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Journal of the American College of Cardiology Vol. 47, No. 2, 2006© 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00P

EAR IN CARDIOLOGY SERIES

he Year in Valvular Heart Diseasehahbudin H. Rahimtoola, MB, FRCP, MACP, MACC, DSC(HON)

ublished by Elsevier Inc. doi:10.1016/j.jacc.2005.11.023

os Angeles, California

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ERITABLE COMPONENTF VALVULAR HEART DISEASE (VHD)

he Utah Population Database is a population-based gene-logical resource composed of Utah pioneers and theirescendants that contains electronic records of 2,237,324

ndividuals. The familial relative risk of death for age �65ears was four times higher in first-degree relatives of thoseith aortic valve disease (Table 1) (1).

THEROSCLEROSIS, CALCIFICATION,ND BONE FORMATION IN VALVES

alcific aortic stenosis (AS). Early lesions are similar totherosclerosis, with prominent accumulation of “athero-enic” lipoprotein, including low-density lipoprotein (LDL)nd lipoprotein(a), evidence of LDL oxidation, an inflam-atory cell infiltrate, and microscopic calcification. In late

esions, there are more prominent accumulation of lipid cellsnd extracellular matrix (Fig. 1) (2).

itral valve. Rabbits fed a 1.0% cholesterol diet showedn increase in connective tissue and collagen formation,ncreased myofibroblast proliferating cell nuclear antigen-taining and alpha-actin-positive staining cells, macro-hages, significant deposition of osteopontin, and increased

evels of osteopontin ribonucleic acid expression. Rabbitsed cholesterol and atorvastatin showed markedly lowertherosclerotic lesions (Fig. 2) (3).heumatic valves. Calcification within the rheumatic

alves was not seen in degenerative or normal valves.ascular endothelial growth factor was present in areas of

nflammation. Immunohistochemistry localized osteopontinnd osteocalcin to areas of smooth muscle cells withinicrovessels and proliferating myofibroblast, and their pro-

ein expression was upregulated in the calcified rheumaticalves (Fig. 3) (4).

From the Division of Cardiovascular Medicine, Department of Medicine,AC�USC Medical Center, Keck School of Medicine, University of Southernalifornia, Los Angeles, California. Dr. Rahimtoola is a Distinguished Professor,niversity of Southern California; the George C. Griffith Professor of Cardiology;

nd a Professor of Medicine, Keck School of Medicine at USC. This review includesrticles published from July 2004 to June 2005, with one exception. Dr. Rahimtoolaas received honoraria from ATS; Edwards Life-Sciences; St. Jude Medical; Pfizer;merican College of Physicians; the American College of Cardiology Foundation;

ndiana University; the University of California, Los Angeles; the University ofalifornia, Irvine; Northwestern University; Cornell University; Creighton Univer-

ity; Thomas Jefferson University; Cedars-Sinai Medical Center; Harvard Medical

�chool; and the University of Wisconsin.Manuscript received September 22, 2005, accepted November 9, 2005.

ORTIC STENOSIS

ardiovascular magnetic resonance imaging (CMR) inS. The intra- and interobserver variability of aortic valve

rea (AVA) by CMR ranged from �0.18 to �0.13 cm2 androm �0.11 to 0.16 cm2. Patients underwent CMR 7 � 5ays after cardiac catheterization (CC; n � 39); 10 � 8 daysfter transthoracic echocardiography (TTE; n � 41); and� 5 days after transesophageal echocardiography (TEE;� 35). The sensitivity and specificity to detect AVA �0.8

m2 by CC for CMR was 78% and 79%; for TTE was 74%nd 67%, and for TEE was 70% and 70% (5).

OMMENT. There was a time delay between CMR andther tests, but the procedural reproducibility of CMR wasot documented. Performance of CC may have been lesshan ideal because aortic pressure was measured by “pullack;” also, the method of determining oxygen consumptions not given. Sensitivity and specificity to detect AVA �1.0m2 is not given but would have been of value to know.

here is end-systole in aortic pressure tracing to assessVA? Animal experimental AS showed the location of endf systolic outflow at the incisura may occur after leftentricular (LV) pressure has fallen below aortic pressure, atimes called “hang out.” It occurs for a minuscule period ofime (18 ms) at a time when the flow rate is very small (�10l/s). In patients, depending on whether one uses the

ressure crossover or at the incisura to calculate systolicjection period, the flow rate and pressure gradient wereifferent. In 38 patients, the values for AVA for the pressurerossover and incisura methods were 0.9 � 0.33 versus.88 � 0.36; the value for absolute difference in AVA wasery small (0.02 � 0.02) (6).

OMMENT. In the example provided, the LV and aorticressures are less than satisfactory (Fig. 4).-type natriuretic peptide. B-type natriuretic peptide

BNP) was regulated by systolic and diastolic load, suggest-ng that myocardial stretch modulates BNP (7).nduction of local angiotension II-producing system.ngiotensin-converting enzyme (ACE) and chymase, two

ngiotensin-forming enzymes, are present in aortic valvesnd are upregulated in AS valves (8).

eights of aortic valves to severity of AS. Three hundredwenty-four patients had “isolated” aortic valve replacementAVR) for AS, had peak LV to systemic arterial peakystolic pressure gradients �10 mm Hg, and had calculatedVA. As the weights of the valves increased from �1 g to

6 g, the average peak gradient increased and AVA

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428 Rahimtoola JACC Vol. 47, No. 2, 2006The Year in Valvular Heart Disease January 17, 2006:427–39

ecreased; the r values between the valve weight to gradientanged from 0.49 to 0.62, and to AVA ranged from �0.28o �0.44 (9).

igure 1. (A) Potential pathways depicting calcific aortic valve disease.etalloproteinase. (B) Histological findings in early and late lesions of calc

able 1. FRR Estimates Among the Early Age at Death Cases

Cause of Death Category Relatives, n Death

ortic valve disease (n � 202)First-degree relatives 959Second-degree relatives 2,274itral valve disease (n � 579)First-degree relatives 3,658Second-degree relatives 8,384

ll valvular diseases (n � 852)First-degree relatives 4,856Second-degree relatives 11,144

