Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide...

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CLINICAL RESEARCH

Manifest disease, risk factors for sudden cardiacdeath, and cardiac events in a large nationwidecohort of predictively tested hypertrophiccardiomyopathy mutation carriers: determiningthe best cardiological screening strategyImke Christiaans1,2, Erwin Birnie3, Gouke J. Bonsel3, Marcel M.A.M. Mannens1,Michelle Michels4, Danielle Majoor-Krakauer5, Dennis Dooijes5, J. Peter van Tintelen6,Maarten P. van den Berg7, Paul G.A. Volders8, Yvonne H. Arens9,Arthur van den Wijngaard9, Douwe E. Atsma10,Apollonia T.J.M. Helderman-van den Enden9,11, Arjan C. Houweling12, Karin de Boer13,Jasper J. van der Smagt14, Richard N.W. Hauer15, Carlo L.M. Marcelis16,Janneke Timmermans17, Irene M. van Langen1,6, and Arthur A.M. Wilde2*

1Department of Clinical Genetics, Academic Medical Centre, Amsterdam, the Netherlands; 2Department of Cardiology, Academic Medical Centre, Amsterdam, the Netherlands;3Institute of Health Policy and Management, Erasmus Medical Centre, Rotterdam, the Netherlands; 4Department of Cardiology, Thoraxcentre, Erasmus Medical Centre, Rotterdam,the Netherlands; 5Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands; 6Department of Genetics, University Medical Centre Groningen,Groningen, the Netherlands; 7Department of Cardiology, University Medical Centre Groningen, Groningen, the Netherlands; 8Department of Cardiology, Maastricht UniversityMedical Centre, Maastricht, the Netherlands; 9Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands; 10Department of Cardiology,Leiden University Medical Centre, Leiden, the Netherlands; 11Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands; 12Department of ClinicalGenetics, VU University Medical Centre, Amsterdam, the Netherlands; 13Department of Cardiology, VU University Medical Centre, Amsterdam, the Netherlands; 14Department ofMedical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands; 15Department of Cardiology, University Medical Centre Utrecht, Utrecht, the Netherlands;16Department of Clinical Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; and 17Department of Cardiology, Radboud University NijmegenMedical Centre, Nijmegen, the Netherlands

Received 5 July 2010; revised 17 February 2011; accepted 8 March 2011; online publish-ahead-of-print 1 April 2011

Aims We investigated the presence of a clinical diagnosis of hypertrophic cardiomyopathy (HCM), risk factors for suddencardiac death (SCD), and cardiac events during follow-up in predictively tested—not known to have a clinical diag-nosis of HCM before the DNA test—carriers of a sarcomeric gene mutation and associations with age and gender todetermine the best cardiological screening strategy.

Methodsand results

One hundred and thirty-six (30%) of 446 mutation carriers were diagnosed with HCM at one or more cardiologicalevaluation(s). Male gender and higher age were associated with manifest disease. Incidence of newly diagnosed mani-fest HCM was ,10% per person-year under the age of 40 years and .10% in older carriers, although numbers weresmall in carriers ,15 years. Twenty-three percent of carriers, with and without manifest disease, had established riskfactor(s) for SCD (no significant difference). During an average follow-up of 3.5+ 1.7 years two carriers, both withmanifest disease, died suddenly (0.13% per person-year). A high-risk status for SCD (≥2 risk factors and manifestHCM) was present in 17 carriers during follow-up (2.4% per person-year). Age but not gender was associatedwith a high-risk status for SCD.

Conclusion Thirty percent of carriers had or developed manifest HCM after predictive DNA testing and risk factors for SCDwere frequently present. Our data suggest that the SCD risk is low and risk stratification for SCD can be omitted

* Corresponding author. Tel: +31 0 205663072, Fax: +31 0 206962609, Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected]

European Heart Journal (2011) 32, 1161–1170doi:10.1093/eurheartj/ehr092

at University L

ibrary Utrecht on July 10, 2012

http://eurheartj.oxfordjournals.org/D

ownloaded from

mailto:[email protected]





http://eurheartj.oxfordjournals.org/

in carriers without manifest disease and that frequency of cardiological evaluations can possibly be decreased incarriers between 15 and 40 years as long as hypertrophy is absent.

