravascular ultrasound findings

ariable

1 Mo (n � 46) 1 Yr

olumetricAverage vessel area (mm3/mm) 13.3 � 3 12.Average plaque area (mm3/mm) 2.1 � 1* 3.ross sectionalMinimum luminal area (mm) 4.9 � 2 4.Maximum % cross-sectional narrowing 27 � 14† 3Maximum intimal thickness (mm) 0.7 � 0.5‡ 0.laque morphologySoft 90%Fibrofatty 4%Mixed 2%Calcific 4%

* p � 0.02; † p � 0.003; ‡p � 0.05; §p � 0.03.

able 3elationship between index of microcirculatory resistance, fractional flow

ariable IMR � 20 (n � 6

Plaque volume 21.0 � 11%aximum % cross-sectional narrowing 38.9 � 18%

FR 0.86 � 0.06*

* p � 0.0035.

umably because of the effects of donor heart ischemia

nd/or early recipient immunologic effects.20 We also foundn a group with IVUS evaluation at baseline and 1 year afterT that negative remodeling played a more prominent role

n luminal loss early after HT than seen in this study.21

ikely the changes in coronary physiology are not univer-al, but recipients with certain clinical characteristics maye more or less susceptible. Because of the lack of long-erm serial data, we could not do subgroup analyses. Long-erm follow-up of matched patients will be crucial to con-rm the findings in this study. In addition, this study did not

nclude consecutive patients and was a retrospective analy-is; some patients were excluded because of medical con-itions, such as elevated creatinine, and others for logisticeasons. Finally, determining the prognostic importance ofhese physiologic measurements and volumetric IVUS find-ngs will be critical.

1. Fearon WF, Balsam LB, Farouque HM, Caffarelli AD, Robbins RC,Fitzgerald PJ, Yock PG, Yeung AC. Novel index for invasively as-sessing the coronary microcirculation. Circulation 2003;107:3129–3132.

2. Fearon WF, Aarnoudse W, Pijls NH, De Bruyne B, Balsam LB, CookeDT, Robbins RC, Fitzgerald PJ, Yeung AC, Yock PG. Microvascularresistance is not influenced by epicardial coronary artery stenosisseverity: experimental validation. Circulation 2004;109:2269–2272.

3. Aarnoudse W, Fearon WF, Manoharan G, Geven M, van de Vosse F,Rutten M, De Bruyne B, Pijls NH. Epicardial stenosis severity doesnot affect minimal microcirculatory resistance. Circulation 2004;110:2137–2142.

4. De Bruyne B, Pijls NHJ, Smith L, Wievegg M, Heyndrickx GR.Coronary thermodilution to assess flow reserve: experimental valida-tion. Circulation 2001;104:2003–2006.

5. Pijls NH, De Bruyne B, Smith L, Aarnoudse W, Barbato E, BartunekJ, Bech GJ, Van De Vosse F. Coronary thermodilution to asses flow

Time After Transplantation

8) 2 Yrs (n � 22) 3–5 Yrs (n � 27) �5 Yrs (n � 10)

12.5 � 3 12.2 � 4§ 9.7 � 2§

3.1 � 2 3.2 � 2 2.7 � 2

4.2 � 1 4.2 � 2‡ 2.9 � 1‡

41 � 20 46 � 16 46 � 18‡ 1.1 � 0.6 1.0 � 0.6 0.9 � 0.5

67% 65% 52%14% 12% 10%9% 1% 6%9% 15% 32%

, and intravascular ultrasound results

20 � IMR � 40 (n � 50) IMR �40 (n � 34)

20.8 � 11% 20.5 � 11%39.4 � 18% 40.4 � 19%0.87 � 0.07 0.90 � 0.06*

(n � 4

5 � 30 � 2*

6 � 29 � 20†

9 � 0.4

73%13%4%9%

reserve

7)

reserve: validation in humans. Circulation 2002;105:2480–2484.

1

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1607Miscellaneous/Coronary Anatomy and Physiology After HT

6. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, FitzgeraldPJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. AmericanCollege of Cardiology clinical expert consensus document on stan-dards for acquisition, measurement and reporting of intravascularultrasound studies (IVUS). A report of the American College ofCardiology Task Force on Clinical Expert Consensus Documents.J Am Coll Cardiol 2001;37:1478–1492.

7. Fearon WF, Nakamura M, Lee DP, Rezaee M, Vagelos RH, Hunt SA,Fitzgerald PJ, Yock PG, Yeung AC. Simultaneous assessment offractional and coronary flow reserves in cardiac transplant recipients:Physiologic Investigation for Transplant Arteriopathy (PITA study).Circulation 2003;108:1605–1610.

8. St. Goar FG, Pinto FJ, Alderman EL, Valantine HA, Schroeder JS,Gao SZ, Stinson EB, Popp RL. Intracoronary ultrasound in cardiactransplant recipients. In vivo evidence of “angiographically silent”intimal thickening. Circulation 1992;85:979–987.

9. Kobashigawa JA, Tobis JM, Starling RC, Tuzcu EM, Smith AL,Valantine HA, Yeung AC, Mehra MR, Anzai H, Oeser BT, et al.Multicenter intravascular ultrasound validation study among hearttransplant recipients: outcomes after five years. J Am Coll Cardiol2005;45:1532–1537.

0. Tuzcu EM, Kapadia SR, Sachar R, Ziada KM, Crowe TD, Feng J,Magyar WA, Hobbs RE, Starling RC, Young JB, et al. Intravascularultrasound evidence of angiographically silent progression in coronaryatherosclerosis predicts long-term morbidity and mortality after car-diac transplantation. J Am Coll Cardiol 2005;45:1538–1542.

1. Caracciolo EA, Wolford TL, Underwood RD, Donohue TJ, Bach RG,Miller LW, Kern MJ. Influence of intimal thickening on coronaryblood flow responses in orthotopic heart transplant recipients. A com-bined intravascular Doppler and ultrasound imaging study. Circulation1995;92:II182–II190.

2. Kern MJ. Coronary physiology revisited : practical insights from thecardiac catheterization laboratory. Circulation 2000;101:1344–1351.

3. De Bruyne B, Bartunek J, Sys SU, Pijls NH, Heyndrickx GR, WijnsW. Simultaneous coronary pressure and flow velocity measurements in
humans. Feasibility, reproducibility, and hemodynamic dependence of
coronary flow velocity reserve, hyperemic flow versus pressure slopeindex, and fractional flow reserve. Circulation 1996;94:1842–1849.

4. Ng M, Yeung AC, Fearon WF. Invasive assessment of the coronarymicrocirculation: superior reproducibility and less hemodynamic de-pendence of index of microcirculatory resistance as compared to cor-onary flow reserve. Circulation 2006;113:2054–2061.

5. Mazur W, Bitar JN, Young JB, Khalil AA, Vardan S, Short BC, RiveraJM, Raizner AE, Farmer JA, Zoghbi WA, Kleiman NS. Progressivedeterioration of coronary flow reserve after heart transplantation. AmHeart J 1998;136:504–509.

6. Konig A, Spes CH, Schiele TM, Rieber J, Stempfle HU, Meiser B,Theisen K, Mudra H, Reichart B, Klauss V. Coronary Doppler mea-surements do not predict progression of cardiac allograft vasculopathy:analysis by serial intracoronary Doppler, dobutamine stress echocar-diography, and intracoronary ultrasound. J Heart Lung Transplant2002;21:902–905.

7. Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ,Bartunek J, Koolen JJ. Measurement of fractional flow reserve toassess the functional severity of coronary-artery stenoses. N EnglJ Med 1996;334:1703–1708.

8. Pijls NH, Van Gelder B, Van der Voort P, Peels K, Bracke FA,Bonnier HJ, el Gamal MI. Fractional flow reserve. A useful index toevaluate the influence of an epicardial coronary stenosis on myocardialblood flow. Circulation 1995;92:3183–3193.

9. Moien-Afshari F, Skarsgard PL, McManus BM, Laher I. Cardiactransplantation and resistance artery myogenic tone. Can J PhysiolPharmacol 2004;82:840–848.

0. Fearon WF, Hirohata A, Nakamura M, Luikart H, Lee DP, Vagelos R,Hunt SA, Valantine HA, Fitzgerald PJ, Yock PG, Yeung AC. Discor-dant changes in epicardial and microvascular coronary physiologyafter cardiac transplantation: Physiologic Investigation for TransplantArteriopathy II (P.I.T.A. II) study. J Heart Lung Transplant 2006;25:765–771.

1. Fearon WF, Potena L, Hirohata A, Sakurai R, Yamasaki M, Luikart H,Lee J, Vana ML, Cooke JP, Mocarski ES, et al. Changes in coronaryarterial dimensions early after cardiac transplantation. Transplantation
2007;83:700–705.

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Incidental Detection of Cancers and Other Non-Cardiac Abnormalities onCoronary Multislice Computed Tomography

Yoshiyuki Kawano, MDa,*, Akira Tamura, MDa, Yukie Goto, MDb, Kazuhiro Shinozaki, MDb,Hirofumi Zaizen, MDb, and Junichi Kadota, MD, PhDa

The investigators prospectively examined 625 consecutive patients who underwent coro-nary multislice computed tomography (MSCT) for suspected coronary artery disease(CAD) and evaluated the presence or absence of cancers and other noncardiac abnormal-ities on the original transverse sectional images of MSCT. Eight patients with knowncancers were excluded from the analysis. The remaining 617 patients (344 men, 273women; mean age 66 � 12 years) were analyzed. Cancers were found in 7 patients (1.13%)on the multislice computed tomographic images, including 4 lung cancers (0.65%), 2thyroid cancers (0.32%), and 1 hepatic cancer (0.16%). In addition, nonmalignant abnor-malities (nodules, tumors, or lymphadenopathies) were also found in 142 patients (23.01%),consisting of 58 postinflammatory lung nodules (9.40%), 49 hepatic cysts or hemangiomas(7.94%), 18 benign thyroid tumors (2.92%), 12 mediastinal lymphadenopathies (1.94%), 4benign mammary gland tumors (0.65%), and 1 esophageal submucosal tumor (0.16%). Inconclusion, cancers and other noncardiac abnormalities are often found in patients whoundergo coronary MSCT for suspected CAD. Because patients who undergo coronaryMSCT for suspected CAD are mostly elderly and therefore may have unrecognized cancersor other noncardiac abnormalities, care should thus be taken not to overlook these abnor-malities when analyzing the multislice computed tomographic images. © 2007 Elsevier
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ultislice computed tomography (MSCT) is an establishedool for detecting coronary artery disease (CAD).1–3 Whenoronary MSCT is performed in patients who are suspectedf having CAD, cancers and other noncardiac abnormalitiesan sometimes be incidentally found on the images. To theest of our knowledge, however, there have so far been noystematic studies concerning the prevalence of unrecog-ized cancers and other noncardiac abnormalities on mul-islice computed tomographic images. Accordingly, weought to elucidate the prevalence of cancers and otheroncardiac abnormalities on the images of patients whonderwent coronary MSCT for suspected CAD.

ethods and Results

rom March 2005 to May 2006, we prospectively exam-ned 625 consecutive patients (347 men, 278 women;ean age 66 � 12 years) who underwent coronary MSCT

or suspected CAD and evaluated the presence or absencef cancers and other noncardiac abnormalities on themages. Eight patients with known cancers were excludedrom the analysis. The remaining 617 patients (344 men,73 women; mean age 66 � 12 years) were analyzed.SCT was performed using the Toshiba multislice Aq-

ilion 64 system (Toshiba Medical Systems, Tokyo, Ja-

aSecond Department of Internal Medicine, Oita University, Yufu; andDivision of Cardiovascular Medicine, Koseiren Tsurumi Hospital, Beppu,apan. Manuscript received November 19, 2006; revised manuscript re-eived and accepted January 10, 2007.