HD (n � 2,717)First-degree relatives 13,095Second-degree relatives 25,560

p � 0.0001 (significant after Bonferroni correction); †p � 0.001. From Horne et aFRR � familial relative risk; RHD � rheumatic heart disease.

ubendothelial elastic lamina. In late lesion, arrow indicates elastic lamina is disp100). From Freeman and Otto (2). Prints of figure provided by C.M. Otto,

OMMENT. Peak gradients were measured from LV tosystemic” arterial pressure and not to ascending aorticressure; mean gradients are not presented. The r values

interleukin; TGF � transforming growth factor; and MMP � matrixrtic valve disease. In early lesion, arrow indicates displacement of normal

served, n Deaths Expected, nFRR (95% CI)

for Age <65 yrs

0 2.5 4.02 (1.93–7.4)*8 7.2 1.11 (0.48–2.18)

7 16.8 2.80 (2.05–3.72)†2 35.7 1.74 (1.33–2.23)†

1 39.0 1.82 (1.42–2.30)†5 98.7 1.17 (0.96–1.40)

2 201.6 1.94 (1.76–2.15)†6 317.8 1.12 (1.01–1.24)

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429JACC Vol. 47, No. 2, 2006 RahimtoolaJanuary 17, 2006:427–39 The Year in Valvular Heart Disease

ere small. The method of measurement of cardiac outputs not described. Aortic valve replacement was performed in

any patients with moderate AS, in some with mild AS,nd in one with minimal AS (AVA �2.0 cm2)!

utcome of 622 asymptomatic adults with “hemodynam-cally significant” AS. The authors stated, “The purpose ofhe present study was to evaluate the natural history ofsymptomatic, hemodynamically significant valvularS . . .” (10). Six hundred ninety-four patients aged �40

ears with valvular AS fulfilled entry criteria; 72 patients hadVR initially, and the remaining 622 formed the study

roup. During follow-up, 297 developed symptoms but 9030%) did not have surgery, and 325 remained asymptom-tic but 145 (45%) had surgery. The probability of remain-ng free of cardiac symptoms while unoperated was 82% atne year, 67% at two years, and 33% at five years. At 10ears, there were six patients at risk.

OMMENT. Can one evaluate the natural history whenhere were no uniform criteria by which to perform or denyurgery in the asymptomatic and symptomatic patients? Thencidence of performances of coronary arteriography and ofssociated significantly obstructive coronary artery diseaseCAD) in patients who were aged 72 � 11 years is not

igure 2. Light microscopy of rabbit mitral valves and papillary muscle. Co12. (A) Alpha-actin immunostain, (B) RAM-11, macrophage immunosteopontin immunostain. From Makkena et al. (3). Prints of figure prov

rovided. In the Otto study (11), 42% of asymptomatic H

atients subsequently underwent coronary arteriography,nd 50% of these had significantly obstructive CAD, in-luding left main and three-vessel CAD. In the presenttudy, were cardiac symptoms and events due to AS and/orAD? Of interest, mortality of those undergoing surgery

ersus no surgery in those who developed symptoms was1.7% versus 77.7%, and in those who remained asymptom-tic 28% versus 57%; time from onset of symptoms tourgery and from symptoms and/or surgery to death is notrovided.o pharmacological agents reduce progression and/or

everity of AS? Beta-blockers, ACE-I, and angiotensin re-eptors blocks do not do so (12,13). A retrospective studyuggested statins do (13); a randomized trial was negative (14).

eyde’s syndrome. Of 3.8 million patients dischargedrom public hospitals in the Republic of Ireland, thencidence of gastrointestinal bleeding in the presence of ASas 0.9% with an odds ratio of 4.5, 95% confidence interval

CI) 3.0 to 6.8, and a p value of �0.0001 (15).

ORTIC REGURGITATION (AR)

V repair (AVrep) for AR. Aortic valve repair was per-ormed in 57% of patients undergoing surgery for AR.

diet, cholesterol, and cholesterol � atorvastatin. All frames, magnification(C) Proliferating cell nuclear antigen, (D) Masson trichrome stain, (E)

by N.M. Rajamannan, MD.

ntrol

ospital mortality was 3.9% (16); reoperation for recurrent

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430 Rahimtoola JACC Vol. 47, No. 2, 2006The Year in Valvular Heart Disease January 17, 2006:427–39

R was 3.3%. In patients with isolated repair, isolated rootepair, and a combination of both, at five years the incidencef AR grade �II was 19%, 16%, and 6%, respectively; thencidence of reoperation was 7%, 5%, and 2%, respectively.

ffectiveness of beta-blockade in experimental “chronic”R. Thirty-eight 38 male Wistar rats were studied (17).etoprolol treatment, compared to no treatment, resulted

n a smaller increase in LV size, prevented reduction of leftentricular ejection fraction (LVEF), increased the expres-ion of B1-adrenoreceptor messenger ribonucleic acid, andeduced G-protein receptor kinase 2 levels. Collagen I andII in ribonucleic acid levels were reduced. Cardiac myocyteypertrophy was also reduced.

ICUSPID AORTIC VALVE (BAV)

ortic root dilation. In 162 consecutive patients withAV, age 23.6 � 19.8 years (18), the dimensions at the

inuses of Valsalva, sinotubular junction, and ascendingorta were increased (Table 2).Vrep for AR. Of 132 patients with BAV � AR, 57% had

igure 3. Identification of bone matrix markers in calcified human rheumo myofibroblast staining cells (magnification �40). All others, magnificancalcified degenerative mitral valve (D2). From Rajamannan et al. (4). P

Vrep and 43% had AVR (19). By multivariate analysis, s

Vrep was associated with eccentric jet direction, cusphickening, commissural thickening, and cusp calcification.