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Hypertrophic cardiomyopathy † Sudden cardiac death † Risk stratification † Genetic

IntroductionHypertrophic cardiomyopathy (HCM) is a common genetic diseaseassociated with an increased mortality due to heart failure,thrombo-embolic complications, and sudden cardiac death(SCD). Several factors associated with an elevated risk of SCD inHCM patients have been identified.1 The risk of SCD is �1%annually in patients with manifest HCM but increases to 5%annually or more if risk factors for SCD are present.2,3 It hasbeen proposed that in patients with ≥1 risk factor, the implan-tation of an internal cardioverter defibrillator (ICD), a therapywith proven efficacy in the prevention of SCD, should beconsidered, and in patients with ≥2 risk factors should beadvised.1,4– 6

Mutations in sarcomeric genes are identified in �50% of HCMpatients.7 After identification of a pathogenic mutation in anHCM patient (the proband), relatives can be identified or excludedas mutation carrier by means of predictive genetic testing (cascadescreening). Proven mutation carriers should be referred for regularcardiological evaluation according to the ACC/ESC consensusdocument, including risk stratification for SCD.1 As predictive mol-ecular testing is not yet widespread, most countries restrict riskstratification for SCD to relatives who are found to have manifestdisease on echocardiography. Therefore, in relatives carrying thefamilial mutation, not much is known about: (i) the risk of develop-ing manifest HCM, (ii) the presence and development of riskfactors for SCD, and (iii) the association of these risk factorswith an increased risk of SCD. This hampers optimal managementof mutation-carrying relatives.

This study reports the results of systematic follow-up in a largegroup of relatives with a proven familial mutation in one of the sar-comeric genes identified through cascade screening. These rela-tives were predictively tested; they were not known to have aclinical diagnosis of HCM before the DNA test. We address thepresence of a clinical diagnosis of HCM, of risk factors for SCD,and of cardiac events during follow-up. As gender and age havepreviously been described to be related to disease penetrance,8–12

we also assessed the associations of our outcome measures withage and gender trying to establish the best cardiological screeningstrategy.

Methods

PopulationIn HCM, families with a disease-causing mutation predictive genetictesting can give more certainty than electrocardiogram (ECG) andechocardiography about which relatives are at risk of developingHCM and which relatives are not. As genetic testing excludes the rela-tives identified as non-carrier from cardiological follow-up, in the

Netherlands genetic testing of relatives is performed before cardiolo-gical testing. We included relatives, carrying the familial mutation, whowere not known to have a clinical diagnosis of HCM at the time ofDNA testing (i.e. predictive genetic testing). Almost all includedmutation carriers had not been cardiologically evaluated before theDNA test. Probands, affected relatives, and relatives not carrying thefamilial mutation were excluded. All included mutation-carrying rela-tives provided written informed consent for anonymous scientificuse of their data.

We identified 446 mutation-carrying relatives came from 166families with a putative pathogenic mutation in the MYBPC3, MYH7,TNNT2, TPM1, or MYL2 gene. The distribution of the mutated genesin the relatives was similar as in the probands. DNA analysis was per-formed according to a previously published protocol.9,13 Geneticcounselling and testing of (probands and) relatives are only providedby University Hospitals in the Netherlands. All eight Dutch UniversityHospitals included mutation carriers. Uptake of predictive genetictesting in part of these families has been previously described andwas 39% in the first year after identification of the causal mutation.14

In first-degree relatives, the percentage of carriers was 50.6% followingautosomal dominant inheritance.