*Corresponding author: Tel: 81-0-97-586-5804; fax: 81-0-97-549-245.

hE-mail address: [email protected] (Y. Kawano).


an), with a collimation of 64 � 0.5 mm and a rotationime of 0.4 seconds. The tube current was 300 mA, at 120V (depending on patient size). Nonionic contrast me-ium (Omnipaque 300; Daiichi Pharmaceutical Co., Ltd.,okyo, Japan) was intravenously administered in thentecubital vein, with an amount of 50 ml and a flow ratef 3.5 ml/s, followed by a 30-ml saline flush at a flow ratef 3.0 ml/s. As soon as the signal in the ascending aortaeached a predefined threshold of �100 HU, the scantarted automatically, and the entire volume of the heartas acquired during an inspiratory breath hold of approx-

mately 8 to 10 seconds. During the multislice computedomographic examination, electrocardiography was si-ultaneously performed for retrospective gating of the

ata. An initial data set was reconstructed at 75% of theR interval, with a slice thickness of 0.5 mm and a

econstruction interval of 0.3 mm. The presence or ab-ence of cancers and other noncardiac abnormalities wasvaluated on original transverse sectional images ofSCT by an experienced radiologist. When the radiolo-

ist recommended further examinations for the noncar-iac abnormalities detected on the images, additionalxaminations were carried out.

The radiologist pointed out 149 noncardiac abnormal-ties in 149 patients and recommended further examina-ion for 36 of them. The final diagnoses of the noncardiacbnormalities detected in the multislice computed tomo-raphic images are listed in Table 1. Of 617 patients,ancers were found in 7 patients (1.13%) on the images,ncluding 4 lung cancers (0.65%), 2 thyroid cancers0.32%), and 1 hepatic cancer (0.16%). These 7 patients
ad all been referred from clinics for evaluations of
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1609Miscellaneous/Detection of Cancers on Coronary MSCT

uspected CAD using coronary MSCT. Other nonmalig-ant abnormalities (nodules, tumors, or lymphadenopa-hies) were found in 142 patients (23.01%), including 58ostinflammatory lung nodules (9.40%), 49 hepatic cystsr hemangiomas (7.94%), 18 benign thyroid tumors2.92%), 12 mediastinal lymphadenopathies (1.94%), 4enign mammary gland tumors (0.65%), and 1 esopha-eal submucosal tumor (0.16%).

iscussion

he number of patients with cancer has been increasingorldwide.4 Aging and smoking are risk factors for CAD

nd various cancers.5–13 It has been reported that about 75%f patients with cancer are aged �60 years.4 Because pa-ients who undergo coronary MSCT for suspected CAD areostly elderly, they may have unrecognized cancers. In the

resent study, we prospectively investigated the prevalencef cancers and other noncardiac abnormalities on the imagesf patients who underwent coronary MSCT for suspectedAD. The mean age of the patients was 66 � 12 years, andancers and other noncardiac abnormalities were indeed

able 1he final diagnoses of noncardiac abnormalities detected on multisliceomputed tomographic images

bnormality n (%)

verall abnormalities 149 (24.15%)ancers 7 (1.13%)Lung 4 (0.65%)Thyroid 2 (0.32%)Hepatic 1 (0.16%)onmalignant abnormalities 142 (23.01%)Postinflammatory lung nodules 58 (9.40%)Hepatic cysts/hemangiomas 49 (7.94%)Benign thyroid tumors 18 (2.92%)Mediastinal lymphadenopathies 12 (1.94%)Benign mammary gland tumors 4 (0.65%)Esophageal submucosal tumor 1 (0.16%)

ound in 1.13% and 23.01%, respectively.

1. Nieman K, Cademartini F, Lemos PA, Raaijmakers R, PattynamaPMT, de Feyter PJ. Reliable noninvasive coronary angiography withfast submillimeter multislice spiral computed tomography. Circulation2002;106:2051–2054.

2. Hoffmann MH, Shi H, Schmitz BL, Schmid FT, Lieberknecht M,Schulze R, Ludwig B, Kroschel U, Jahnke N, Haerer W, et al. Non-invasive coronary angiography with multislice computed tomography.JAMA 2005;293:2471–2478.

3. Leber AW, Knez A, von Ziegler F, Becker A, Nikolaou K, Paul S,Wintersperger B, Reiser M, Becker CR, Steinbeck G, Boekstegers P.Quantification of obstructive and nonobstructive coronary lesions by64-slice computed tomography. A comparative study with quantitativecoronary angiography and intravascular ultrasound. J Am Coll Cardiol2005;46:147–154.

4. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ.Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–130.

5. Hirose K, Hamajima N, Takezaki T, Kuroishi T, Kuzuya K, Sasaki S,Tokudome S, Tajima K. Smoking and dietary risk factors for cervicalcancer at different age group in Japan. J Epidemiol 1998;8:6–14.

6. Wakai K, Inoue M, Mizoue T, Tanaka K, Tsuji I, Nagata C, TsuganeS. Tabacco smoking and lung cancer risk: an evaluation based on asystematic review of epidemiological evidence among the Japanesepopulation. Jpn J Clin Oncol 2006;36:309–324.

7. Tavani A, Negri E, Franceschi S, La Vecchia C. Tabacco and otherrisk factors for oesophageal cancer in alcohol non-drinkers. Eur JCancer Prev 1996;5:313–318.

8. Fujino Y, Mizoue T, Tokui N, Kikuchi S, Hoshiyama Y, ToyoshimaH, Yatsuya H, Sakata K, Tamakoshi A, Ide R, et al. Cigarette smokingand mortality due to stomach cancer: findings from the JACC Study.J Epidemiol 2005;15(suppl):S113–S119.

9. Nagata C, Mizoue T, Tanaka K, Tsuji I, Wakai K, Inoue M, TsuganeS. Tabacco smoking and breast cancer risk: an evaluation based on asystematic review of epidemiological evidence among the Japanesepopulation. Jpn J Clin Oncol 2006;36:387–394.

0. Tanaka K, Tsuji I, Wakai K, Nagata C, Mizoue T, Inoue M, TsuganeS. Cigarette smoking and liver cancer risk: an evaluation based on asystematic review of epidemiological evidence among the Japanesepopulation. Jpn J Clin Oncol 2006;36:445–456.

1. Lowenfels AB, Maisonneuve P. Risk factors for pancreatic cancer.J Cell Biochem 2005;95:649–656.

2. Niwa Y, Wakai K, Suzuki S, Tamakoshi K, Lin Y, Yatsuya H, KondoT, Nishio K, Yamamoto A, Tokudome S, et al. Cigarette smoking andthe risk of ovarian cancer in the Japanese population: findings from theJapanese Collaborate Cohort study. J Obstet Gynaecol Res 2005;31:144–151.

3. Mizoue T, Inoue M, Tanaka K, Tsuji I, Wakai K, Nagata C, TsuganeS. Tabacco smoking and colorectal cancer risk: an evaluation based ona systematic review of epidemiologic evidence among the Japanese
population. Jpn J Clin Oncol 2006;36:25–39.

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Relation Between Depressive Symptoms and Common CarotidArtery Atherosclerosis in American Persons >65 Years of Age†

Mohammed F. Faramawi, MD, PhD, MPHa,*, Jeanette Gustat, PhD, MPHa,Rachel P. Wildman, PhD, MPHb, Janet Rice, PhDa, Eric Johnson, MB, BS, PhDc,

and Roger Sherwin, MDa

Few epidemiologic studies have examined the association between depressive symptomsand atherosclerosis in subjects aged >65 years. Most of these studies were cross sectionaland could not determine the temporality between depressive symptoms and the develop-ment of abnormal common carotid artery (CCA) intima-media thickness (CCA-IMT). Toinvestigate the association between depressive symptoms and CCA atherosclerosis insubjects aged >65 years, data from 3,781 participants aged >65 years from the Cardio-vascular Health Study were analyzed. The presence of depressive symptoms was measuredby the Center for Epidemiologic Studies Depression Scale, while CCA-IMT as an indicatorof CCA atherosclerosis was measured by B-mode carotid ultrasonography. Multivariategeneralized estimation equations adjusted for age, gender, race, alcohol intake, bloodglucose status, body mass index, and time showed that subjects aged >65 years withdepressive symptoms had larger CCA-IMTs than those who did not have such symptoms(� � 18.26 �m, SE 8.06, p � 0.03). Using 1,000 and 1,140 �m as cut-off points to excludeparticipants who had abnormal CCA-IMTs at baseline, the adjusted relative risks and thecorresponding 95% confidence intervals of developing abnormal CCA-IMT over 3 yearswere 1.30 (95% confidence interval 1.10 to 1.44) and 1.21 (95% confidence interval 1.00 to1.46), respectively. Similar results were obtained after excluding participants with preva-lent cardiovascular disease at baseline. In conclusion, these data indicate that depressivesymptoms are associated with the development of atherosclerosis in subjects aged >65
years. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1610–1613)
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he prevalence of depressive symptoms in subjects aged65 years in the United States ranges from 11% to 20%.1epressive symptoms are not only an important risk factor

or the development of coronary heart disease (CHD) eventsn healthy subjects2 and for recurrent events in patients wholready have CHD3–5 but are also associated with the de-elopment of heart failure.6,7 Little is known about the rolef atherosclerosis as an important mechanism responsibleor the link between such symptoms and adverse cardiovas-ular outcomes.8 Few epidemiologic studies have examinedhe association between depressive symptoms and athero-clerosis in subjects aged �65 years, and those studies wererimarily cross sectional. The present analyses were carried

aTulane University School of Public Health & Tropical Medicine, Newrleans, Louisiana; bAlbert Einstein College of Medicine, Bronx, Nework; and cUniversity of North Texas Health Science Center, Fort Worth,exas. Manuscript received October 28, 2006; revised manuscript receivednd accepted December 28, 2006.

The Cardiovascular Health Study is conducted and supported by theational Heart, Lung, and Blood Institute, Bethesda, Maryland, in collab-ration with the Cardiovascular Health Study investigators.

*Corresponding author: Tel: 504-988-0551; fax: 504-988-1568.E-mail address: [email protected] (M.F. Faramawi).

† This report was prepared using a limited-access data set obtained byhe National Heart, Lung, and Blood Institute and does not necessarilyeflect the opinions or views of the Cardiovascular Health Study or the

oational Heart, Lung, and Blood Institute.


ut to address the paucity of epidemiologic data exploringhe relation between depressive symptoms and atheroscle-osis in subjects aged �65 years,9 testing the hypothesis thatresence of depressive symptoms in subjects aged �65ears is related to atherosclerosis.

ethods

he Cardiovascular Health Study (CHS) is an observationaltudy of risk factors associated with the development androgression of CHD and stroke in subjects aged �65ears.10 This study is the most extensive yet undertaken byhe National Heart, Lung, and Blood Institute to studyardiovascular disease exclusively in subjects aged �65ears. Random samples were obtained from the Health Careinancing Administration Medicare lists in 4 geographicreas (Forsyth County, North Carolina; Sacramento County,alifornia; Washington County, Maryland; and Pittsburgh

Allegheny County], Pennsylvania). From 1989 to 1990,,201 participants were recruited and were examined yearlyrom 1989 to 1999. Details regarding the CHS design andhe characteristics of the original CHS cohort have beenublished previously.10,11 Eligible participants had to be 65ears of age, able to give informed consent, and able toespond to questions without proxy respondents. For theurrent analyses, participants had to have data from the989 and 1992 examinations. Those who were taking anti-epressant drugs, nontricyclic and tricyclic antidepressants,
r hypolipidemic drugs were excluded from analyses be-
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1611Miscellaneous/Depressive Symptoms and Atherosclerosis in the Elderly

ause antidepressant drugs could be prescribed for nonpsy-hiatric indications, such as pain management and the in-uction of sleep,12 whereas hypolipidemic drugs mayecrease common carotid artery (CCA) intima-media thick-ess (CCA-IMT).13 Potential respondents who were wheel-hair bound at home, institutionalized, or receiving cancerreatment at baseline were also excluded.