OMMENT. There are no data on patient outcomes atollow-up.alve-sparing aortic root replacement by the remodeling

echnique: a “reasonable option?” This procedure waserformed in 60 patients with BAV (Group A) and in 130atients with tricuspid aortic valve (Group B) (20). Com-aring Group A to Group B, hospital mortality was 0%ersus 5%; at five years, freedom from AR grade �2 was 4%ersus �17% (p � 0.07), and freedom from reoperation was8% versus 98% (Fig. 5).

ITRAL STENOSIS (MS)

atheter balloon commissurotomy (CBC) duringregnancy. Thirty-six patients, age 25.8 � 4.3 years, un-erwent CBC at a mean gestational period of 26.5 � 5.3eeks; 25 patients were in New York Heart Association

NYHA) functional class III/IV (21), 23 had a Massachu-

alves. Stains as in Figure 2. C � osteocalcin immunostain. Arrow points10. Micro CT 3D reconstruction of calcified rheumatic valve (D1) and

of figure provided by N.M. Rajamannan, MD.

atic v

etts General Hospital (MGH) echocardiographic score of

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431JACC Vol. 47, No. 2, 2006 RahimtoolaJanuary 17, 2006:427–39 The Year in Valvular Heart Disease

8, and 13 had a score �8. Fluoroscopy time was �2 minn 8.3%, 2 to 4 in 55.6%. The procedure was successful in 35f 36 patients with reduction of left atrial (LA), pulmonaryrtery (PA) pressures, and an increase of mitral valve areaMVA) from 0.74 to 1.59 cm2 (all p � 0.001). Mitralegurgitation (MR) increased by two grades in 19.4%; noneeeded valve surgery. There were no abortions or stillbirths;ll children did well long-term and had normal mentalevelopment. All patients were in NYHA functional classesand II.ricuspid regurgitation (TR) regresses after CBC. Of 53atients with severe MS and TR grade �2, on a 1 to 3 scale,R regressed after CBC in 51% (22). Patients in whom TR

egressed were younger and had lower incidence of atrialbrillation (AFib), higher PA pressure, higher prevalence ofunctional TR, and more severe MS (p � 0.005).

igure 4. (A) Adapted from Bermejo et al. (6). Pressure tracings obtained wmall. Both left ventricular (LV) diastolic and aortic pressure pulses look dand is frequently in the arch. There is a large “hang out.” (B) Simultaneoustenosis. Note the LV diastolic pressures are not damped, and the ascendis very brief and minimal. The ascending aortic pressure shows the anac

irector, Interventional and Alex Durairaj, MD, Director, Cardiac CatheVAI � aortic valve area index; SEP � systolic ejection period.

able 2. Aortic Dimensions of Different Levels With BAVsnd Controls

VariablePatients With BAVs

(n � 162)Controls

(n � 162)

nnulus (mm/m2) 15.4 � 4.7 14.4 � 4inuses of Valsalva (mm/m2) 22 � 6.5* 19.5 � 5.1inotubular junction (mm/m2) 19.5 � 6.3† 16.7 � 4.1scending aorta (mm/m2) 23.7 � 7.3† 18.6 � 4.7ortic arch (mm/m2) 15.1 � 4.7 14.4 � 3.8escending aorta (mm/m2) 12.4 � 3.2 12.3 � 2.9bdominal aorta (mm/m2) 10.2 � 3 10.5 � 2.5

alues are expressed as mean � SD. *p � 0.01; †p � 0.001. From Cecconi M et al.

r18).

BAV � bicuspid aortic valve.

etter LV function with chordal preservation at time ofVR for rheumatic mitral valve disease (MVD). Pa-

ients who had complete chordal preservation (n � 250) onollow-up had smaller LV end-diastolic and end-systolicolumes and higher LVEF than those who had completexcision of subvalvular apparatus or who had preservationnly of posterior chordopapillary apparatus (23). The lastroup had better LVEF than those who had completexcision of subvalvular apparatus.

agnetic resonance imaging (MRI) for estimation ofeverity of MS. In 17 patients the MVA by MRI showed“good” correlation with CC (n � 17; r � 0.89) and a

easonable one with TTE (n � 20; r � 0.81) (24).redicting mean PA wedge pressure from Doppler

ecording. Two-dimensional Doppler and tissue Dopp-er imaging were performed simultaneously with righteart catheterization in 51 consecutive patients (aged 64

11 years) with MVD: 35 with moderately severe toevere MR and 16 with moderate to severe MS (25). Theatio of isovolumic relaxation time (IVRT) to TE-Ea for

R and for MS had r values of �0.92 and �0.88,espectively, both p � 0.001. The ratio of IVRT to � hadvalues of �0.74 for MR and �0.85 for MS (both p �.001).

OMMENT. In patients with MR, IVRT/TE-Ea of �15, theean PA wedge pressure ranged from about 15 to 38 mmg, and in MS with IVRT/TE-Ea of �4.5, mean PA wedge

ressure ranged from about 15 to 36 mm Hg. For MR forn IVRT/� of about 1.2 to 1.8, the mean PA wedge pressure

-F double lumen catheter. Both lumens, especially the aortic one, are very. Lumen of the aortic opening is about 15 to 20 cm from the LV openingnd aortic pressure from two separate catheters in patient with severe aorticrtic catheter, which is about 1 to 2 cm above the valve, shows “hang out”notch” on the ascending limb. Tracings provided by Anil Mehra, MD,tion Laboratory, LAC�USC Medical Center. AVA � aortic valve area;

ith 8mpedLV ang aorotic “

anged from about 10 to 25 mm Hg, and in MS for an

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432 Rahimtoola JACC Vol. 47, No. 2, 2006The Year in Valvular Heart Disease January 17, 2006:427–39

VRT/� of 1.2 to 1.6, mean PA wedge ranged from 16 to 32m Hg. All cited values are from a review of their Figuresand 4.