DataFrom all predictively tested mutation-carrying relatives, a family historywas recorded with the information on SCD in relatives up to the thirddegree. Carriers were advised to regularly undergo cardiological evalu-ation, including complete risk stratification with an ECG, echocardio-gram, 24 h ambulatory Holter recording, and an exercise test.1

Clinical parameters from all their cardiological evaluations (often per-formed in local hospitals) after predictive genetic testing wererecorded.

The HCM phenotype was assessed using echocardiography. Inadults, a clinical diagnosis of HCM was made when on echocardiogra-phy the maximal left ventricular wall thickness was ≥13 mm and/orsevere systolic anterior movement of the mitral valve was present.15

In children ,16 years, the clinical diagnosis was made, when on echo-cardiography a maximal wall thickness ≥ 2 SD for their body surfacearea was present.

The following risk factors for SCD were assessed:

(i) Family history of premature SCD. Unexpected non-traumatic prema-ture death within 1 h after the onset of symptoms and withoutprevious severe symptoms in (a) relative(s), includingun-witnessed unexpected nocturnal death and equivalents suchas successful resuscitation or appropriate ICD discharge. Withrespect to the age and degree of kinship and number of the rela-tive(s) involved, we use the definition most used in the literature:two relatives with SCD ,40 years.16 –18

(ii) Unexplained syncope. Unexplained syncope, judged not to beneurocardiogenic.

(iii) Non-sustained ventricular tachycardia (NSVT). One or more runs of≥3 consecutive ventricular extrasystoles at a rate of ≥120 b.p.m.

I. Christiaans et al.1162

at University L



ownloaded from


lasting for ,30 s at exercise test or 24 h ambulatory Holterrecording.

(iv) Extreme left ventricular hypertrophy. Maximum left ventricular wallthickness of ≥30 mm on echocardiography.

(v) Abnormal blood pressure response (ABPR) during upright exercise. Afailure of the systolic blood pressure to rise by .20 mmHgfrom baseline values, or a fall of .10 mmHg from themaximum blood pressure during upright exercise (treadmillBruce protocol or bicycle protocol).

The cumulative number of risk factors is the number of the above-mentioned five risk factors for SCD that are positive. Carriers weredefined to be at high risk for SCD when manifest HCM and ≥2 riskfactors for SCD were present or when they had previously experi-enced an aborted cardiac arrest (ventricular fibrillation) or sustainedventricular tachycardia (VT).

Outcome measures during follow-up were a clinical diagnosis ofHCM, death, cardiovascular death, SCD, heart transplantation, andappropriate ICD discharge. As a proxy outcome for SCD, we used ahigh-risk status for SCD. All included carriers had at least one cardio-logical evaluation. Information on mortality was retrieved from thecentral Dutch Community Registration, and in case of death thecause of death was retrieved by contacting the general practitioneror the Dutch Bureau of Statistics.

Predictively tested carriers were included in this prospective cohortstudy from 1999 when the first relative was identified as mutationcarrier through cascade screening until December 2008. Because ofthe increasing number of HCM patients in whom DNA diagnostics isperformed and the subsequent cascade screening of the relatives,the inclusion of predictively tested mutation-carrying relatives alsoshows an increase in time. Follow-up on mortality related outcomemeasures (death, cardiovascular death, SCD) ended in May 2009.

Statistical analysisData are expressed as mean (SD) or as a frequency, where appropri-ate. Comparison of subgroups for continuous and categorical variableswas performed using linear and logistic regression, respectively. For allmodels, the generalized estimating equations method was used tocorrect for correlations between carriers due to family relations.

For all carriers, the times from birth to HCM diagnosis and to high-risk status for SCD were calculated, as well as from time of DNA diag-nostics. For time to a clinical diagnosis of HCM and time to a high-riskstatus for SCD, carriers without a clinical diagnosis of HCM or withouta high-risk status for SCD, respectively, were censored at the date ofthe last cardiological evaluation. For carriers without a clinical diagnosisof HCM at the first cardiological evaluation, follow-up to a clinical diag-nosis of HCM and a high-risk status for SCD were calculated starting atthe date of first cardiological evaluation.