Depressive symptoms were assessed annually with thehortened (10-item) version of the Center for Epidemiologictudies Depression Scale, a self-report measure of depres-ive symptoms experienced in the past week. Each of the 10tems is coded on a scale of 0 to 3 points, for a maximum of0 points. A higher score indicates greater depressive symp-oms. This version has been shown to be effective in de-ecting depression in subjects aged �65 years and in pa-ients with mood disorders.14,15 For the present study, aut-off score of �8 was used as an indicator of the presencef depressive symptoms, consistent with previous CHS de-ression analyses.16

Duplex ultrasonography of the left and right carotidrteries was performed using an SSA-270 (Toshiba Amer-can Medical Systems, Tustin, California) equipped with a.0-MHz transducer. Images obtained included a single lat-ral view of the distal common carotid artery showing theear and far walls and 3 views of the carotid bulb. Dopplermages were recorded at the site of the maximum acceler-tion of blood flow. Data quality was assessed througheriodic duplicate studies to assess the intra- and intertech-ician reproducibility of field center and reading centerechnicians.10,17 Intima-media thickness was calculated forhe CCA as the mean of the maximum wall thicknesses forhe near and far walls on the left and right sides: (maximumeft near wall � maximum left far wall � maximum rightear wall � maximum right far wall)/4. This measure wassed in a previous CHS study.17

Descriptive analysis was conducted to explore the char-cteristics of the participants at baseline. The means andDs of the continuous variables (CCA-IMT, body mass

ndex, and cholesterol) and the percentages of the categor-cal variables (age, gender, race, smoking, alcohol intake,bnormal blood glucose level, CHD, stroke, and hyperten-ion) by depressive symptoms were calculated. Means wereompared using Student’s t test, while proportions wereompared using the chi-square test.

Two types of longitudinal analyses were carried out.nitially, repeated measures of depression and CCA-IMTere modeled, with CCA-IMT analyzed as a continuousariable. Generalized estimation equation analyses wereonducted to calculate the average difference betweenhe CCA-IMTs of participants with and without depressiveymptoms. To establish temporality between depressiveymptoms and CCA-IMT, additional analyses were carriedut excluding participants with abnormal CCA-IMTs ataseline, and the development of an abnormal CCA-IMT atollow-up was examined. The definition of the upper normalimit used for defining the normal range of CCA-IMT isrbitrary and is frequently set at the 75th upper percentile ofhe CCA-IMT distribution. However, because CCA-IMT isonsidered a candidate marker of cardiovascular risk,18 theormal value should be chosen according to an increased
isk rather than the distribution within a population.19 Pub- c
ished epidemiologic studies have reported that a value ofCA-IMT �1,000 �m at any age is associated with a

ignificantly twofold increased risk for myocardial infarc-ion and/or cerebrovascular disease.19 On the basis of therevious information, a CCA-IMT �1,000 �m and a CCA-MT greater than the 75th percentile of the CCA-IMT dis-ribution were used to designate abnormal CCA-IMT in 2eparate sets of analyses.18,19 Using 1,000 �m as a cut-offoint, participants with CCA-IMTs �1,000 �m at baselineere excluded, and participants who had CCA-IMTs1,000 �m at follow-up were considered to have devel-

ped abnormal CCA-IMTs. The previous steps were re-eated using the 75th percentile as a cut-off point. Unad-usted and adjusted (for age, gender, race, blood glucosetatus, and alcohol intake) general linear models were con-ucted to calculate the relative risks for developing anbnormal CCA-IMT given the presence of depressiveymptoms at baseline. Finally, a linear regression was con-ucted to examine the relation between the change in CCA-MT as a dependent continuous variable with the baselineepressive symptoms status as an independent categoricalariable.

Age, gender, race, blood glucose status, smoking, alco-ol intake, hypertension, blood cholesterol, and body massndex were potential confounders. The change in the �

able 1emographic characteristics, chronic diseases, common carotid artery

therosclerosis, and cholesterol level by depressive symptoms

ariable Depressive Symptoms pValue

Absent(CES-D �8)

Present(CES-D �8)

(n � 3,258) (n � 519)

ge (yrs)*65–70 1,426 (43.77%) 210 (40.46%) 0.13�70–76 1,104 (33.89%) 173 (33.33%)�76 728 (22.34%) 136 (26.21%)en* 1,495 (45.89%) 157 (30.25%) �0.01onwhite* 156 (4.79%) 38 (7.32%) 0.02ver smoked* 1,730 (53.13%) 277 (53.47%) 0.90rink alcohol* 1,803 (44.56%) 248 (51.94%) �0.01hronic heart disease* 516 (15.84%) 121 (23.31%) �0.01troke* 94 (3.00%) 21 (4.06) 0.15bnormal blood

glucose status*‡886 (27.31%) 139 (26.99) 0.88

ypertension*§ 1,777 (54.61%) 299 (57.22%) 0.20CA-IMT (�m)† 1,041.16 (200.00) 1,057.85 (195.00) 0.12holesterol (mg/dl)† 209.00 (37.27) 211.00 (38.28) 0.30ody mass index

(kg/m2)26.33 (3.86) 26.48 (4.39) 0.42

Values are expressed as mean � SD or number of participants (percent-ge).

*Pearson’s chi-square test was used.†Student’s t test was used.‡Blood glucose status: normal blood glucose level �110 mg/dl, abnor-al blood glucose level �110 mg/dl.§Hypertension: normotensive: systolic blood pressure �140 mm Hg and

iastolic blood pressure �90 mm Hg. Hypertensive: systolic blood pres-ure �140 mm Hg or diastolic blood pressure �90 mm Hg or takingntihypertensive medication.ES-D � Center for Epidemiologic Studies Depression Scale.

oefficient of depressive symptoms after adding these vari-

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bles revealed that only age, gender, race, blood glucosetatus, and alcohol intake were true confounders.

esults

he characteristics of the study participants at baseline areresented in Table 1. Those with depressive symptoms wereore likely to be women, nonwhite, and alcohol drinkers

han those without depressive symptoms (p �0.05). Histo-ies of CHD were more prevalent in the depressive symp-oms group (p �0.05). Age, abnormal blood glucose status,ypertension, and cholesterol level were not significantlyssociated with depressive symptoms (p �0.05). The meanCA-IMT of those with depressive symptoms was larger

han the mean CCA-IMT of those without depressive symp-oms, but the difference was not significant (p � 0.12).

The unadjusted generalized estimation equation analysishowed a positive association between depressive symp-oms and CCA-IMT (p �0.01; Table 2). After adjusting forhe effect of time between CCA-IMT measurements, theagnitude of the positive association remained significant

ut decreased. Those with depressive symptoms had thickerommon carotid artery walls than those who did not haveepressive symptoms. After adjusting for time as well as thether covariates, the difference between the CCA-IMTs ofhe participants with depressive symptoms and the CCA-MTs of those without depressive symptoms remained pos-tive and significant (p �0.05). In the previous analysis, thenteraction term between time and depressive symptomsas not significant, nor was the interaction term bet-een depressive symptoms and gender (p �0.05 foroth).Therefore, the full model was used. Excluding partic-pants with cardiovascular diseases (CHD and stroke) didot materially alter the magnitude of the associations ofepressive symptoms with CCA-IMT in unadjusted or ad-usted analyses.

When individuals with CCA-IMTs �1,000 �m at base-ine were excluded, the unadjusted and adjusted relativeisks showed that participants with depressive symptoms ataseline were 1.30 times more likely to develop an abnor-al CCA-IMTs by follow-up. The results were similarhen the 75th percentile value (1,140 �m) was used as a

able 2eneralized estimation equation analysis of the association betweenepressive symptoms and common carotid artery intima-media thickness

ariable Unadjusted Adjusted* Adjusted†

(n � 3,781) (n � 3,781) (n � 3,692)

atients with cardiovasculardisease included

� (SE) 40.73 (8.51) 20.48 (8.18) 18.26 (8.06)p Value �0.01 0.01 0.03atients with cardiovascular

disease excluded� (SE) 36.14 (9.22) 16.20 (8.87) 20.32 (8.76)p Value �0.01 0.06 0.02

* Adjusted for time.† Adjusted for age, gender, blood glucose status, alcohol intake, bodyass index, and time.

ut-off point to classify abnormal CCA-IMT. Additionally, w

he results were materially unchanged when subjects withVD at baseline were excluded. Finally, those who hadepressive symptoms at baseline had a CCA-IMT increasef 35.41 �m (� � 35.41 �m, SE 14.41, p � 0.01) afterdjusting for baseline CCA-IMT, age, gender, race, bloodlucose status, alcohol intake, and body mass index.

iscussion

his population-based longitudinal study showed that theresence of depressive symptoms at baseline was associatedith larger CCA-IMTs in subjects aged �65 years. Addi-

ionally, these data showed that when participants withbnormal CCA-IMTs at baseline were excluded, those par-icipants remaining with depressive symptoms at baselineere 30% more likely to develop abnormal CCA-IMTs at

ollow-up than those without depressive symptoms at base-ine (data not shown) and that in the full sample, depressiveymptoms at baseline were associated with a 35.41 �mncrease in CCA-IMT.

CCA-IMT probably reflects the early development oftherosclerosis as a multistage process.20 The findings ofhe present study show that the presence of depressiveymptoms is an important risk factor for the early devel-pment of atherosclerosis in subjects aged �65 years andnderscore the need for health care practitioners to mon-tor depressive symptoms in subjects aged �65 years.he alleviation of depressive symptoms in subjects aged65 years is important because it improves the quality

f life.21 Nevertheless, it is unknown if the miti-ation of depressive symptoms improves cardiovascularutcomes.22 Thus, the current results call for future re-earch to explore the effect of alleviation of such symp-oms on atherosclerosis and adverse cardiovascular out-omes. Exercise could be 1 of the tools that alleviateepressive symptoms. Researchers have reported sub-tantial benefits of exercise training programs in reducingepressive symptoms.23 Exercise training decreased de-ressive symptoms as effectively as antidepressant med-cation in subjects with depressive symptoms.23

The present study is 1 of the few epidemiologic studieso examine the relation between CCA-IMT and depressiveisorders in subjects aged �65 years. The conclusions ofhe previous few studies9,24–28 were in line with the conclu-ion of the present study; nevertheless, this study had char-cteristics that distinguish it from the other similar studies.ost of the previously conducted studies explored the as-

ociation of the depressive symptoms with CCA-IMT inen only28 or women only.26 One study’s participants were

0% men.27 In the present analysis, men (43.75%) as well asomen (56.25%) were included. Most of the previous stud-

es included middle-aged populations.25–28 One study in-luded subjects aged �65 years.9 Most of the epidemiologictudies conducted to test the relation between depressiveymptoms and atherosclerosis were cross-sectional.9,24–26

he cross-sectional design does not allow the examinationf the temporal association between depressive symptomsnd CCA-IMT as an indicator for atherosclerosis. Twoongitudinal studies assessed the relation between depres-ive symptoms and CCA-IMT. In Haas et al’s27 study,
hich was described as a 10-year longitudinal study, carotid