ITRAL REGURGITATION

cute pulmonary edema (APE) with ischemic mitralegurgitation (IMR). Of 28 patients aged 65 � 11 yearsith IMR, those with episodes of APE (Group I) were

ompared to 46 patients without history of APE, all ofhom had previous acute myocardial infarction and LV

ystolic dysfunction (26). On exercise, patients in Group Iad less reduction of LV end-systolic volume (p � 0.06),

ess reduction of LV wall motion index (p � 0.02), andreater increases of tenting area, regurgitant volume, effec-ive regurgitant orifice area, and tricuspid pressure gradientall p � 0.001).Fib after MV repair (MVrep)/MVR is common. Of62 patients in sinus rhythm and with no previous history ofFib who had MVrep/MVR, 69 (9%) developed early AFibithout recurrence (Group I); 67 (8.8%) had early AFib and

lso had late AFib at 10 years (Group II); and 44 (5.8%)eveloped only late new AFib (Group III) (27). Group Iatients were characterized by angina class and lowerVEF, but not by LA enlargement (LAE), which wasiagnosed as LA dimension �50 mm. Sixty-seven of 13649%) of those with early AFib developed late AFib. LargeA size independently predicted early AFib (p � 0.01) and

ate AFib (p � 0.003). Postoperative AFib was associatedith an increased higher risk of stroke or heart failure (HF)

adjusted risk ratio 1.46; 95% CI 1.04 to 2.05; p � 0.03).he authors concluded that for patients with LA enlarge-ent, “. . . surgery may be considered earlier in the course of

he disease.”

OMMENT. This was an interesting study. Patients withate AFib had higher systolic and diastolic blood pressure.

nly 10% of those with late AFib had an “ischemic”

igure 5. (A) Actuarial freedom from aortic regurgitation grade �II afterrom reoperation. From Aicher et al. (20).

tiology; 31% had MVR, of whom 47% had mechanical s

alves; there is no information on preservation of chordo-apillary apparatus (see the previous text); also, was rheu-atic another etiology? Left atrial dimensions were not

orrected for body size; the American Society of Echocar-iography recommends maximum LA diameter in the A-Piew �2.0 cm/m2 (�36 ml/m2) as normal. The exactumber of patients who initially had LAE can be calculated.t is stated that of patients with LAE, 20% (n � 136)eveloped early AFib; thus about 680 patients probably hadAE and 111 had late AFib, which is 16% (111 of 680).urgery in 680 patients to save 111 from having late AFibuts 569 patients at risk for mortality and morbidity botharly and late after surgery. Also, the incidence of late AFibas about 2% per year (12% at 5 years, 19% at 10 years).ggressive treatment of co-morbid conditions and antico-

gulation for late AFib is important but is not described. Inhe Atrial Fibrillation Follow-up Investigation of Rhythm

anagement study, larger LA diameters were associatedith recurrent AFib (p � 0.01) but not with stroke (p �.44) (28); patients had warfarin with an internationalormalized ratio (INR) goal of 2 to 3. Moreover, in theurrent era catheter ablation of AFib is possible.symptomatic patients with MR. Four hundred fifty-six

456) asymptomatic patients (LVEF 0.70 � 0.08%), 63%en, with organic MR were studied (29). The estimated

ve-year survival (�SE) of death from any cause, deathrom cardiac causes, and cardiac events (death from cardiacauses, HF, or new AFib) with medical management were2 � 3%, 14 � 3%, and 33 � 3%, respectively. Independenteterminants of survival were increasing age, the presence ofiabetes, and increasing effective regurgitant orifice (ERO).hose with ERO �40 mm2 when compared to those withRO of �20 mm2 had increased event rates. Two hundred

hirty-two patients had surgery: 94 for symptoms, 91 forcho parameters, and 47 by physician and patient prefer-nces. Those who had surgery had better outcomes. Theuthors concluded, “patients with an ERO of �40 mm2

c root remodeling in bicuspid and tricuspid valves. (B) Actuarial freedom

hould promptly be considered for cardiac surgery.”

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433JACC Vol. 47, No. 2, 2006 RahimtoolaJanuary 17, 2006:427–39 The Year in Valvular Heart Disease

OMMENT. The accompanying editorial (30) pointed outome of the limitations with regard to the conclusion andecommended a randomized trial of surgery on the basis ofRO. Earlier, Robert L. Frye, the most senior cardiologist

t the Mayo Clinic and past president of the Americanollege of Cardiology (ACC), had recommended a ran-omized trial of surgery in asymptomatic patients withevere MR (31). The cardiac causes of death averaged 3%er year, but was MR the cause of death? Patients’ age was3 � 14 years, but there are no data on the percentage ofatients who at entry had coronary arteriography andignificantly obstructive CAD. Important details of “medi-al management,” for example, actual treatment and effec-iveness of therapy of co-morbid conditions such as hyper-ension, were not provided. Twenty percent of those whoad MVR/MVrep had surgery by physician and patientreferences.

RICUSPID REGURGITATION

ulmonary thromboendarterectomy (PTE) reduces/bolishes pulmonary hypertension (PHTN) and severeR. Twenty-seven patients with severe TR underwentTE; TR resolved in 19 (70%) (Group A) and wasersistent in 8 (30%) (Group B) (32). By echo/Doppler,roup A patients had greater reduction of PA systolic

ressure than Group B (85 � 16 mm Hg to 36 � 8 mm Hgs. 87 � 29 mm Hg to 55 � 26) (p � 0.019) (Fig. 6). Byardiac catheterization data, the fall in PA systolic pressureas also greater in Group A than in Group B (37 � 16 mmg vs. 16 � 13 mm Hg; p � 0.004). No difference was

bserved in tricuspid annular diameter, apical displacementf the tricuspid valve, or other features between the tworoups. The authors concluded, “After significant PA pres-ure reduction by PTE, severe functional TR with a dilatednnulus may improve without annuloplasty despite dilatedricuspid annulus diameters.”

