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Relation of Clinical, Echocardiographic and ElectrocardiographicFeatures of Cardiac Amyloidosis to the Presence of the

Transthyretin V122I Allele in Older African-American Men

Daniel Jacobson, MDa, Clement Tagoe, MDb, Arthur Schwartzbard, MDc, Alan Shah, MDd,James Koziol, PhDe, and Joel Buxbaum, MDe,*

Previous studies have shown that 3% to 4% of African Americans carry an amyloidogenicallele of the human serum protein transthyretin (TTR V122I). The allele appears to havean absolute anatomic risk for cardiac amyloid deposition after 65 years of age. In this study,a case-control comparison was performed of clinical, echocardiographic, and electrocar-diographic characteristics of 23 age at risk carriers of the amyloidogenic allele and 46 age-,gender-, and ethnically matched noncarriers being evaluated for cardiac disease usingstandard clinical testing. The 2 groups were matched for blood pressure and the cardiacejection fraction. None of the subjects had a prestudy diagnosis of cardiac amyloidosis.Carriers of the amyloidogenic allele were found to have statistically significant increases inthe occurrence of many of the echocardiographic features of cardiac amyloidosis relative tothe noncarriers and a higher frequency of congestive heart failure and atrial fibrillation.The observations suggest that TTR V122I represents a substantial risk for clinicallysignificant cardiac amyloidosis in elderly African American men, behaving as an age-dependent autosomal dominant disease-associated allele. The diagnosis is difficult to makebut can be suspected in African Americans aged >60 years on the basis of age, echocar-diographic evidence of diastolic dysfunction, and interventricular septal thickening, even inthe absence of more recently available sophisticated echocardiographic techniques forevaluating long-axis function and cardiac magnetic resonance imaging. Positive results forthe amyloidogenic TTR V122I allele support the diagnosis and define the origin of thedisease, which can be confirmed by endomyocardial biopsy. © 2011 Elsevier Inc. All

rights reserved. (Am J Cardiol 2011;108:440–444)

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Mutant and wild-type forms of the serum protein trans-thyretin (TTR) cause cardiac amyloidosis.1 Three percent to4% of African Americans carry an amyloidogenic allele ofthe human TTR gene (TTR V122I).2 A large autopsy studyshowed that all carriers of the allele aged �60 years hadsome degree of anatomic cardiac amyloidosis, but clinicalpenetrance was not determined.3 In the Beta-Blocker Eval-ation in Survival Trial (BEST) of �-blocker therapy for

congestive heart failure (CHF), in which cardiac amyloid-osis was exclusionary, 10% of African Americans with New

aVeterans Affairs Boston Healthcare System and Boston UniversitySchool of Medicine, Boston, Massachusetts; bDepartment of Medicine,

lbert Einstein College of Medicine, Bronx, New York; cMedical Servicesepartment of Veterans Affairs New York Harbor Healthcare System;

dDepartment of Medicine, New York University School of Medicine, NewYork, New York; and eDepartment of Molecular and Experimental Med-cine and the W.M. Keck Autoimmune Disease Center, Scripps Researchnstitute, La Jolla, California. Manuscript received December 18, 2010;evised manuscript received and accepted March 16, 2011.

These studies were supported by grant R01 AG19259 from the Na-ional Institutes of Health, Bethesda, Maryland, to Dr. Buxbaum.

Dr. Jacobson has been a paid consultant for FoldRx Pharmaceuticals,ambridge, Massachusetts. Dr. Buxbaum has been a paid consultant foroldRx Pharmaceuticals; Alnylam Pharmaceuticals, Cambridge, Massa-husetts; and Isis Pharmaceuticals, Carlsbad, California.

*Corresponding author: Tel: 858-784-8885; fax: 858-784-8891.

cE-mail address: jbux@scripps.edu (J. Buxbaum).