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1613Miscellaneous/Depressive Symptoms and Atherosclerosis in the Elderly

ltrasonography was not performed at baseline. Therefore,articipants who had atherosclerosis were not excluded.hus, the possibility that those with depressive symptoms ataseline had existing atherosclerosis could not be ignored.27

n the present analysis, those who had abnormal CCA-IMTst baseline were excluded. This allowed the establishmentf temporality between depressive symptoms and CCA-MT as an indicator of atherosclerosis. In another longitu-inal study, conducted by Everson et al,28 the participantsere middle-aged men. In the present study, the participantsere aged �65 years. Subjects aged �65 years have a veryroad spectrum of degree of atherosclerosis. This may helpn detecting an association, which could not be found in aomogenous middle-aged population.9

Several pathways may link depressive symptoms withtherosclerosis. Depressive symptoms are associated withad eating habits, a sedentary lifestyle, a lack of exercise,nhanced sympathetic activity, vascular inflammation, andlatelet activation.29,30 These factors contribute significantlyo the pathway linking the atherosclerosis process withepressive symptoms.29,30

This study should be viewed in the context of its limi-ations. Because of the longitudinal nature of the study,ome participants were lost to follow-up. Participants lost toollow-up were older, had a higher prevalence of depressiveymptoms and chronic diseases (namely, hypertension,eart disease, and abnormal blood glucose), and had thickerCA-IMT values than those who remained in the study

p �0.05). Therefore, the current results likely underesti-ate the true association between depressive symptoms and

ubclinical atherosclerosis. The internal carotid artery car-ies a greater atherosclerotic burden than the CCA. How-ver, because of a considerable amount of missing data forhe internal carotid artery near and far wall readings, inter-al carotid artery intima-media thickness could not be cal-ulated. Therefore, our results using CCA-IMT measuresikely underestimate the association between depressiveymptoms and subclinical atherosclerosis.

1. Djernes JK. Prevalence and predictors of depression in populations ofelderly: a review. Acta Psychiatr Scand 2006;113:372–387.

2. Lett HS, Blumenthal JA, Babyak MA, Sherwood A, Strauman T, RobinsC, Newman MF. Depression as a risk factor for coronary artery disease:evidence, mechanisms, and treatment. Psychosom Med 2004;66:305–315.

3. Stewart RA, North FM, West TM, Sharples KJ, Simes RJ, ColquhounDM, White HD, Tonkin AM. Depression and cardiovascular morbidityand mortality: cause or consequence? Eur Heart J 2003;24:2027–2037.

4. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a riskfactor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med 2004;66:802–813.

5. Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM, KrishnanKR, Nemeroff CB, Bremner JD, Carney RM, Coyne JC, et al. Mooddisorders in the medically ill: scientific review and recommendations.Biol Psychiatry 2005;58:175–189.

6. Abramson J, Berger A, Krumholz HM, Vaccarino V. Depression andrisk of heart failure among older persons with isolated systolic hyper-tension. Arch Intern Med 2001;161:1725–1730.

7. Williams SA, Kasl SV, Heiat A, Abramson JL, Krumholz HM, Vac-carino V. Depression and risk of heart failure among the elderly: aprospective community-based study. Psychosom Med 2002;64:6–12.

8. Elovainio M, Keltikangas-Jarvinen L, Kivimaki M, Pulkki L, Puttonen S,Heponiemi T, Juonala M, Viikari JS, Raitakari OT. Depressive symptomsand carotid artery intima-media thickness in young adults: the Cardiovas-
cular Risk in Young Finns Study. Psychosom Med 2005;67:561–567.
9. Tiemeier H, van Dijck W, Hofman A, Witteman JC, Stijnen T, BretelerMM. Relationship between atherosclerosis and late-life depression: theRotterdam Study. Arch Gen Psychiatry 2004;61:369–376.

0. Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, KronmalRA, Kuller LH, Manolio TA, Mittelmark MB, Newman A, et al. TheCardiovascular Health Study: design and rationale. Ann Epidemiol1991;1:263–276.

1. Tell GS, Fried LP, Hermanson B, Manolio TA, Newman AB, BorhaniNO. Recruitment of adults 65 years and older as participants in theCardiovascular Health Study. Ann Epidemiol 1993;3:358–366.

2. Gerstman BB, Jolson HM, Bauer M, Cho P, Livingston JM, Platt R.The incidence of depression in new users of beta-blockers and selectedantihypertensives. J Clin Epidemiol 1996;49:809–815.

3. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu C, Alaupovic P,Kwong-Fu H, Azen SP. Reduction in carotid arterial wall thicknessusing lovastatin and dietary therapy: a randomized controlled clinicaltrial. Ann Intern Med 1996;124:548–556.

4. Irwin M, Artin KH, Oxman MN. Screening for depression in the olderadult: criterion validity of the 10-item Center for Epidemiological StudiesDepression Scale (CES-D). Arch Intern Med 1999;159:1701–1704.

5. Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening fordepression in well older adults: evaluation of a short form of theCES-D (Center for Epidemiologic Studies Depression Scale). Am JPrev Med 1994;10:77–84.

6. Steffens DC, Helms MJ, Krishnan KR, Burke GL. Cerebrovasculardisease and depression symptoms in the cardiovascular health study.Stroke 1999;30:2159–2166.

7. O’Leary DH, Polak JF, Kronmal RA, Savage PJ, Borhani NO, Kittner SJ,Tracy R, Gardin JM, Price TR, Furberg CD. Thickening of the carotidwall. A marker for atherosclerosis in the elderly? Cardiovascular HealthStudy Collaborative Research Group. Stroke 1996;27:224–231.

8. Aminbakhsh A, Mancini GB. Carotid intima-media thickness mea-surements: what defines an abnormality? A systematic review. ClinInvest Med 1999;22:149–157.

9. Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J. Intima-media thickness: a new tool for diagnosis and treatment of cardiovas-cular risk. J Hypertens 2002;20:159–169.

0. Cheng KS, Mikhailidis DP, Hamilton G, Seifalian AM. A review ofthe carotid and femoral intima-media thickness as an indicator of thepresence of peripheral vascular disease and cardiovascular risk factors.Cardiovasc Res 2002;54:528–538.

1. Miller MD, Schulz R, Paradis C, Houck PR, Mazumdar S, Frank E,Dew MA, Reynolds CF III. Changes in perceived health status ofdepressed elderly patients treated until remission. Am J Psychiatry1996;153:1350–1352.

2. Whooley MA. Depression and cardiovascular disease: healing thebroken-hearted. JAMA 2006;295:2874–2881.

3. Lavie CJ, Milani RV. Adverse psychological and coronary risk profilesin young patients with coronary artery disease and benefits of formalcardiac rehabilitation. Arch Intern Med 2006;166:1878–1883.

4. Tiemeier H, Breteler MM, van Popele NM, Hofman A, Witteman JC.Late-life depression is associated with arterial stiffness: a population-based study. J Am Geriatr Soc 2003;51:1105–1110.

5. Spence JD, Bots ML. Ultrasound measurement of atherosclerosis re-sponse: Carotid intima-media thickness measurements in interventionstudies. Stroke 2004;35:87–88.

6. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, IzzoJL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ.Seventh report of the Joint National Committee on Prevention, Detec-tion, Evaluation, and Treatment of High Blood Pressure. Hypertension2003;42:1206–1252.

7. Haas DC, Davidson KW, Schwartz DJ, Rieckmann N, Roman MJ,Pickering TG, Gerin W, Schwartz JE. Depressive symptoms are inde-pendently predictive of carotid atherosclerosis. Am J Cardiol 2005;95:547–550.

8. Everson SA, Kaplan GA, Goldberg DE, Salonen R, Salonen JT.Hopelessness and 4-year progression of carotid atherosclerosis. TheKuopio Ischemic Heart Disease Risk Factor Study. ArteriosclerThromb Vasc Biol 1997;17:1490–1495.

9. Musselman D, Tomer A, Manatunga A, Knight B, Porter M, Kasey S,Marzec U, Harker L, Nemeroff C. Exaggerated platelet reactivity inmajor depression. Am J Psychiatry 1996;153:1313–1317.

0. Glassman AH, Shapiro PA. Depression and the course of coronary
artery disease. Am J Psychiatry 1998;155:4–11.

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A Comparison by Medicine Residentsof Physical Examination Versus Hand-Carried

Ultrasound for Estimation of Right Atrial Pressure

J. Matthew Brennan, MD, John E. Blair, MD, Sascha Goonewardena, MD, Adam Ronan, MD,Dipak Shah, MD, Samip Vasaiwala, MD, Erica Brooks, MD, Ari Levy, MD,

James N. Kirkpatrick, MD, and Kirk T. Spencer, MD*

Physicians’ ability to accurately estimate right atrial (RA) pressure from bedside evaluationof the jugular venous waveform is poor, particularly when performed by physicians intraining. Conventional ultrasound measurement of the inferior vena cava (IVC) accuratelypredicts RA pressure, but the cost, lack of portability, and specialized training required toacquire and interpret the data render this modality impractical for routine clinical use. Theobjective of this study was to compare physical examination with hand-carried ultrasound(HCU) in the detection of elevated RA pressure (>10 mm Hg). After limited training (4hours didactic and 20 studies), 4 internal medicine residents using an HCU device esti-mated RA pressure from images of the IVC in 40 consecutive patients <1 hour afterright-sided cardiac catheterization. RA pressure was also estimated from examination ofthe jugular venous pulse (JVP) in 40 patients before right-sided cardiac catheterization. RApressure was successfully estimated from HCU images of the IVC in 90% of patients,compared with 63% from JVP examination. The sensitivity for predicting RA pressure >10mm Hg was 82% with HCU and 14% from JVP inspection. Specificities were similarbetween the techniques. Overall accuracies were 71% using HCU and 60% with JVPassessment. In conclusion, internal medicine residents with brief training in echocardiog-raphy can more frequently and more accurately predict elevated RA pressure using HCUmeasurements of the IVC than with physical examination of the JVP. © 2007 Elsevier
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n this study, we sought to compare the accuracies of phys-cal examination and hand-carried ultrasound (HCU), per-ormed by internal medicine residents with limited ultra-ound training, for the estimation of right atrial (RA)ressure using right-sided cardiac catheterization as the goldtandard for comparison.

ethods

he University of Chicago Institutional Review Board ap-roved the protocol. Eighty-four consecutive patients re-erred for right-sided cardiac catheterization were enrolled.ight-sided cardiac catheterization was performed using aow-directed pulmonary artery catheter. After obtainingentral venous access, the catheter was advanced into theight atrium, where RA pressure was acquired after propereroing and calibration. Several cardiac cycles were re-orded, and mean RA pressure was calculated using a he-odynamic software package (Mac-Lab, GE Medical Sys-

ems Information Technologies, Waukesha, Wisconsin).Forty-four patients underwent brief echocardiographic

xaminations using an HCU device (Optigo, Philips Medi-

The University of Chicago, Chicago, Illinois. Manuscript receivedctober 25, 2006; revised manuscript received and accepted January 10,007.

cE-mail address: [email protected] (K.T. Spencer).

al Systems, Andover, Massachusetts). This 6.6-pound de-ice provides 2-dimensional images and has a limited num-er of controls for the adjustment of image depth and gain.mages can be frozen and scrolled for on-line review.

Internal medicine residents with minimal echocardio-raphic exposure and no previous formal training in ultra-onography performed the HCU studies. Each of the resi-ents underwent 4 hours of formal didactic ultrasoundraining and performed 20 sonographer-supervised acquisi-ions and measurements of the inferior vena cava (IVC)rom the subcostal approach. The IVC was assessed with theatient reclined in the supine position �1 hour before orfter catheterization by a resident blinded to the results ofhe catheterization. IVC image quality was rated as poor,air, or good on the basis of prespecified criterion. Pooruality images were omitted from the analysis.