OMMENT. These findings are impressive and suggest anmportant role for PTE early when TR is mild or evenarlier when PHTN is moderate or severe.

igure 6. Preoperative and postoperative severity of pulmonary hyperten-ion (by echocardiographic measurements) stratified by resolved (openars) or persistent (solid bars) tricuspid regurgitation before and after

hulmonary thromboendarterectomy (PTE). PAS � pulmonary arteryystolic pressure. From Sadeghi et al. (32).

amage to tricuspid valve (TV) by permanent pacemakerPPM) or implantable cardioverter-defibrillator (ICD)ead. Of 41 patients, 7 had perforation of TV by PPM orCD leads, 4 had lead enlargement of the TV, 16 had leadmpingement of TV leaflets, and 14 had lead adherents toV (33). The septal leaflet was perforated in six of seven

ases. Transthoracic echocardiography diagnosed 12% ofatients with TV leaflet perforation or impingement, and3% of patients were diagnosed as having severe TR.ransesophageal echocardiography showed TV malfunctionue to PPM lead in 45% and severe TR in all. Time fromPM implantation to operation was 72 months (range 2 to28 months).V tethering predicts residual TR after tricuspid annu-

oplasty. Two hundred sixteen patients with functional TRad two-dimensional TTE before and 5 � 4 days after TVnnuloplasty and left heart valve surgery (34). Multivariatenalysis showed age, tethering distance, and severity ofreoperative TR (all p � 0.001) were independent predic-ors of residual TR. The sensitivity and specificity inredicting residual TR after surgery were 86% and 80% forethering distances �0.76 cm and 82% and 84% for teth-ring areas �1.63 cm2.R due to flail TV leaflets: medical and surgical out-

ome. In 60 patients with TR due to “flail leaflets” (35), theost common cause was trauma (n � 37), of which 19 were

ue to blunt trauma and 18 to iatrogenic chordal severing,ost from RV biopsy. Survival at 10 years was 61 � 10%.ricuspid surgery was performed in 33 patients at five years

n 55 � 7%. The composite event rate of dyspnea or HF,ew AFib, cardiac surgery, or death at 10 years was 7513%.

PORTS ACTIVITIES FOR PATIENTS WITH VHD

he ACC Bethesda Conference has made suggestions (36).

NFECTIVE ENDOCARDITIS (IE)

merican Heart Association (AHA) scientific statement. De-cribes recommendations for the diagnosis, anti-microbialherapy, and management of IE (37).

olecular approach to diagnose IE. Broad-range poly-erase chain reaction (PCR) targeting bacterial and fungal

DNA followed by direct sequencing was applied to 52xcised heart valves with suspected IE and from 16 patientsithout any sign of IE. The sensitivity, specificity, and theositive and negative predictive values for the bacterialroad-range PCR were 41.2%, 100%, 100%, and 34.8%38).

OMMENT. The accompanying editorial (39) describes thetrength and weakness of this study.

aximum of three TEEs is necessary for diagnosis. Two

undred sixty-two patients with 266 episodes of suspected

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434 Rahimtoola JACC Vol. 47, No. 2, 2006The Year in Valvular Heart Disease January 17, 2006:427–39

E were referred for TTE/TEE (40). Of these, 47.8% hadefinite IE, 30.4% had possible IE, and in 21.8% theiagnosis was rejected. Diagnostic findings from TTE andEE in the first examination were 21.2% and 68.5%,

espectively; reclassifications after the second examinationere 13.5% and 46.9%, respectively, and after the third

xamination were 7.5% and 20%, respectively. After thehird examination, the yield was zero.

ntibiotic prophylaxis: better education needed. Theuro Heart Survey on Valvular Heart Disease (41) docu-ented antibiotic treatment was started before blood cul-

ures were obtained in 71% of patients with IE. Fiftyercent of those with native VHD had been educated inndocarditis prophylaxis, and 33% regularly attended dentalollow-up. Only 50% of patients with IE who had had arocedure at risk during the preceding year had receiveddequate prophylaxis. The authors concluded: “. . . Im-rovement of patient management through education andmplementation of guidelines . . .” is justified.oor mid-term outcome for medically successfully

reated IE. Sixty-seven of 151 (44%) patients with IE wereuccessfully treated (42). Thirty-five underwent late surgeryo correct sequelae of the infection, and 21 of 35 (68%) ofhose who underwent late surgery died during follow-up.orty patients (60%) died from cardiovascular causes as airect consequence of IE or because of worsening of thenderlying cardiac disease. Survival rates without cardiacurgery at 1, 3, and 5 years were 54%, 29%, and 20%,espectively.ong-term results of MVrep. Thirty-seven consecutiveatients (43) underwent MVrep in “active endocarditis”sing Carpentier’s techniques between 1989 and 1994;perative mortality was one (3%), and one patient hadeoperation for pericardial patch dehiscence. At 10 years,urvival was 80% and freedom from MV reoperation was1%.MVrep versus MVR: 154 patients underwent surgery

etween 1980 and 1996 (44); 63% had MVR and 37% hadVrep. The 30-day mortality was 3.2%; 4% after MVR and

% after MVrep. Survival at 1, 5, and 10 years was 93%,1%, and 61%, respectively; survival at 10 years tended to beetter with MVrep (p � 0.15). Patients who had undergoneVrep were less frequently in NYHA functional classes

II/IV (0% vs. 29%; p � 0.002), had a lower incidence ofFib (29% vs. 47%; p � 0.04), tended to have less dyspnea

20% vs. 38%; p � 0.07), and needed reoperation lessrequently (1.8% vs. 6.5%).

ryopreserved aortic valve homograft for active aorticE. From 1992 to 2002 (45), 104 patients had cryopre-erved aortic valve homograft; 73% had IE of native valve,7% for prosthetic valve; 80% had isolated aortic IE.ospital mortality was 5%. At 10 years, actuarial survival

ate was 83%, freedom from reoperation was 76%, andreedom from recurrent IE was 93%. There were no

hromboembolic complications.