0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.amjcard.2011.03.069

York Heart Association class III and IV CHF aged �60years carried the amyloidogenic allele, suggesting that clin-ical penetrance did not accompany anatomic deposition, thediagnosis of cardiac amyloidosis was difficult to make, theCHF was caused by other disease, or some combination ofthe 3.4 To obtain information about the frequency and nat-ral history of cardiac disease in living TTR V122I carriers,e compared the clinical findings, echocardiographic re-

ults, and electrocardiographic results of a group of Africanmerican male veterans aged �60 years carrying the amy-

oidogenic allele to those of variant-negative age-, gender-,nd ethnically matched controls.

ethods

The research protocol was approved by the institutionaleview boards of the New York Harbor Healthcare Systemf the United States Department of Veterans Affairs andew York University Medical Center. All patients gave

nformed consent for genotyping and record review. Studyubjects and controls were selected from a cohort of 471frican American men aged �60 years who received theirealth care at the New York Harbor Healthcare Systemrom 1995 to 2004 and gave permission for deoxyribonu-leic acid analysis. Most of the study subjects (n � 383) hadeen referred for echocardiography for clinical indications,ut some (n � 88) were recruited from noncardiology

linics, had no known histories of cardiac disease, and

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441Cardiomyopathy/African American TTR V122I Allele Carriers

underwent echocardiography only for study purposes. Ex-clusion criteria included a known personal or family historyof amyloidosis, known severe cardiac valvular disease, orprevious heart transplantation.

All subjects found to carry the TTR V122I allele,whether found in the population screened from the ultra-sound laboratory (n � 20) or the general hospital (n � 4),were classified as subjects. For each subject, 2 controlsnegative for the TTR V122I allele, matched with the subjectfor gender, age, hypertension (systolic measurement �140mm Hg, diastolic measurement �90 mm Hg) and the pres-ence or absence of documented coronary artery disease,were selected from the 2 genotyped cohorts. Because ascer-tainment was within the context of attendance at a tertiarytreatment facility, the subjects did not represent a demo-graphic sample of community-dwelling African Americans.By design, we included subjects thought to have cardiacdisease (because they were referred for echocardiography)to determine what proportion of disease in such an “at-risk”population could be attributed to the amyloidogenic allele.

The 471 enrolled patients were assessed by a cardiologistunaware of their allele status and followed in the cardiologyclinic for the duration of the study. Data collected includedbody mass index, blood pressure, lipid profile, smokingstatus, co-morbid conditions including diabetes mellitus,pacemaker or implantable cardioverter-defibrillator status,chemotherapy, renal function, serum protein electrophoresisresults, and the presence of antinuclear antibodies.

Echocardiography was performed using an ATL 3000machine (Advanced Technology Laboratories, Bothell,Washington) with a 2.5-MHz transducer. Dimensions weremeasured in M and 2-dimensional imaging modes. Leftventricular posterior wall thickness was measured in theparasternal long-axis view, as was ventricular septal thick-ness, both by 2-dimensional imaging and M-mode measure-ments.5 The left ventricular ejection fraction was measuredsing end-systolic and end-diastolic volumes. A normaljection fraction was defined as 55% to 80%. Mitral decel-ration times were measured by Doppler technique. Amer-can Society of Echocardiography criteria were used toefine the presence or absence of right ventricular hyper-rophy. Standard 12-lead electrocardiography was per-ormed. All electrocardiograms and echocardiograms werenterpreted retrospectively by 2 independent readers un-ware of the subjects’ genotypes.

The presence of CHF was determined clinically beforechocardiographic evaluation by symptoms (fatigue, dys-nea, paroxysmal nocturnal dyspnea) and signs (peripheraldema, cardiomegaly on physical examination and/or chest-ray), as well as review of the medical record for thedministration of drugs used to treat CHF (i.e., diuretics, �

blockers, and digoxin).Genotyping was performed on deoxyribonucleic acid

extracted from buccal swab or blood samples. The TTRV122I status was assayed by polymerase chain reaction andrestriction analysis according to standard protocols used inour laboratory.6 All genotype results were confirmed byrepeat testing with appropriate positive and negative con-trols for each genotype. Allele-positive subjects were in-formed as to their genotype and followed in the cardiology

clinic. T

Results are expressed as mean � SD. Statistical analysiswas performed using Prism (GraphPad Software, Inc., SanDiego, California). Group comparisons with continuous datawere undertaken with the nonparametric Mann-Whitney Utest, and Fisher’s exact test was used with discrete data. A pvalue �0.05 was considered statistically significant.

esults

The frequency of the TTR V122I allele in the subjectseferred to the echocardiography laboratory was 5.5%,hile that in the general hospital population was 4.5%. Theifference was not statistically significant.