After visualizing the IVC, 3 separate 2-dimensional im-ging loops were acquired, taking care to maximize the IVCiameter throughout the respiratory cycle. Images werehen frozen and reviewed to find the maximum IVCiameter (IVCDmax) during passive respiration within 2.0m of the junction of the IVC and the right atrium.atients were then asked to perform a brief rapid inspi-ation or sniff, and additional loops were recorded. Theinimum IVC diameter (IVCDmin) was then measured as

he smallest IVC size recorded during the sniff. The IVC
ollapsibility index (IVCCI) was calculated using the
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1615Methods/Right Atrial Pressure Using Hand-Carried Ultrasound

ormula [(IVCDmax � IVCDmin)/IVCDmax] � 100. Allalues were the average of 3 measurements.

Forty of the patients who underwent right-sided cardiacatheterization were studied to assess the residents’ abilityo evaluate RA pressure using the jugular venous pulseJVP). A resident blinded to the right-sided cardiac cathe-erization results examined the JVP �1 hour before cathe-erization. The residents estimated mean RA pressure byxamining the JVP using the technique they had learneduring medical school and residency training. The physi-ians did not perform HCU examinations in these patients,ecause they could not have been blinded to their own JVPvaluations of RA pressure.

RA pressure �10 mm Hg was chosen to represent alinically significant elevation in RA pressure. The sensi-ivity and specificity of the resident-performed HCU exam-nations were determined using traditional cutoffs for IVCize and collapsibility (IVCDmax 2.0 cm and IVCCI 50%,espectively).1 Likewise, the sensitivity and specificity ofhe residents’ estimations of RA pressure from JVP exam-nation were determined. Student’s t-test was used to eval-ate intergroup differences, and a weighted � statistic wasomputed for agreement.

esults

dequate ultrasound images were obtained in 90% of pa-ients (60% good quality, 30% fair quality); the remaining 4atients, who had poor image quality, were excluded fromnalysis. Eighty patients, with an average age of 50 � 15ears (65% men, 35% women) and an average body surfacerea of 2.0 � 0.3 m2, were analyzed. Age and body surfacerea did not differ among patients with good, fair, andoor images (p �0.05). The mean RA pressure was 7.4 �.4 mm Hg.

In the hands of medical residents, HCU devices could besed to assess IVC size and collapsibility to estimate RAressure in 90% of cases. An IVCDmax �2 cm had fair toood sensitivity (70%), specificity (80%), and accuracy78%) for predicting RA pressure �10 mm Hg. When anVCCI �50% was used to predict RA pressure �10 mmg, the overall accuracy (68%) was comparable with that of

VC size, with somewhat better sensitivity (90%) but lowerpecificity (60%). IVCCI and IVC size had excellent neg-tive predictive values of 89% and 95%, respectively, withomewhat poor positive predictive values (54% and 43%,espectively). By combining the criteria for IVC collapsibil-ty and size, sensitivity (82%) and specificity (67%) werentermediate to those of either technique alone.

Medical residents failed to visualize the JVP in 37% ofhe 40 patients in whom it was attempted. In these patients,A pressure was neither consistently high nor consistently

ow. RA pressure in subjects with nonvisualized JVPs was5 mm Hg in 5 patients, �5 but �10 mm Hg in 7 patients,

nd �10 mm Hg in 3 patients. The average body surfacerea of patients in whom the JVP was visualized was notignificantly different from those in whom it was not visu-lized (2.06 � 0.29 vs 2.14 � 0.30 m2, p � 0.42). JVPssessment had an accuracy of 60% and specificity of 78%or predicting RA pressure �10 mm Hg in the 63% of
atients in whom it was visualized (Table)1. The residents e
ere particularly poor at distinguishing when the JVP waslevated, identifying this in only 1 of the 7 patients (sensi-ivity 14%). The negative and positive predictive values ofVP (70% and 20%, respectively) were likewise the poorestf all the parameters tested.

The patients were categorized into subgroups of RAressure on the basis of a standard combination of IVCCInd IVCD cutoffs.2 When the patients were grouped intoA pressure ranges by the residents’ HCU measurements asell as their estimations of JVP (Table 1), the agreement forA pressure classification was identical for HCU and JVPstimation (32%). However, the weighted � statistic, whichakes into account the degree of mismatch, was superior forCU (0.42 vs 0.07).The most common misgrouping of RA pressure using

CU was overestimating RA pressure in patients who ac-ually had RA pressures �5 mm Hg. This increased theumber of false-positive elevated RA pressure estimations,ontributing to the somewhat low positive predictive valueor HCU. Conversely, the most common misgrouping ofA pressure by JVP estimation was to assign patients to theto 10 mm Hg group whose RA pressures were either

igher (10 to 15 mm Hg) or lower (�5 mm Hg). Theesidents placed 64% of their JVP estimates in the 5 to0 mm Hg range, whereas only 36% were actually in thatange. These false-negative classifications led to the poorensitivity for JVP.

iscussion

xamination of the JVP is the mainstay of the bedsidestimation of RA pressure and a cornerstone of the cardio-ascular physical examination. The detection of elevatedVPs in patients with heart failure predicts elevated pulmo-ary capillary wedge pressures and portends poorer prog-oses.3–5 However, the JVP is often difficult to accuratelyscertain because of patients’ body habitus, the presence ofugular catheters, an inability to position patients, and pooratient cooperation. This limitation of JVP assessment wasonfirmed in this study, in which medical residents failed toscertain the JVP in 37% of subjects.

Even when the JVP is assessed by experienced examin-

able 1ight atrial pressure classifications by hand-carried ultrasound and

ugular venous pulse examination (percent of patients)

ariable RA Pressure Classification byInvasive Catheterization (mm Hg)

�15 10–15 5–10 �5

A pressure estimation by HCU�15 3 3 0 010–15 9 11 9 145–10 0 3 6 26�5 0 3 3 11A pressure estimation by JVP

examination�15 0 0 0 010–15 0 4 8 85–10 4 20 20 20�5 0 0 8 8

rs, the results are suboptimal.4,6–8 In inexperienced hands,

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he results of JVP examination are even less accurate.9 Aecent abstract compared JVP and central venous pressureeasurements in 64 patients in an intensive care unit after a

raining session designed to instruct physicians in the properethod for JVP assessment.9 These investigators found a

oor correlation between invasive and physical examinationstimation of RA pressure (r � 0.30). Without a specificraining session, the correlation between RA pressure andVP estimation in this study was similarly poor at 0.17. TheVP results do not suggest a systematic error in the tech-ique used to inspect the JVP but rather that residentsended to classify most patients into the “safe” normal rangef 5 to 10 mm Hg.

Using size and collapsibility, ultrasound examination ofhe IVC has proved to be a robust surrogate marker of RAressure.1,10,11 Unfortunately, the size, complexity, and costf a standard-platform ultrasound machine make their use athe point of care difficult. Many of these limitations areeadily addressed with HCU technology.12–16 The substan-ially lower cost of HCU devices as well as their increasedortability and ease of use greatly increase their utility at theoint of care. Not all cardiac findings can be evaluated withhese limited devices; more subtle abnormalities, such aseft ventricular wall motion, are more difficult to discern.17

owever, HCU assessment of the IVC by ultrasound tech-icians has recently been shown to be similar to that of atandard platform (96% agreement, � � 0.87).16 In addition,hese devices are significantly simpler to operate, and theiriagnostic utility by personnel with limited ultrasound train-ng has been proved in multiple clinical settings.17–25

1. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation ofright atrial pressure from the inspiratory collapse of the inferior venacava. Am J Cardiol 1990;66:493–496.

2. Otto CM. Textbook of Clinical Echocardiography. Philadelphia, Penn-sylania: W. B. Saunders, 2004:541.

3. Drazner MH, Rame JE, Stevenson LW, Dries DL. Prognostic impor-tance of elevated jugular venous pressure and a third heart sound inpatients with heart failure. N Engl J Med 2001;345:574–581.

4. Stevenson LW. Are hemodynamic goals viable in tailoring heart fail-ure therapy? Hemodynamic goals are relevant. Circulation 2006;113:1020–1027.

5. Badgett RG, Lucey CR, Mulrow CD. Can the clinical examinationdiagnose left-sided heart failure in adults? JAMA 1997;277:1712–1719.

6. Eisenberg PR, Jaffe AS, Schuster DP. Clinical evaluation compared topulmonary artery catheterization in the hemodynamic assessment ofcritically ill patients. Crit Care Med 1984;12:549–553.

7. Davison R, Cannon R. Estimation of central venous pressure byexamination of jugular veins. Am Heart J 1974;87:279–282.

8. Stein JH, Neumann A, Marcus RH. Comparison of estimates of rightatrial pressure by physical examination and echocardiography in pa-tients with congestive heart failure and reasons for discrepancies. Am JCardiol 1997;80:1615–1618.

9. Demeria DD, MacDougall A, Spurek M, Reid J, Laframboise K,
Taylor-Gjevre RM, Gjevre JA. Comparison of clinical measurement of
jugular venous pressure versus measured central venous pressure.Chest 2004;126:747S-.

0. Nagueh SF, Kopelen HA, Zoghbi WA. Relation of mean right atrialpressure to echocardiographic and Doppler parameters of right atrialand right ventricular function. Circulation 1996;93:1160–1169.

1. Simonson JS, Schiller NB. Sonospirometry: a new method for nonin-vasive estimation of mean right atrial pressure based on two-dimen-sional echographic measurements of the inferior vena cava duringmeasured inspiration. J Am Coll Cardiol 1988;11:557–564.

2. Kirkpatrick JN, Davis A, Decara JM, Hong AE, Kurtz PL, Balasia B,Spencer KT. Hand-carried cardiac ultrasound as a tool to screen forimportant cardiovascular disease in an underserved minority healthcare clinic. J Am Soc Echocardiogr 2004;17:399–403.

3. Kobal SL, Tolstrup K, Luo H, Neuman Y, Miyamoto T, Mirocha J,Naqvi TZ, Siegel RJ. Usefulness of a hand-carried cardiac ultrasounddevice to detect clinically significant valvular regurgitation in hospi-talized patients. Am J Cardiol 2004;93:1069–1072.

4. Rugolotto M, Chang CP, Hu B, Schnittger I, Liang DH. Clinical use ofcardiac ultrasound performed with a hand-carried device in patientsadmitted for acute cardiac care. Am J Cardiol 2002;90:1040–1042.

5. Fedson S, Neithardt G, Thomas P, Lickerman A, Radzienda M, De-Cara JM, Lang RM, Spencer KT. Unsuspected clinically importantfindings detected with a small portable ultrasound device in patientsadmitted to a general medicine service. J Am Soc Echocardiogr 2003;16:901–905.

6. Vourvouri EC, Schinkel AF, Roelandt JR, Boomsma F, Sianos G,Bountioukos M, Sozzi FB, Rizzello V, Bax JJ, Karvounis HI, Polder-mans D. Screening for left ventricular dysfunction using a hand-carried cardiac ultrasound device. Eur J Heart Fail 2003;5:767–774.

7. DeCara JM, Lang RM, Koch R, Bala R, Penzotti J, Spencer KT. Theuse of small personal ultrasound devices by internists without formaltraining in echocardiography. Eur J Echocardiography 2002;4:141–147.

8. Alexander JH, Peterson ED, Chen AY, Harding TM, Adams DB,Kisslo JA Jr. Feasibility of point-of-care echocardiography by internalmedicine house staff. Am Heart J 2004;147:476–481.