nv

NTICOAGULANT AND ANTI PLATELET THERAPY

arfarin dose requirement is related to gene encodingitamin K epoxide reductase complex 1 (VKORC1). Tenommon non-coding VKORC1 single-nucleotide polymor-hisms were identified and five major haplotypes werenferred. A low-dose haplotype group (A) and a high-doseaplotype group (B) were identified (46). The maintenanceose (mean � SE) of warfarin differed among the threeaplotype group combinations (p � 0.001) (Fig. 7). Vita-in K epoxide reductase complex 1 haplotype Groups A

nd B explained approximately 25% of the variance in dose.he frequency of Group A haplotypes predictive of lowerarfarin dose was higher in the Asian Americans (89%) and

ower in the African Americans (14%) than in the Europeanmericans (37%) (p � 0.001 for both comparisons). The

roup distribution (A or B) was also different between theseopulations. Thus, the molecular mechanisms of warfarinose response appear to be regulated at the transcriptional

evel.ntiplatelet plus moderate-intensity anticoagulation is

he most effective? The National Study for Prevention ofmbolism in Atrial Fibrillation, a prospective, randomized,pen-label study, was performed in 13 hospitals (47).atients with chronic or paroxysmal AFib were included;

hose at low risk were excluded. At high risk were patientsith MS with or without prior embolism. These patientsere randomized to anticoagulation with acenocoumarol

international normalized ratio [INR] range 2 to 3) or aombination of trifusal 600 mg (equivalent to aspirin 300g) and INR 1.4 to 2.4. Primary outcome was a composite

f vascular death, transient ischemic attack, and non-fataltroke or systemic embolism. The combined therapy groupad fewer primary events, a log hazard ratio of 0.51, a 95%I 0.27 to 0.96, and a p value of 0.03.

OMMENT. The accompanying editorial cautioned that theuthors’ conclusion that in the combination therapy the

igure 7. Mean warfarin doses according to VKORC1 haplotype combi-

ation (A/A, A/B, or B/B) in all patients and in those with wild-type andariant CYP2C9. From Reider et al. (46).

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435JACC Vol. 47, No. 2, 2006 RahimtoolaJanuary 17, 2006:427–39 The Year in Valvular Heart Disease

ower limit of an INR of two is the safe limit is premature48).spirin or warfarin after AVR with biological prostheticeart valve (PHV) Patients undergoing AVR with biolog-

cal PHV received warfarin (n � 41, INR between 2 and 3)r aspirin 100 mg/day (n � 108) by surgeon’s choice (49).uring the first three months, there was no statistically

ignificant difference between the two groups with regard toerebral ischemic events, major bleeding events, stroke-freentervals, and overall survival.

Between 1993 and 2000, 1,151 patients underwent AVRith bioprosthesis. By surgeon preference, 624 had earlyostoperative anticoagulation (AC�) and 529 did notAC�) (50). Operative mortality was 4.1%. Postoperativeerebrovascular accident occurred in 2.4% of the AC�roup and in 1.9% of the AC� group. The incidence oferebral events at �30 days in the AC� group was 1.5%.he incidence of re-exploration for bleeding in the AC�roup was 5.0% and in the AC� group was 7.4% (p �.085).

OMMENT. Seventy-eight percent of patients in the AC�roup received antiplatelet therapy. Thus, both of the abovetudies did not evaluate the role of antiplatelet therapyersus placebo.

ERCUTANEOUS HEART VALVE PROCEDURES

ercutaneous mitral annuloplasty (PMA) for MR inxperimental HF (51). STUDY 1. Percutaneous mitral an-uloplasty, using a novel annuloplasty device with twonchors, reduced annular dimension and severity of MR ataseline and after phenylephrine infusion to increase after-oad. Pressure volume analysis demonstrated no acute im-airment of LV function.

TUDY 2. Seven animals were studied four weeks after devicelacement for HF. The mitral annulus decreased from.75 � 0.08 to 3.37 � 0.23 (p � 0.05), and the severity ofR was reduced (MR jet area/LA area from 0.33 � 0.03 to

.11 � 0.04; p � 0.05).ociety of Thoracic Surgeons (STS)/American Associa-

ion for Thoracic Surgery/Society for Cardiovascularngiography and Interventions position statement

52). The recommendations were endorsed by the ACCnd AHA.

PECIAL SURGICAL SITUATIONS

imited durability of valve repair in patients with previ-us mediastinal radiation therapy. Twenty-two patientsge 61 � 14 years underwent valve repair, 15 � 9 years afterediastinal radiation therapy (53). Follow-up was 3.7 � 3.3

ears. “Early” mortality was 14%. Of 19 early survivors,verall survival, freedom from cardiac death, and freedomrom valve reoperation or cardiac transplantation at five

ears were 66%, 85%, and 88%, respectively.

f

urgery in octogenarians. Aortic valve replacement forevere AS � coronary artery bypass grafting (CABG): Oneundred fifteen patients aged 82.3 � 2.1 years underwentVR (62%) or AVR � CABG (38%). Aortic valve area was.62 � 0.15 cm2 (54). Hospital mortality was 8.5%. Theve-year survival was 69.4%. At five years the survival foratients with bioprosthesis was 81.7% versus 56.7% with aechanical valve (p � 0.02). Predictors of late mortalityere LVEF (p � 0.01), preoperative HF (p � 0.03), and

he type of prosthesis (p � 0.03). Preoperatively, 79% weren NYHA functional classes III to IV. Postoperatively, 94%ere in classes I to II.Valve surgery � CABG: In 405 patients, several different

rocedures were performed (55). “Early” mortality was 6.4%nd ranged from 0% to 10%; it was 4.3% for AVR and 8.2%or AVR � CABG; 5.7%. for MVR/MVrep � CABG. Atve years, survival after AVR was 66 � 5%; after MVurgery, 68 � 9% (p � 0.12). Concomitant CABG did notffect late survival. Independent predictors of late deathere age �85 years and LVEF �0.40. At a median

ollow-up of two years, NYHA functional class was im-roved: preoperative 78% classes II to IV and 18% class I;ostoperative 72% class I and 17% class II.Surgery for isolated non-rheumatic MR: Fifty-nine pa-