Table 1 lists the demographic features of the 23 amy-oidogenic allele carriers and 46 controls. The 2 groups weref similar median age and body mass index. Evidence oforonary disease, either by angiography or clinically dem-nstrated myocardial infarction, was similar in the 2 groups,s was the prevalence of diabetes mellitus. Compromisedenal function was more common in the V122I group, al-hough it was not determined if it was related to amyloidephropathy. Two additional allele carriers were not in-luded in the analysis. One had a clinical diagnosis ofultiple myeloma, and an endomyocardial biopsy could not

e performed to determine the nature of the cardiac amyloidi.e., whether it was related to immunoglobulin L-chain or

Table 1Demographic features of amyloidogenic transthyretin allele carrierscompared to controls

Genotype Cases(n � 23)

TTR V122I

Controls(n � 46)

TTR V122V

pValue

Age (years) 72.8 � 7.4 73.0 � 7.3 NS*Body mass index (kg/m2) 25.8 � 5.4 26.8 � 5.1 NS*Diabetes mellitus 5/19 (26%) 11/46 (24%) NS†

Creatinine (mg/dl) 2.0 � 2.0 1.4 � 0.9 0.13*lood urea nitrogen (mg/dl) 26 � 21 18 � 12 0.06*ystolic blood pressure (mm Hg) 133 � 22 138 � 19 0.33*iastolic blood pressure (mm Hg) 74 � 11 74 � 10 0.78*ean blood pressure (mm Hg) 93 � 13 96 � 12 0.48*

Data are expressed as mean � SD or as number (percentage).* Mann-Whitney U test.† Fisher’s exact test.

Table 2Reasons for echocardiography in transthyretin V122I carriers andcontrols

Presumptive Diagnosis TTR V122I TTR V122V p Value*

Coronary artery disease 5 (22%) 11 (24%) NSHypertension 1 (4%) 10 (22%) 0.09Heart failure 8 (35%) 6 (13%) 0.04Chest pain 0 (0%) 4 (9%) NSStudy only 3 (13%) 3 (7%) NSOther 3 (13%) 7 (15%) NSUnknown 3 (13%) 5 (11%) NSTotal 23 46

* Fisher’s exact test.

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Twenty of the 23 allele carriers (87%) had sufficientclinical evidence of heart disease to be referred for echo-cardiography. The reasons for referral to echocardiographyare listed in Table 2. Although a larger number of controlswere referred with the diagnosis of hypertension or hyper-tensive heart disease, the frequency of hypertension (de-fined as systolic pressure �140 mm Hg or diastolic pressure�90 mm Hg) and the average systolic, diastolic, and meanblood pressures at the time of echocardiography were notsignificantly different between the control and the TTRV122I groups. In no instance was cardiac amyloidosis thereferring diagnosis. Three patients in each group (i.e., thoseidentified in the general hospital population) underwentechocardiography only for study purposes, with genotypingperformed before echocardiography.

Among the subjects referred for echocardiography, therewas a statistically significantly higher incidence of CHF inthe TTR V122I allele carriers than in the controls. Threepatients (1 TTR V122I carrier and 2 controls) developedheart failure during the observation period. When allelecarriers and controls who were not referred for cardiacultrasonography were included in the comparison, 9 of 23V122I carriers and 8 of 46 V122V carriers had evidence ofCHF (relative risk 2.0, 95% confidence interval 1.04 to 3.71,

Table 3Electrocardiographic findings in transthyretin V122I carriers and controls

Feature TTR V122I TTR V1

Heart rate (beats/min) 81 � 17 73 � 1trial fibrillation/flutter 5/23 (22%) 4/46 (9trial premature complexes 7/19 (37%) 4/45 (9entricular premature complexes 5/23 (22%) 3/46 (7onduction defects 13/23 (57%) 21/46 (4ow voltage throughout† 2/23 (9%) 1/46 (2acemaker 2/23 (9%) 0/46 (0waves 10/23 (43%) 3/46 (7

oltage/mass ratio 0.085 0.103

The Mann-Whitney U test was used to compare continuous variables, a* p �0.05.† Low voltage was defined as total amplitude of the QRS complex in e

Table 4Echocardiographic findings in transthyretin V122I carriers and controls

Feature TTR V122I TTR V122V p Value

jection fraction 58.7 � 15 59.7 � 14 NSMean interventricular septal

thickness (cm)1.35 � 0.31 1.19 � 0.24 0.04*

Mean posterior ventricularwall thickness (cm)

1.30 � 0.31 1.17 � 0.24 0.054

Right ventricular hypertrophy 6/23 (26%) 1/46 (2%) 0.004*Mitral deceleration time (ms) 174 � 68 210 � 54 0.054Left atrial size (cm) 4.43 � 0.96 4.21 � 0.77 0.42Mitral E/A ratio 0.83 � 0.25 0.79 � 0.36 0.29Frequency of “granular

sparkling”8/23 (35%) 1/46 (2%) 0.0004*

Data are expressed as mean � SD or as number (percentage).The Mann-Whitney U test was used to compare continuous variables,

and Fisher’s exact test was used for dichotomous variables.* p �0.05.

p � 0.07).