9. Decara JM, Kirkpatrick JN, Spencer KT, Ward RP, Kasza K, FurlongK, Lang RM. Use of hand-carried ultrasound devices to augment theaccuracy of medical student bedside cardiac diagnoses. J Am SocEchocardiogr 2005;18:257–263.

0. Hellmann DB, Whiting-O’Keefe Q, Shapiro EP, Martin LD, Martire C,Ziegelstein RC. The rate at which residents learn to use hand-held echo-cardiography at the bedside. Am J Med 2005;118:1010–1018.

1. Kimura BJ, Amundson SA, Willis CL, Gilpin EA, DeMaria AN.Usefulness of a hand-hold ultrasound device for bedside examinationof left ventricular function. Am J Cardiol 2002;90:1038–1039.

2. Kirkpatrick JN, Belka V, Furlong K, Balasia B, Jacobs LD, Corcoran M,Anderson AS, Pastoret A, Spencer KT. Effectiveness of echocardio-graphic imaging by nurses to identify left ventricular systolic dysfunctionin high-risk patients. Am J Cardiol 2005;95:1271–1272.

3. Kobal SL, Trento L, Baharami S, Tolstrup K, Naqvi TZ, Cercek B,Neuman Y, Mirocha J, Kar S, Forrester JS, Siegel RJ. Comparison ofeffectiveness of hand-carried ultrasound to bedside cardiovascularphysical examination. Am J Cardiol 2005;96:1002–1006.

4. Manasia AR, Nagaraj HM, Kodali RB, Croft LB, Oropello JM, Kohli-Seth R, Leibowitz AB, DelGiudice R, Hufanda JF, Benjamin E,Goldman ME. Feasibility and potential clinical utility of goal-directedtransthoracic echocardiography performed by noncardiologist inten-sivists using a small hand-carried device (SonoHeart) in critically illpatients. J Cardiothorac Vasc Anesth 2005;19:155–159.

5. Bruce CJ, Montgomery SC, Bailey KR, Tajik J, Seward JB. Utility ofhand-carried ultrasound devices used by cardiologists with and withoutsignificant echocardiographic experience in the cardiology inpatient
and outpatient settings. Am J Cardiol 2002;90:1273–1275.

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Cardioversion for Atrial Fibrillation: Does Inflammation Matter?

Timothy Watson, MRCP, Puneet Kakar, MRCP, and Gregory Y.H. Lip, MD*

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The long-term maintenance of sinus rhythm after cardio-ersion for atrial fibrillation (AF) has long been acknowledgeds problematic. Even after initial successful restoration of sinushythm, some 53% patients will return to AF over the follow-ng months, whereas only approximately 25% remain in sinushythm at 5 years.1,2 This is despite an aggressive rhythmontrol strategy, using serial attempts at cardioversion andoncomitant antiarrhythmic drug prescription. More recently,he advent of catheter-based (and surgical-based) technologiesas offered the potential of a cure for AF, with some promisingesults,3 but even after these procedures, recurrence, oftensymptomatic, is common, further highlighting the difficultiesncountered in maintaining sinus rhythm.4,5

What contributes to the poor results of cardioversion andong-term maintenance of sinus rhythm? Structural andlectrical remodeling within the atria may perpetuate AF—hat is, “AF begets AF”—admittedly in an experimentaloat model.6 These remodeling changes include progressiveeft atrial dilatation and increasing atrial fibrosis,7 the loss ofate adaptation, and the prolongation of atrial conductivity.8alcium may also accumulate within atrial myocytes,

hereby shortening the atrial refractory period, and hence,romoting the propagation of multiple wavelet reentry cir-uits.7 The net result is that the biophysical properties oftrial tissue are altered at microscopic and macroscopicevels in AF,9 thereby serving to perpetuate the arrhythmia.

Does inflammation have a role in this, contributing to theerpetuation and maintenance of AF? Although the precisetimulus for the initiation of these atrial changes remainsoorly understood, an increasing body of evidence suggestshat inflammation may be central to this pathogenic pro-ess.10 The histology of atrial biopsies taken from patientsith AF has demonstrated evidence of inflammatory infil-

rates and oxidative damage within the atrial tissue.11,12 Ofourse, these changes may clearly be a consequence of thearious underlying co-morbidities that commonly associateith AF (e.g., ischemic heart disease, hypertension, diabe-

es mellitus). However, this observation holds true even forhose with lone AF, thereby raising the possibility thatnflammation may still play some role in the initiation ofF, at least in this patient group.12

Systemic indexes of inflammation are also reported inF.10 For example, C-reactive protein (CRP) is a circulating

cute-phase reactant and is considered the prototypic down-tream marker of inflammation.13,14 CRP is synthesized byhe liver in response primarily to interleukin-6 (IL-6) but alsoo interleukin-1. Many markers of inflammation exist, but

University Department of Medicine, City Hospital, Birmingham,nited Kingdom. Manuscript received December 28, 2006; revised manu-

cript revised and accepted December 28, 2006.*Corresponding author: Tel: 44-0-121-507-5080; fax: 44-0-121-554-

083.
aE-mail address: [email protected] (G.Y.H. Lip).

igh-sensitivity CRP (hs-CRP) is probably the most robust andeproducible.14 Indeed, there is a consistent, significant asso-iation between baseline hs-CRP levels and cardiovascularisk, an association that holds true across many popula-ions.14,15 hs-CRP also appears to correlate with an increasingF burden and is associated with the persistence of AF.16,17

urthermore, hs-CRP levels appear to correlate with increasinguration of AF and left atrial size, effectively supporting linksmong inflammation, AF burden, and structural remodeling.18

n addition to being predictive for the future development ofF, hs-CRP is as a consistent predictor of early relapse after

uccessful cardioversion for AF, even after adjustment foronfounding factors, such as hypertension and ischemic heartisease.10

Although many studies have demonstrated the potentialmportance of CRP, the role of IL-6 remains questionable.lthough Roldan et al19 reported increased levels of IL-6 inatients with AF, this would appear to be related to underlyingo-morbidities such as hypertension and coronary artery dis-ase rather than directly related to AF per se. This has fueledpeculation that abnormalities of inflammation in AF mayimply reflect the various co-morbidities that often coexist.

Given the prognostic value of inflammatory indexes inardiovascular disease, what is the prognostic value in AF?he relation between AF and excess morbidity and mortal-

ty is irrefutable. Specifically, there is a high risk for strokend thromboembolism, for which there is evolving evidencehat AF may contribute to a hypercoagulable state.20 Al-hough the precise mechanisms that “drive” this process re-ain poorly understood, it is plausible that inflammation may

erald an important avenue of investigation. Indeed, Conwayt al21 were able to establish that elevated IL-6 levels were anndependent predictor of the composite of stroke or death in aohort of high-risk patients with AF. More recently, Lip et al22

nvestigated the associations among CRP, CD40 ligand (aarker of platelet activation with links to inflammation), and

troke risk in patients with AF. This study revealed a signifi-ant positive association between elevated CRP levels, but notD40 ligand, and stroke risk, as well as prognosis (mortality,ascular events).

Given the consistent association between AF and inflam-ation, are the abnormalities noted simply a consequence of

he various confounding factors that commonly coexist withF and that may also contribute to an inflammatory re-

ponse in their own right? The link would appear to remainomewhat tenuous with questions remaining on “cause andffect.” Despite this, there remains a great deal of interest inharmacologic agents that may modify the inflammatoryrocess, in particular drugs that modulate the renin-angio-ensin-aldosterone system (RAAS).10 Of note, angiotensinI has been shown to possess a number of proinflammatoryroperties. In particular, this hormone increases the produc-ion of proinflammatory cytokines (e.g., IL-6 and tumorecrosis factor-�), adhesion molecules (e.g., vascular cell
dhesion molecule-1), monocyte chemoattractant protein-1,
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nd selectins (e.g., P-selectin).23,24 Similarly, through theelease of various chemokines (e.g. cytokine-induced neu-rophil chemoattractant), angiotensin II is able to initiateeutrophil recruitment.24 Importantly, atrial tissue expressesngiotensin-converting enzyme and angiotensin II recep-ors25 and thereby holds the capacity for the local produc-ion and utilization of angiotensin II. There is also histologicvidence to support the upregulation of these receptors inF,26 with the expression of angiotensin II receptors being

inked with increased atrial cell death and leukocyte infil-ration. All these would support a potential (complex) rela-ion among the RAAS, inflammation, and AF.

In this issue of the American Journal of Cardiology,veit et al27 report on the effect of candesartan and various

nflammatory markers on the maintenance of sinus rhythmfter cardioversion for AF. Unsurprisingly, their studyhowed that low levels of hs-CRP and E-selectin at baselineere consistent with a greater probability of cardioversion

uccess at 6 months; however, this did not hold true forther inflammatory markers, notably IL-6, CD40 ligand,nd tumor necrosis factor-�. Rather curiously, despite firminks among AF, inflammation, and the RAAS, the investi-ators found no evidence that candesartan affected the var-ous markers of inflammation at baseline. Interestingly,veit et al27 demonstrated that the restoration and mainte-ance of sinus rhythm for 6 months had little impact oneducing hs-CRP levels.

Although these data may well be tainted by the complex-ties of investigating any group of patients with numerouso-morbidities, this must surely strengthen the argument thatnflammation in AF is simply a reflection of underlying vas-ular disease. Perhaps a holistic approach to AF is needed, withcomprehensive clinical assessment and management of all

o-morbid risk factors and appropriate “upstream” therapieshat address various aspects of cardiovascular risk reduction,ncluding RAAS blockade, good blood pressure control,mega-3 fatty acids, and statins. Central to AF managementust also be appropriate risk stratification and antithrombotic

herapy. Only then can our management of this common ar-hythmia—AF is being described as the “new epidemic”—ruly improve.

1. Crijns HJ, Van Gelder IC, Van der Woude HJ, Grandjean JG, Tiele-man RG, Brugemann J, De Kam PJ, Ebels T. Efficacy of serialelectrical cardioversion therapy in patients with chronic atrial fibrilla-tion after valve replacement and implications for surgery to cure atrialfibrillation. Am J Cardiol 1996;78:1140–1144.

2. Bertaglia E, D’Este D, Zerbo F, Zoppo F, Delise P, Pascotto P. Success ofserial external electrical cardioversion of persistent atrial fibrillation in main-taining rhythm; a randomized study. Eur Heart J 2002;23:1522–1528.

3. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G,Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneousinitiation of atrial fibrillation by ectopic beats originating in the pul-monary veins. N Engl J Med 1998;339:659–666.

4. Hindricks G, Piorkowski C, Tanner H, Kobza R, Gerds-Li JH, Car-bucicchio C, Kottkamp H. Perception of atrial fibrillation before andafter radiofrequency catheter ablation: relevance of asymptomatic ar-rhythmia recurrence. Circulation 2005;112:307–313.

5. Karch MR, Zrenner B, Deisenhofer I, Schreieck J, Ndrepepa G, DongJ, Lamprecht K, Barthel P, Luciani E, Schomig A, Schmitt C. Freedomfrom atrial tachyarrhythmias after catheter ablation of atrial fibrilla-tion: a randomized comparison between 2 current ablation strategies.Circulation 2005;111:2875–2880.

6. Wijffels MC, Kirchhof CJ, Dorland R, Power J, Allessie MA. Electrical
remodeling due to atrial fibrillation in chronically instrumented conscious
goats: roles of neurohumoral changes, ischemia, atrial stretch, and highrate of electrical activation. Circulation 1997;96:3710–3720.

7. Boldt A, Wetzel U, Lauschke J, Weigl J, Gummert J, Hindricks G,Kottkamp H, Dhein S. Fibrosis in left atrial tissue of patients withatrial fibrillation with and without underlying mitral valve disease.Heart 2004;90:400–405.