ients, age 80 years or older (82 � 2 years), had first-timeVrep (n � 46) or MVR (n � 13). The etiology was

degenerative” in 95% (56). Operative mortality was 1.7%.he five-year survival was 61%. Preoperatively, 79% were inYHA functional classes III/IV; postoperatively, 78% were

n NYHA functional classes I/II.mproved patient outcomes with hybrid approach.wenty-six patients, median age 72 years (range 53 to 91

ears) had percutaneous coronary intervention and within aedian of 5 days (range 0 to 14 days) underwent primary or

eoperative valve surgery (57). Patients were at high riskith an expected STS-predicted mortality of 22%. With theybrid approach, the operative mortality was 3.8% and theedian blood loss 900 ml, and 22 patients (85%) required

lood transfusions. Survival rates at one, three, and fiveears were 78%, 56%, and 44%, respectively.uro score for predicting late mortality. One thousandne hundred five operative survivors who had undergonesolated valve surgery � CABG were studied (58); theve-year mortality (by Euro score) is shown in Table 3.perative mortality of MR surgery with LVEF0.30. An STS database of 14,582 patients showed oper-

tive (30-day) mortality for patients with LVEF �0.30

able 3. Survival After Valve Surgery � CABG

Standard Euro Score 5-Year Survival*†

5 90.0 � 2.3%5 to �8 85.1 � 2.3%8 to �11 64.8 � 3.3%11 55.1 � 3.7%

p � 0.001, log rank test with adjustment for trend; †of operative survivors. Adapted

rom Toumpoulis IK et al. (58).

CABG � coronary artery bypass grafting.

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436 Rahimtoola JACC Vol. 47, No. 2, 2006The Year in Valvular Heart Disease January 17, 2006:427–39

n � 727) versus LVEF �0.30 (n � 13,855) was 5.4%ersus 3.1% (p � 0.001). Low LVEF was not a significantactor for mortality after controlling for other factors (59).n patients with LVEF �0.30 versus �0.30, mortality after

Vrep was 1.4% and 1.53%, respectively, and after MVRas 7.69% and 10.18%, respectively.

ROSTHETIC HEART VALVES

tarr-Edwards PHV is durable for more than 40ears. Since 1960, the Starr-Edwards valve has been usedn 3,653 of 8,300 PHVs that were inserted by Starr and hisolleagues. The original models had “some engineering”lterations up to 1964. In 1965, the models A1200/A1260nd M6120, called “extended-cloth prosthesis,” have beenirtually unchanged and have been used continuously sincehat time to present (called “Current”). Actuarial analysishows survival rates at 10, 20, and 30 years for AVR were3%, 23%, and 8%, respectively, and for MVR were 51%,3%, and 8%, respectively; for AVR, the 40-year survivalas 4%. The standard error for all these values was 1%.here have been no deaths from structural valve deteriora-

ion (SVD) among patients with the “current” valves. Theurvival and incidence of thromboembolism with “current”alve are shown in Figure 8 (60).

igh-temperature-fixed (HTF) bioprosthesis in theoung. From January 1991 to September 1998, 50 youngatients (ages range 7 months to 35 years; 22.7 � 6.8 years)nderwent single HTF bioprostheses in two hospitals (Parisnd Ho Chi Minh City) based on social, medical, andeographical contraindications to anticoagulants. At nineears the actuarial survival was 95 � 3.6%, and freedomrom reoperation was 87.6 � 7.1% (61); 91.7 � 8% afterVR and 80% � 12.6 after MVR.

OMMENT. Does HTF represent another important aspectf bioprosthetic preparation? HTF at 30° to 50°C (“Thermo

igure 8. (A) Actuarial survival curves after aortic valve regurgitation (AVR) anB) Kaplan-Meier (KM) actuarial and actual freedom from thromboembolism

ix”) is used for preparation of the Edwards PERIMOUNTAGNA valve.

VD of St. Jude Toronto stentless porcine valve. At 5nd 10 years, the actuarial survival rates were 89.2% and8%, respectively, and the rates of actuarial freedom fromVD were 98.8% and 77.9%, respectively (62).

OMMENT. The rate of SVD at 10 years is similar to thateen with stented porcine valves (63).ow rate of use of bioprostheses for AVR in patients >65

ears? Eighty thousand four hundred seventy patients aged65 years undergoing AVR during 1999 to 2001 were

dentified from 1,045 U.S. hospitals’ Medicare Part A files64). Use of bioprostheses increased from 28% in the firstecile to 68% in the10th decile of hospital volumes. Bio-rosthetic valve use increased (p � 0.001) from 44% in 1999o 52% in 2001, and with age, from 36% in patients aged 65o 69 years and to 60% in patients age �90 years.

OMMENT. The only data from randomized trials showinghe very low rate of SVD after bioprosthetic AVR in thosege �65 years is from the Veterans Administration trialhose 18-year (mean 15 years) follow-up data was pub-

ished in the Journal of the American College of Cardiology inctober 2000 (65). Also see discussion of surgery in

ctogenarians in the preceding text. It would be of interesto have similar data for 2004 to 2005.

omograft replacement of the mitral valve. The opera-ive mortality in 108 patients was 3.8%. The estimate“actual”) of reoperation was 19% at eight years; 80% ofeoperations were due to SVD (66). At eight years, theurvival was 80 � 6%; freedom from cardiac events (cardiaceaths and reoperation) was 71 � 6%. There were 5eoperations within 3 months and 10 late reoperations.

perative mortality for replacing mitral PHV. Operativeortality was 4.7% (5 of 106 patients) (67). Multivariate

nalysis showed prior myocardial infarction and “non-

d mitral valve regurgitation (MVR) in the “current” Starr-Edwards valves.after AVR and MVR with “current” valve. From Gao et al. (60).