Table 3 lists the prevalence of electrocardiographic fea-tures of cardiac disease in the TTR V122I allele carrierscompared to the controls. A number of nonspecific features,including heart rate, frequency of premature atrial com-plexes, atrial fibrillation, and the presence of Q waves,sometimes displaying a pseudoinfarction pattern, were morefrequent in the allele carriers. Overall low voltage (totalamplitude of the QRS complex in each limb lead �0.5 mV),a relatively specific (but insensitive) feature of cardiac am-yloidosis, was infrequent.7 Table 4 lists the echocardio-raphic features of cardiac amyloidosis in the 2 groups.

iscussion

The initial association of a valine-to-isoleucine aminocid substitution in the serum protein TTR (TTR V122I)as noted in the amyloid fibrils extracted from the heart of

n elderly African American man and confirmed in 2 addi-ional probands.7–11 Biophysical studies showed that the

mutant protein was less kinetically stable than wild-typeTTR, accounting for its propensity to form amyloid.12 Alarge autopsy study revealed that all heterozygous carriersof the V122I allele had some degree of cardiac TTR depo-sition after 65 years of age, demonstrating that anatomi-cally, the allele behaved as an autosomal dominant gene.3

In contrast to heterozygous allele carriers aged �65years in the African American cohort of the ArteriosclerosisRisk in Communities (ARIC) study, V122I subjects aged�65 years in the Cardiovascular Health Study (CHS)showed more frequent CHF, greater mortality, and featuresof cardiac amyloidosis more commonly than did homozy-gous wild-type TTR subjects.13 Hence, clinical manifesta-tions related to TTR amyloid deposition in heterozygouscarriers are generally seen after 65 years of age, with TTRV122I behaving as an autosomal dominant allele with age-dependent anatomic and clinical penetrance. It is not yetstatistically clear that homozygous carriers develop diseaseearlier than heterozygotes, but such an observation wouldnot be surprising.

We hypothesized that the allele would be more commonin a group of patients deemed to be at high risk for cardiacdisease. However the frequency of the amyloidogenic allelein the subjects referred for echocardiography (5.5%) wasnot significantly higher than in age-matched and ethnically

Relative Risk 95% Confidence Interval p Value

— 0.02*1.9 0.92–3.73 0.144.1 1.4–13 0.01*3.4 0.89–13.1 0.101.2 0.5–1.3 0.464.0 0.38–42.0 0.263.2 0.106.7 2.0–22.0 0.005*

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We also reasoned that in an elderly population, with avariety of cardiac pathologies, if TTR V122I were respon-sible, the carriers would display manifestations of cardiacamyloidosis more frequently than homozygous wild-typeTTR subjects. That appears to be true. Echocardiographicabnormalities associated with amyloidosis were more fre-quent in the V122I carriers than in the wild-type TTRsubjects. When the TTR V122I carriers were compared towild-type TTR subjects, interventricular septal thicknesswas significantly greater. Mitral deceleration time was sig-nificantly shorter in the absence of CHF, with the differenceapproaching significance in the entire group, indicating thatthe amyloidogenic allele carriers displayed more evidenceof diastolic dysfunction. Neither septal thickening nor mi-tral deceleration time alone was predictive of a subject’scarrying the TTR V122I allele, having sensitivities of 0.70and 0.76, respectively, and specificities of about 0.5 (areaunder the receiver-operating characteristic curve approxi-mately 0.65 for each). However, combining these parame-ters reflecting abnormal anatomy (interventricular septalthickness �1.2 cm) and diastolic dysfunction (mitral decel-eration time �215 ms) identified TTR V122I carriers in thisopulation (with a presumed absolute anatomic risk forardiac TTR amyloid deposition) with 90% specificity and7% sensitivity (area under the curve 0.72). Right ventric-lar hypertrophy has recently gained attention as an amy-oid-associated finding and is relatively rare in coronary orypertensive disease.14 Adding its presence to interventric-lar septal thickness (�1.2 cm) and mitral deceleration time�215 ms) increases specificity but not sensitivity. Thetatistically significant difference in the frequency of in-reased echogenicity, so-called granular sparkling of themage, although not specific, is more frequent in amyloid-sis than in any other cardiac disease.15