Kaplan–Meier curves were calculated for time to a clinical diagnosisof HCM and time to a high-risk status for SCD for all carriers, with/without stratification by sex. All analyses were carried out usingSPSS (version 15.0). P-values , 0.05 (two-sided) were consideredsignificant.

Results

First cardiological evaluationIn the period between 2001 and 2008, 446 relatives were identifiedas mutation carrier by predictive DNA testing. Clinical parametersat first evaluation from part of the carriers have been published.9,19

Mean age (+SD) of carriers was 39.3+ 17.6 (range 1–86) years

and 195 (44%) were male. Although all carriers were not known tohave a clinical diagnosis of HCM and most had not been cardiolo-gically evaluated before the predictive DNA test, at first cardiolo-gical evaluation a clinical diagnosis of HCM was made in 107 (24%)carriers. Risk factors for SCD were frequently present; 33% of allcarriers had one or more risk factors (29% had one risk factor, 4%had more risk factors; Table 1).

Differences between carriers with vs. those without a clinicaldiagnosis of HCM at first cardiological evaluation are displayed inTable 1. Carriers in whom a clinical diagnosis of HCM was madeat first evaluation were significantly older than carriers in whomhypertrophy was absent at that time (45.4+ 17.8 vs. 37.4+17.6years, P-value , 0.001) and were more often of male gender(57.0 vs. 39.5%, P-value ¼ 0.002). Extreme left ventricular hyper-trophy was by definition only present in carriers with a clinicaldiagnosis of HCM. Non-sustained ventricular tachycardia was sig-nificantly more often detected during Holter recordings in carrierswith a clinical diagnosis of HCM (P-value ¼ 0.002), although thisdifference was not significant in carriers ,50 years. There wasno significant difference in the cumulative number of risk factorsbetween carriers with and without a clinical diagnosis of HCM.

Risk stratification for SCD was incomplete in 41% of mutationcarriers at first cardiological evaluation. The risk factors ABPRand NSVT were evaluated in only 66 and 71% of carriers, respect-ively. There were no significant associations between clinicalcharacteristics and incomplete risk stratification, except for thecumulative number of risk factors. As expected, the cumulativenumber of risk factors for SCD was significantly higher in carrierswho had been evaluated for all risk factors (P-value ¼ 0.017).Twenty-four percent of carriers with incomplete risk stratificationhad ≥1 risk factor for SCD compared with 39% of the carrierswith complete evaluation.

Cardiological evaluations duringfollow-upIn the entire cohort (n ¼ 446), the average follow-up time frombirth to the last cardiological evaluation was 39.8+17.6 years(range 1.4–86.7). In the carriers without a clinical diagnosis ofHCM at the first cardiological evaluation (n ¼ 239), averagefollow-up time from birth to last cardiological evaluation was38.0+ 15.5 years (range 8.7–82.7).

Duration of follow-up in all 446 carriers from date of the DNAtest result onwards on mortality related outcome measures wason average (+SD) 3.5+1.7 years (range 0–9.8 years). Durationof follow-up from date of the DNA test result onwards on cardi-ologically evaluated outcome measures (clinical diagnosis of HCM,heart transplantation, appropriate ICD discharge) ended at thetime of last cardiological evaluation and was on average (+SD)1.7+ 1.7 years (range 0–9.2 years), as only 238 carriers hadmore than one cardiological evaluation. None of the carriers waslost to follow-up.