8. Hertervig EJ, Yuan S, Carlson J, Kongstad-Rasmussen O, Olsson SB.Evidence for electrical remodelling of the atrial myocardium in patientswith atrial fibrillation. A study using the monophasic action potentialrecording technique. Clin Physiol Funct Imaging 2002;22:8–12.

9. Spach MS, Dolber PC. Relating extracellular potentials and theirderivatives to anisotropic propagation at a microscopic level in humancardiac muscle. Evidence for electrical uncoupling of side-to-side fiberconnections with increasing age. Circ Res 1986;58:356–371.

0. Boos CJ, Anderson RA, Lip GY. Is atrial fibrillation an inflammatorydisorder? Eur Heart J 2006;27:136–149.

1. Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van WagonerDR, Bauer JA. Impaired myofibrillar energetics and oxidative injuryduring human atrial fibrillation. Circulation 2001;104:174–180.

2. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A.Histological substrate of atrial biopsies in patients with lone atrialfibrillation. Circulation 1997;96:1180–1184.

3. Venugopal SK, Devaraj S, Jialal I. Effect of C-reactive protein onvascular cells: evidence for a proinflammatory, proatherogenic role.Curr Opin Nephrol Hypertens 2005;14:33–37.

4. Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ,Verma S. New markers of inflammation and endothelial cell activa-tion, part I. Circulation 2003;108:1917–1923.

5. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, MassaroJM, D’Agostino RB, Franzblau C, Wilson PW. Plasma concentrationof C-reactive protein and risk of ischemic stroke and transient ischemicattack: the Framingham study. Stroke 2001;32:2575–2579.

6. Sata N, Hamada N, Horinouchi T, Amitani S, Yamashita T, MoriyamaY, Miyahara K. C-reactive protein and atrial fibrillation. Is inflamma-tion a consequence or a cause of atrial fibrillation? Jpn Heart J2004;45:441–445.

7. Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, CarnesCA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, Van Wagoner DR.C-reactive protein elevation in patients with atrial arrhythmias: inflam-matory mechanisms and persistence of atrial fibrillation. Circulation2001;104:2886–2891.

8. Watanabe T, Takeishi Y, Hirono O, Itoh M, Matsui M, Nakamura K,Tamada Y, Kubota I. C-reactive protein elevation predicts the occur-rence of atrial structural remodeling in patients with paroxysmal atrialfibrillation. Heart Vessels 2005;20:45–49.

9. Roldan V, Marin F, Blann AD, Garcia A, Marco P, Sogorb F, Lip GY.Interleukin-6, endothelial activation and thrombogenesis in chronicatrial fibrillation. Eur Heart J 2003;24:1373–1380.

0. Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleu-kin-6 and C-reactive protein to the prothrombotic state in chronic atrialfibrillation. J Am Coll Cardiol 2004;43:2075–2082.

1. Conway DS, Buggins P, Hughes E, Lip GY. Prognostic significance ofraised plasma levels of interleukin-6 and C-reactive protein in atrialfibrillation. Am Heart J 2004;148:462–466.

2. Lip GY, Patel JV, Hughes E, Hart RG. High sensitivity C-reactiveprotein and soluble CD40 ligand as indices of inflammation andplatelet activation in 880 patients with nonvalvular atrial fibrillation:relationship to stroke risk factors, stroke risk stratification schema andprognosis. Stroke 2007;38:1229–1237.

3. Das UN. Is angiotensin-II an endogenous pro-inflammatory molecule?Med Sci Monit 2005;11:155–162.

4. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J.Inflammation and angiotensin II. Int J Biochem Cell Biol 2003;35:881–900.

5. Ohmichi N, Iwai N, Shimoike H, Izumi M, Watarida S, Mori A,Nakamura Y, Kinoshita M. Assessment of the angiotensin II-formingpathway in human atria. Heart Vessels 1997(suppl):116–118.

6. Goette A, Staack T, Rocken C, Arndt M, Geller JC, Huth C, AnsorgeS, Klein HU, Lendeckel U. Increased expression of extracellular sig-nal-regulated kinase and angiotensin-converting enzyme in humanatria during atrial fibrillation. J Am Coll Cardiol 2000;35:1669–1677.

7. Tveit A, Seljeflot I, Grundvold I, Abdelnoor M, Smith P, Arnesen H.Effect of candesartan and various inflammatory markers on mainte-nance of sinus rhythm after electrical cardioversion for atrial fibrilla-
tion. Am J Cardiol 2007;99:1544–1548.

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A New Generation of Coronary Vasodilators in Stress PerfusionImaging

Ami E. Iskandrian, MDa,*

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Although the cardiovascular effects of adenosine have beentudied for almost 8 decades,1,2 it was not until 1990 that therst report was published on the use of adenosine in stressyocardial perfusion imaging (MPI) with radiotracers.3 In

995, adenosine (Adenoscan, Astellas, Deerfield, Illinois) waspproved by the U.S. Food and Drug Administration for stressesting (adenosine, in the form of Adenocar (Astellas), waspproved earlier in 1990 for the treatment of supraventricularachycardia). At present, Adenoscan is used in approximately0% of patients who undergo pharmacologic stress MPI, andasodilator MPI is the fastest growing segment, accounting forpproximately 40% of the roughly 8.5 million stress MPItudies performed annually in the United States alone. Aden-sine is also used in other stress imaging modalities, such as-dimensional echocardiography and magnetic resonance im-ging, and in cardiac catheterization laboratories (either inravenous or intracoronary) to study coronary hemodynamicssessment, where for practical purposes it has replaced intra-oronary papaverine.1,2

Adenosine is a naturally occurring ligand of 4 distinctubtypes of cell membrane G-protein coupled recep-ors.1,2,4–6 The synthesis and elimination pathways are wellescribed. The activation of A-2a receptors is responsibleor coronary vasodilatation and an increase in myocardiallood flow (MBF). Unlike in exercise, the increase in MBFs not related to double product, and there is no indicationhat combining exercise with adenosine causes the furtherugmentation of MBF. A modest increase in heart rate isost likely due to direct sympathetic stimulation, not to theodest decrease in blood pressure.5 This sympathetic stim-

lation is also the result of A-2a receptor activation. Acti-ation of the other receptor subtypes (A-2b, A-1, and A-3)s responsible for myriad consequences both desirable (suchs cardiac protection) and undesirable (as side effects).hese side effects include atrioventricular block, broncho-pasm, nonangina chest pains, shortness of breadth, markedypotension, flushing, and headaches. Furthermore, adeno-ine needs to be infused with an infusion pump over 4 to 6inutes in a dose that is adjusted for body weight. Adeno-

ine is popular principally because the degree of coronaryyperemia is predictable at or near maximum and becausedenosine has an extremely short half-life of about 1 sec-nd.1,2,7 For any new stress agent to be considered anlternative to adenosine, it must meet the challenges ofafety, tolerability, potency, short duration of action, andase of administration.

aDivision of Cardiovascular Diseases, Department of Medicine, Uni-ersity of Alabama at Birmingham, Birmingham, Alabama. Manuscripteceived June 20, 2006; revised manuscript received and accepted June 26,006.

hE-mail address: [email protected] (A.E. Iskandrian).

elective A-2a Agonists

urrently, there are 3 such agents in phase III clinical trials.hese agents are hoped to have the desirable features butone of the side effects of adenosine, because that is whatelectivity implies. These agents are regadenoson, binode-oson, and apadenoson. A forth agent (CGS21680) wastudied only in an animal model and is not likely to enterlinical testing.8 The 3 agonists share a common feature ofelectivity, but they do differ in affinity, onset of action,uration of hyperemia, and dosing regimen (fixed oreight-adjusted dose). For example, regadenoson is given

ntravenously as a fixed-dose bolus, whereas binodenosonnd apadenoson are given as weight-adjusted boluses.9,10 Axed dose is more attractive, because it decreases thehances of errors in dosing.

The potency to augment MBF depends on the affinity ofhe agonist for the receptor, the density of the receptors inhe coronary vessels, the intrinsic efficacy of the boundgonist to activate the receptors, and the receptor reserve.4,6

Affinity is defined as the ratio between the rate of drugissociation or release from receptors and the rate of drugssociation or binding to the receptors. Affinity determineshe duration of action. Agonists with high affinity haveonger durations of action than drugs with low or moderateffinity. This difference in affinity could explain the longeruration of hyperemia of binodenoson than regadenosonnd adenosine. Receptor subtype selectivity is concentrationor dose) dependent, which may explain in part why someon-A-2a side effects have been reported with all 3 “selec-ive” agonists; alternatively, some of these side effectsight be produced by A-2a activation and sympathetic

timulation.4,6

In this issue of the American Journal of Cardiology,odgson et al11 present the coronary hemodynamic re-

ponses, measured with the Doppler catheter, in 133 pa-ients after binodenoson administration. This was not aose-response study; each patient at the 18 recruiting cen-ers received 1 of the 5 prespecified doses (0.3, 0.5, or 1g/kg/min by infusion or 1.5 or 3 �g/kg as intravenousolus). Although the 1.5 �g/kg bolus produced coronaryyperemia equivalent to that of intracoronary adenosine,nd the duration of hyperemia was dose related, the range ofugmentation of MBF, the time to peak effect, and theuration of hyperemia were quite variable and unpredictablesee Table 4 in Hodgson et al11). The predictability andonsistency of these parameters are of paramount impor-ance in stress MPI, especially if the stress agent is given as

bolus, because if the radiotracer is injected before peakyperemia is achieved, ischemia detection could be com-romised. This scenario is quite unlike that seen with aden-sine, which is given as an infusion, with the tracer injected
alfway through the infusion. These concerns notwithstand-
www.AJConline.org

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ng, a phase II trial showed comparable MPI results betweeninodenoson and adenosine.9 Patient selection, the severityf stenosis, and a small sample size might hide importantifferences between binodenoson and adenosine, and theesults of a phase III trial would be of great importance. Theurvilinear relation between peak MBF and tracer extrac-ion, especially with technetium-99m-based tracers, mightlso lower the discordance rates between the 2 agents. Theesults of a phase III trial with 1 of the 3 selective A-2agonists showed that regadenoson given as a fixed dose andrapid bolus provided diagnostic information comparableith that obtained using a standard 6-minute adenosine

nfusion.Do we need a new and improved adenosine, which is 1

ay of looking at these elective agonists? The answer is yes,rovided they can offer results comparable with thosechieved using adenosine; can be given as a bolus; have auration of action that is long enough for tracer extraction toe complete but short enough to limit monitoring time, withts associated risk, side effects, and costs of monitoring;ave similar or better side-effect and tolerability profiles asdenosine; and are priced competitively. Head-to-headomparisons between the 3 selective agonists are not yetvailable. More data are also needed on their use in specialatient groups, such as those with bronchospastic lung dis-ase, second-degree or higher atrioventricular block, andeft bundle branch block in which excessive tachycardiaight produce rate-related septal defects in the absence of

esions in the left anterior descending artery, and on theirnteraction with caffeine. A recent report showed that a lowevel of caffeine concentration did not alter the resultsbtained with adenosine MPI.12 Finally, the results in dia-etic patients are of extreme interest, because adenosineffects insulin levels, and insulin and glucose levels affecteak MBF.13 The report by Hodgson et al11 is much neededo better understand how to use this particular agonist intress MPI.

1. Iskandrian AE, Verani MS, eds. Nuclear Cardiac Imaging: Principlesand Applications. 3rd ed. New York: Oxford University Press, 2003:
164–189.
2. Iskandrian AS, Verani MS, Heo J. Pharmacologic stress testing: mech-anism of action, hemodynamic responses, and results in detection ofcoronary artery disease. J Nucl Cardiol 1994;1:94–111.