In contrast to classic teaching noting that cardiac amy-loidosis is associated with low blood pressure,16,17 hyper-ension was equally represented and of similar severity athe time of evaluation in the subjects and controls. None-heless, the abnormalities associated with cardiac amyloid-sis were much more frequent in the carriers of the TTR122I allele. Consistent with this observation, the voltage/ass ratio18 did not differ between the 2 groups, and theean ventricular ejection fraction, the defining measure of

eft ventricular systolic failure, was not decreased, beingimilar in allele carriers and controls. Interestingly, therequency of CHF in the allele carriers with hypertension (7f 18) was higher than in those without the allele withypertension (7 of 39), although the difference did notchieve statistical significance (relative risk 1.96, 95% con-dence interval 0.94 to 4.06, p � 0.11).

If one assumes that an interventricular septal thickness1.1 cm in the presence of the amyloidogenic TTR allele is

vidence for anatomic amyloid deposition, the anatomicenetrance of cardiac amyloidosis in TTR V122I allelearriers in this study was 75% (18 of 23). One third of theTR V122I allele carriers had CHF, atrial fibrillation, oroth compared to 1/6 of the TTR V122V subjects. Thus, inpopulation of elderly African Americans suspected of

aving cardiac disease, carriers of the amyloidogenic allelere twice as likely to have congestive failure or atrial fibril-

ation (relative risk 2.0, 95% confidence interval 0.86 to

.67), data consistent with the allele behaving as an auto-omal dominant gene with age-dependent anatomic andlinical penetrance.

Four TTR V122I carriers, all aged �70 years, had nonatomic evidence consistent with cardiac amyloidosis (al-hough 1 had atrial fibrillation and 1 was unavailable for fullardiac evaluation). Variability in the age of onset of clin-cal disease has been seen with other TTR variants.19 It isossible that these subjects will not develop cardiac amy-oidosis or will become symptomatic later in life.

Although it was not possible to perform endomyocardialiopsies in all these subjects, TTR amyloid was identifiedetrospectively in an intestinal segment surgically removedrom 1 TTR V122I patient before the onset of CHF.

Much of the published research describing the features ofardiac amyloidosis is based on series of patients withevere heart failure, frequently rapidly progressive related tommunoglobulin L-chain amyloidosis. The present studynd the analysis of BEST participants suggest that cardiacmyloidosis in African Americans, even in the presence ofHF and arrhythmia, is not readily diagnosed. Nonetheless,

he characteristic features of diastolic dysfunction, thick-ned cardiac walls and a preserved ejection fraction inarriers of the V122I allele, are consistent with the diagnosisnd suggest the need for a diagnostic endomyocardial bi-psy. A recent analysis of TTR V122I carriers identifiedetrospectively among African Americans referred to a na-ionally recognized amyloid research center primarily forHF gives a picture of much more severe disease (93%HF, interventricular septal thickness 1.68 cm, ejection

raction 38%) suggesting that our investigation, using themyloidogenic allele as a marker has identified subjectsarly in their course.20 Awareness of the diagnosis whenonfronted with an African American man in this age groupith predominant diastolic dysfunction should suggestenotyping for the amyloidogenic allele and more carefulnalysis. Establishing the diagnosis allows clinicians tovoid drugs that may be dangerous in patients with cardiacmyloidosis.21,22

Since the completion of these studies, newer echocardio-graphic and imaging techniques allowing better assessmentsof the quality and function of the myocardium have beenvalidated in cardiac amyloidosis.23–26 However, even with-ut these modalities, our data indicate that African Americanen aged �60 years carrying the amyloidogenic TTR V122I

llele who are referred for cardiac evaluation on clinicalrounds show electrocardiographic abnormalities and echocar-iographic features associated with cardiac amyloidosis morerequently than matched allele-negative controls.

cknowledgments: We wish to thank Dr. Rodney Falk foris helpful critical review of this report.

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