Two hundred and thirty-eight mutation carriers were evaluatedby cardiac function testing more than once during follow-up(Table 2, Figure 1). Between first and last evaluation [average(+SD) duration: 2.9+1.6 years; range 0.2–9.2 years], the per-centage of clinically diagnosed carriers increased from 32 to 44%

HCM mutation carriers: determining cardiological screening strategy 1163

at University L



ownloaded from


(P-value ¼ 0.011) and more carriers were evaluated for all riskfactors (61% at first evaluation and 75% at last evaluation,P-value , 0.001). The cumulative number of risk factors alsoincreased, but this increase in risk factors was not significant. Even-tually, 25 of these 238 carriers (of whom 16 with manifest HCM)had or developed ≥2 risk factors for SCD. Eighteen carriers hadan ICD implanted, 6 had a high-risk status for SCD, and theremaining 12 were regarded by their cardiologist as patients witha high risk as they carried a TNNT2 mutation previously describedas malignant (n ¼ 4), had manifest HCM and 1 risk factor for SCDand SCD in their relatives but insufficient to meet our definition(n ¼ 5), had extreme left ventricular hypertrophy (n ¼ 1), and

had manifest HCM and SCD in close relatives but insufficient tomeet our definition of a positive family history for SCD (n ¼ 2).

We also compared clinical characteristics at first evaluationbetween carriers who did not receive additional cardiologicalevaluations and carriers who did. As expected, a clinical diagnosisof HCM was more often present (P-value , 0.001) and the cumu-lative number of risk factors was higher (P-value ¼ 0.004) at firstevaluation in carriers who had been evaluated more than once.

During the average (+SD) follow-up time of 3.5+1.7 years,four (0.9%) mutation carriers died (mortality rate of 0.26% perperson-year). Two died of non-cardiovascular causes and twodied unexpectedly (SCD rate of 0.13% per person-year).

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 1 Clinical parameters of 446 mutation-carrying relatives at first cardiological evaluation

Clinical parameters All mutation carriers(n 5 446)

Mutation carriers withclinical HCM (n 5 107)

Mutation carriers withoutclinical HCM (n 5 339)

Age (years) 39.3+17.6 (446) 45.4+17.8 (107) 37.4+17.1 (339)***

Aged ,40 years 235 (446, 52.7%) 42 (107, 39.3%) 193 (339, 56.9%)***

Aged 40–65 years 181 (446, 40.6%) 50 (107, 46.7%) 131 (339, 38.6%)

Aged .65 years 30 (446, 6.7%) 15 (107, 14.0%) 15 (339, 4.4%)

Male 195 (446, 43.6%) 61 (107, 57.0%) 134 (339, 39.5%)**

Clinical diagnosis of HCM 107 (446, 23.9%) — —

Palpitations 72 (444, 16.2%) 13 (105, 12.4%) 59 (339, 17.4%)

Chest pain 22 (446, 4.9%) 7 (107, 6.5%) 15 (339, 4.4%)

Atrial fibrillation 7 (446, 1.6%) 2 (107, 1.9%) 5 (339, 1.5%)

Mutated gene

MYBPC3 366 (446, 82.1%) 89 (107, 83.2%) 277 (339, 81.7%)

MYH7 38 (446, 8.5%) 12 (107, 11.2%) 26 (339, 7.7%)

TNNT2 20 (446, 4.5%) 3 (107, 2.8%) 17 (339, 5.0%)

TPM1 20 (446, 4.5%) 3 (107, 2.8%) 17 (339, 5.0%)

MYL2 2 (446, 0.4%) 0 (107, 0.0%) 2 (339, 0.6%)

Presence of risk factors for SCD

Extreme left ventricular hypertrophy 4 (446, 0.9%) 4 (107, 3.7%) 0 (339, 0.0%)***

Non-sustained VT 24 (318, 7.5%) 14 (82, 17.1%) 10 (236, 4.2%)**

,50 years 10 (231, 4.3%) 5 (53, 9.4%) 5 (178, 2.8%)

≥50 years 14 (87, 16.1%) 9 (29, 31.0%) 5 (58, 8.6%)**

Abnormal blood pressure response 44 (296, 14.8%) 13 (76, 17.1%) 31 (220, 14.1%)

,50 years 32 (215, 14.8%) 9 (49, 18.4%) 23 (166, 13.9%)

≥50 years 12 (81, 14.8%) 4 (27, 14.8%) 8 (54, 14.8%)