3. Verani MS, Mahmarian JJ, Hixson JB, Boyce TM, Staudacher RA.Diagnosis of coronary artery disease with adenosine and thallium-201scintigraphy in patients unable to exercise. Circulation 1990;82:80–87.

4. Shryock JC, Snowdy S, Baraldi PG, Cacciari B, Spalluto G, MonopoliA, Ongini E, Baker SP, Belardinelli L. A2A-adenosine receptor re-serve for coronary vasodilation. Circulation 1998;98:711–718.

5. Biaggioni I, Killian TJ, Mosqueda-Garcia R, Robertson RM, Robert-son D. Adenosine increases sympathetic nerve traffic in humans.Circulation 1991;83:1668–1675.

6. Belardinelli L, Shryock JC, Snowdy S, Zhang Y, Monopoli A, LozzaG, Ongini E, Olsson RA, Dennis DM. The A2A adenosine receptormediates coronary vasodilation. J Pharmacol Exp Ther 1998;284:1066–1073.

7. Cerqueira MD, Verani MS, Schwaiger M, Heo J, Iskandrian AS.Safety profile of adenosine stress perfusion imaging: results from theAdenoscan Multicenter Trial Registry. J Am Coll Cardiol 1994;23:384–389.

8. He ZX, Cwajg E, Hwang W, Hartley CJ, Funk E, Michael LH, VeraniMS. Myocardial blood flow and myocardial uptake of 201Tl and 99mTc-sestamibi during coronary vasodilation induced by CGS-21680, aselective adenosine A2A receptor agonist. Circulation 2000;102:438–444.

9. Udelson JE, Heller GV, Wackers FJT, Chai A, Hinchman D, ColemanPS, Dilsizian V, Dicarli M, Hachamovitch R, Johnson JR, et al.Randomized controlled dose-ranging study of the selective adenosineA2a-adenosine receptor reserve for coronary vasodilatation. Circula-tion 2004;109:457–464.

0. Hendel RC, Bateman TM, Cerqueira MD, Iskandrian AE, Leppo JA,Blackburn B, Mahmarian JJ. Initial clinical experience with regade-noson, a novel selective A2A agonist for pharmacologic stress single-photon emission computed tomography myocardial perfusion imaging.J Am Coll Cardiol 2005;46:2069–2075.

1. Hodgson J McB, Dib N, Kern MJ, Bach RG, Barrett RJ. Coronarycirculation responses to binodenoson, a selective adenosine A2a recep-tor agonist. Am J Cardiol 2007;99:1507–1512.

2. Zoghbi GJ, Htay T, Aqel R, Blackmon L, Heo J, Iskandrian AE. Effectof caffeine on ischemia detection by adenosine single-photon emissioncomputed tomography perfusion imaging. J Am Coll Cardiol 2006;47:2296–2302.

3. Srinivasan M, Herrero P, McGill JB, Bennik J, Heere B, Lesniak D,Davila-Roman VG, Gropler RJ. The effects of plasma insulin andglucose on myocardial blood flow in patients with type 1 diabetes
mellitus. J Am Coll Cardiol 2005;46:42–48.

READERS’ COMMENTS

Alcohol-Induced Hypertension—JustHow Much of a CardiovascularRisk Factor?

In their recent report, Klatsky et al1concluded that “the risks of hyperten-sion are similar regardless of amount ofalcohol consumption.” Their conclusionwas supported by data in their cohortshowing similar risk ratios of death be-tween never drinkers and those whoconsumed �3 drinks/day.

We are somewhat puzzled by the di-chotomous views taken by the investi-gators in discussing their study. Theystated in the discussion that “hyperten-sion at any drinking level is far frombenign and that alcohol-associated hy-pertension belongs on the list of reasonsto avoid heavy drinking.” Although weagree with this statement per se, itseems to be a non sequitur to the inves-tigators’ data. Lower risks (p �0.001)for those who reported consuming 1 to2 drinks/day were found for all deathand hospitalization outcomes (the rela-tive risk was 0.8 for all cardiovasculardeaths and 0.8 for cardiovascular hos-pitalizations). In that same patientgroup, the intake of 1 to 2 drinks/daywas related to an increased risk for anoutpatient diagnosis of hypertension(odds ratio 1.1, 95% confidence interval1.1 to 1.2, p �0.001). Would this notindirectly indicate that alcohol-associ-ated hypertension conferred a lowerrisk, at least in those drinking only 1 to2 drinks/day? In addition, former drink-ers had the highest risk for dying fromcoronary artery disease in all 3 bloodpressure strata.

Very similar data were recently re-ported by Beulens et al2 in 11,711 menwith hypertension from the Health Pro-fessionals Follow-Up Study. Theyfound that moderate alcohol consump-tion was associated with a decreasedrisk for coronary artery disease and con-cluded that men with hypertension who

drink moderately and safely may notneed to change their drinking habits.

We certainly do not want to advisecardiac patients to uncritically increasetheir alcohol intake and are well awareof the hazards of excessive alcohol con-sumption. However, by discussing is-sues not directly related to their find-ings, it seems to us that Klatsky et al1invited the misinterpretation of a largeand complicated data set and backedaway from their data.

Aslam Khan, MD

Franz Messerli, MD

New York, New York10 January 2007

1. Klatsky AL, Koplik S, Gunderson E, Kipp H,Friedman GD. Sequelae of systemic hyperten-sion in alcohol abstainers, light drinkers, andheavy drinkers. Am J Cardiol 2006;98:1063–1068.

2. Beulens JW, Rimm EB, Ascherio A,Spiegelman D, Hendriks HF, Mukamal KJ.Alcohol consumption and risk for coronaryheart disease among men with hypertension.Ann Intern Med 2007;146:10–19.

doi:10.1016/j.amjcard.2007.01.015

Reply: We thank Drs. Khan and Mes-serli for their perceptive comments.As they (and our report) point out, thesituation is the result of 3 relations.First is the increased prevalence ofand risk for systemic hypertension inheavier drinkers. Second is the low-ered risk for coronary artery disease inlight to moderate drinkers. Third isthe increased risk for cardiovascularsequelae in patients with hyperten-sion. It is thus correct that patientsreporting 1 to 2 drinks/day simulta-neously have lower coronary arterydisease risk and a slightly greater riskfor hypertension. Hypertension is only1 of the coronary artery disease riskfactors, and moderate drinking favor-ably affects several others. Further-more, only a small proportion of sub-jects with blood pressures �140/90mm Hg reporting 1 to 2 drinks/dayhave alcohol-induced hypertension.The increased risk for hypertension inthese moderate drinkers was approxi-mately 10%, making it likely that ap-proximately 90% had hypertension forother reasons. As we pointed out inour report, we had no way to tell

which patients with alcohol-associ-ated hypertension had alcohol as thecause.

In our statement quoted and ques-tioned by Khan and Messerli,1 weshould have used the term “alcohol-induced hypertension” instead of “al-cohol-associated hypertension” as areason to avoid heavy drinking, andwe regret any resulting misunder-standing.

Although we believe strongly thatmedical advice about drinking alcoholneeds to be individualized, we agreethat a typical moderate drinker with hy-pertension would not be better off toquit drinking. What would almostsurely benefit such a patient would bethe control of hypertension.

Arthur L. Klatsky, MD

Sheri Koplik, MD

Erica Gunderson, PhD

Harald Kipp

Gary D. Friedman, MD

Oakland, California30 January 2007

doi:10.1016/j.amjcard.2007.01.016

Can Multislice ComputedTomography in an AsymptomaticHigh-Risk Population Really Impacton Therapeutic Decision-Making?

We read with interest the report byRomeo el al1 on multislice computedtomography in an asymptomatic, high-risk population. We believe that somepoints should be outlined before recom-mending the use of computed tomo-graphic (CT) coronary angiography in ahigh-risk population. First of all, wehave some doubts regarding the role ofthis new diagnostic technology in theprevention of acute coronary syndromesin asymptomatic patients, as stated bythe Romeo et al1: revascularization inthe absence of angina or documentedischemia is recommended only for pa-tients with left main coronary artery,proximal left anterior descending coro-nary artery, or 3-vessel disease,2 a pop-ulation that is poorly represented insuch series of revascularized patients.Indeed, only 15 of 39 patients met thesecriteria for revascularization.

Second, the presence of coronary ar-tery disease not associated with angina or

*Letters (from the United States) concerning aparticular article in The American Journal of Car-diology� must be received within 2 months of thearticle’s publication, and should be limited (withrare exceptions) to 2 double-spaced typewrittenpages. Two copies must be submitted.

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org

documented ischemia, is a poor predictorof coronary events and the need for re-vascularization by percutaneous coronaryintervention or coronary artery bypassgrafting; indeed, it is a class III recom-mendation (“not indicated”) in the recentAmerican College of Cardiology/Ameri-can Heart Association/Society for Cardio-vascular Angiography and Interventions2

guideline for percutaneous coronary inter-vention.

Third, the study was conducted us-ing 16-slice CT equipment, which isnot longer the best equipment withwhich to perform coronary CT an-giography. It is difficult to believe that100% sensitivity and 98% specificitycould be obtained with such equip-ment; recently, Pugliese et al3 re-ported with 64-slice equipment sensi-tivity of 99%, specificity of 96%,positive predictive value of 78%, andnegative predictive value of 99% on aper segment basis. Although Romeoet al1 should be congratulated for theirresults, we believe that when 124-

slice CT equipment is available in thenear future, coronary CT angiographylikely will drive the therapeutic deci-sion-making process.4

Paolo Cardaioli, MD

Gianluca Rigatelli, MD

Rovigo, Italy8 February 2007

1. Romeo F, Leo R, Clementi F, Razzini C, BorziM, Martuscelli E, Pizzuto F, Chiricolo G,Mehta JL. Multislice computed tomography inan asymptomatic high-risk population. Am JCardiol 2007;99:325–328.

2. Smith SC Jr, Feldman TE, Hirshfeld JW Jr,Jacobs AK, Kern MJ, King SB III, MorrisonDA, O’Neill WW, Schaff HV, Whitlow PL, etal; American College of Cardiology/AmericanHeart Association Task Force on PracticeGuidelines; American College of Cardiology/American Heart Association/Society for Car-diovascular Angiography and InterventionsWriting Committee to Update the 2001 Guide-lines for Percutaneous Coronary Intervention.ACC/AHA/SCAI 2005 guideline update forpercutaneous coronary intervention—sum-mary article: a report of the American Collegeof Cardiology/American Heart AssociationTask Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the

2001 Guidelines for Percutaneous CoronaryIntervention). Circulation 2006;113:156175.

3. Pugliese F, Mollet NR, Runza G, vanMieghem C, Meijboom WB, Malagutti P,Baks T, Krestin GP, deFeyter PJ, CademartiriF. Diagnostic accuracy of non-invasive 64-slice CT coronary angiography in patients withstable angina pectoris. Eur Radiol 2006;16:575–582.

4. Rigatelli G. Calcified plaque: the Achilles’heel of present computed tomography coro-nary angiography for the elderly? J GeriatrCardiol 2006;3:123–124.

doi:10.1016/j.amjcard.2007.02.010

CorrectionIn Butler et al’s “Comparison of

multidetector computed tomography andtwo-dimensional transthoracic echocardi-ography for left ventricular assessment inpatients with heart failure,” (Am J Cardiol2007;99:247–249), Dr. Neilan’s nameand Dr. Jassal’s name are incorrect. Thecorrect names Tomas G. Neilan andDavinder S. Jassal.

doi:10.1016/j.amjcard.2007.02.011


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