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437JACC Vol. 47, No. 2, 2006 RahimtoolaJanuary 17, 2006:427–39 The Year in Valvular Heart Disease

lective” surgical status were statistically significant predic-ors of mortality.

emodynamic performance of various PHVs. Carpentier-dwards pericardial (CEP; PERIMOUNT) versusedtronic Mosaic (MM) Porcine (MMP). 1) An in vitro

tudy of transvalvular resistance versus flow rate of �2 to7 l/min in valve sizes 21, 23, and 25 MMP had lower

esistance than the CEP at low flow rates (3 l/min), afterhich the MMP showed steep increases in resistance, and

t flow rates of �4 l/min the CEP had much lower rates ofesistance (Fig. 9) (68). 2) A prospective randomized trial of00 patients. Prosthetic heart valve areas of the Perimountere larger than those of MMP in the 23 and 25 aortic annulusiameter (71) (Table 4).A comparison of four supra-annular bioprosthesis in

atients with small aortic annulus. A comparison of the CEericardial (Magna) to the CE Pericardial (Perimount),MP, and Soprano valves in the 18- to 20-mm annulus

iameter showed there was no statistically significant dif-erence in valve areas. In the 21- to 23-mm annulusiameter the CE-Magna had the best hemodynamics (72)Table 5).

igure 9. An in vitro study of transvalvular resistance versus flow rate of �2nd Carpentier Edwards Pericardial (Perimount valves) (EP). Adapted from.9 (SD) l/min/m2. Translating that to cardiac output in (l/min) in humansf 1.5, 1.75, and 2.0 cm2) shows the normal cardiac outputs range fromericardial clearly offers much lower resistance. Cardiac indexes in normals

hat in vitro studies of prostetic heart valve evaluate flow rates that are ap

able 4. Prospective Randomized Trial of CEP (Perimount)ersus MMP Valve

Aortic AnnulusDiameter

(mm)

PHV Area Index (cm2/m2)

MMP Valve CEP Valve

21 0.70 � 0.04 0.74 � 0.0723 0.74 � 0.06 0.79 � 0.08*25 0.80 � 0.09 0.85 � 0.09*27 0.88 � 0.10 0.93 � 0.08

p � 0.05. The PHV index was obtained by echocardiography/Doppler at follow-upisits 438 � 352 days (range 180 to 1,133). Adapted from Walther T et al. (71).

CEP � Carpentier-Edwards pericardial; MMP � Medtronic Mosaic porcine;HV � prosthetic heart valve.

(

emodynamic performance of other PHVs. Nineteen-mmMP has a high incidence of mismatch:In 81 consecutive patients (69 female), mean age 78.0 �

.6% moderate valve prosthesis-patient mismatch (VP-PM)defined as valve areas �0.65 to �0.8 cm2/m2) occurred in9.4% and severe VP-PM (valve areas �0.65 cm2/m2)ccurred in 50.6% (73). The 30-day mortality was 9.9%, andurvival at 1 and 2 years was 78.5 � 4.6% and 69.1 � 5.5%,espectively.

Bileaflet mechanical PHVs valve sizes in 21-mm valveolder. In an in vitro model, at flow rates of �4 l/min, thet. Jude Medical Regent-19 and the Sorin Bicarbon Slim

ine had larger effective valve orifice areas than the ATS8-mm, On-X 19-mm and Carbomedics Top Hat�0.005) (74).alve prosthesis-patient mismatch. Effect of MVR onA hypertension: Of 56 patients with “normally” function-

ng mitral PHV (75), 30 patients (54%) had PA hyperten-ion, defined as systolic PA pressure �40 mm Hg, and 40atients (71%) had VP-PM, defined as prosthetic MVA1.2 cm2/m2. There was a “significant” correlation (r �

.64) between systolic PA pressure and prosthetic MVA.he systolic PA pressure in those with VP-PM was signif-

l/min in valve sizes 21, 23, and 25 Medtronic Mosaic Porcine valve (MM)hnel et al. (68). Cardiac index in two studies of normal humans was 3.6 �mall, moderate, or large size body surface areas (body surface areas [BSAs]

o 9.0 l/min. At these flow rates (shaded areas) the Carpentier Edwardsrom Barratt-Boyes and Wood (69) and Ehsani et al. (70). It is importantiate for normals.

able 5. Hemodynamic Comparison for Four Bioprosthesisor Complete Supra-Annular Position

Mean AVG PHV Area

(mm Hg) p Value cm2/m2 p Values

AGNA 8.2 � 4.7 — 1.17 � 0.27 —ERIMOUNT 10.6 � 3.7 0.023 0.94 � 0.36 0.01OSAIC 15.1 � 5.6 �0.001 0.83 � 0.23 �0.001

OPRANO 12.7 � 4.6 0.009 0.87 � 0.20 0.004

values are for CE Magna vs. the other valves. Adapted from Botzenhardt F et al.

to 7Kue

with s4.1 t

72).AVG � aortic valve gradient; PHV � prosthetic heart valve.

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438 Rahimtoola JACC Vol. 47, No. 2, 2006The Year in Valvular Heart Disease January 17, 2006:427–39

cantly higher than in those without VP-PM, 46 � 8 mmg versus 34 � 8 mm Hg (p � 0.001). In multivariate

nalysis, prosthetic MVA was the strongest predictor ofystolic PA pressure. The authors concluded that persistentA hypertension is frequent after MVR and is stronglyssociated with the presence of VP-PM.

OMMENT. The accompanying editorial describes some ofhe limitations of the study (76).

Moderate/severe VP-PM is associated with less LV massegression. Patients with moderate/severe VP-PM (PHVrea �0.9 cm2/m2) had less LV mass regression after AVRompared to those with mild VP-PM (PHV area �0.9m2/m2) 48 � 47 g versus 77 � 49 g (p � 0.002) (77). Thether independent predictors of greater LV mass regressionere female gender and higher preoperative LV mass.

eprint requests and correspondence: Dr. Shahbudin H. Ra-imtoola, Distinguished Professor, University of Southern Cali-ornia, 2025 Zonal Avenue, Los Angeles, California 90033.

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