Unexplained syncope 19 (446, 4.3%) 3 (107, 2.8%) 16 (339, 4.7%)

Family history of SCD 73 (446, 16.3%) 10 (107, 9.3%) 63 (339, 18.6%)

Previous cardiac arrest or VT 1a (446, 0.2%) 1 (107, 0.9%) 0 (339, 0.0%)

Complete evaluation of all six risk factors 262 (446, 58.7%) 71 (107, 66.4%) 191 (339, 56.3%)

Cumulative number of risk factors for SCD

0 risk factors 298 (446, 66.8%) 70 (107, 65.4%) 228 (339, 67.3%)

1 risk factors 130 (446, 29.1%) 28 (107, 26.2%) 102 (339, 30.1%)

≥2 risk factors 18 (446, 4.0%) 9 (107, 8.4%) 9 (339, 2.7%)

Data are mean+ SD or number and proportion (%).HCM, hypertrophic cardiomyopathy; SCD, sudden cardiac death; VT, ventricular tachycardia.aWoman with manifest HCM at first cardiological evaluation at age 79, who developed ventricular fibrillation in the setting of a myocardial infarction at age 55 (at that time nomanifest HCM).Significant differences between carriers with and without a clinical diagnosis of HCM:*P-value , 0.05, **P-value , 0.01, *** P-value , 0.001.


at University L



ownloaded from


A female carrier died at the age of 80 years with documented ven-tricular fibrillation. She had been diagnosed with HCM at the firstevaluation at age 76 and had no risk factors for SCD, but bothNSVT and ABPR had never been evaluated. The other unexpecteddeath was in a man of 59 years who died during his sleep and whohad had no complaints the previous day. He had been diagnosedwith HCM at the first cardiological evaluation at age 58. He hadone risk factor for SCD; NSVT was present during Holter record-ing and exercise testing. None of the carriers received a hearttransplantation and appropriate ICD discharge did not occur inthe 18 carriers who had an ICD implanted. A high-risk status forSCD, our proxy outcome measure for SCD, was present in 17(3.8%) carriers during follow-up (2.4% per person-year).

Kaplan–Meier analyses and incidenceIn total, 136 (30%) mutation carriers were diagnosed with HCM atfirst cardiological evaluation or during follow-up. A clinical diagno-sis of HCM was made after 4.5 years of follow-up in 50% ofcarriers [95% confidence interval (CI): 2.7–6.3 years; Figure 2].Overall, the median age to a clinical diagnosis of HCM was 61.6years (95% CI: 57.4–65.7).

The presence of a clinical diagnosis in time (disease penetrance)differed by gender and age. In male carriers, 50% had a clinical diag-nosis after 2.5 years, whereas in female carriers 50% had a clinicaldiagnosis only after 5.4 years (P-value ¼ 0.002[]). For males andfemales, the median ages were 57.3 and 65.7 years, respectively(Figure 3). The steepness of the increase in a clinical diagnosis ofHCM at different ages shows that older carriers are more proneto develop a clinical diagnosis of HCM (Figure 3).

Since manifest disease could have been present long before thefirst cardiological evaluation, we also assessed disease penetranceand incidence in the 163 carriers who had no clinical diagnosis atfirst cardiological evaluation and received at least one furthercardiological evaluation (Figures 4 and 5). The percentage of car-riers diagnosed with HCM per patient-year was lower than 10%in carriers aged ,40 years and higher than 10% in the older car-riers (Figure 5). Of the 163 carriers in Figure 5, only 11 carrierswere ,15 years of whom only one (a female) developedhypertrophy.

DiscussionA considerable proportion of asymptomatic HCM mutation car-riers identified after predictive genetic testing had manifest HCMat first cardiological evaluation or developed manifest diseaseduring follow-up. Penetrance of manifest HCM is known to be age-dependent and HCM is detected more often in males.10– 12,17 Thisis also shown by our data because older age and male gender wererisk factors for developing manifest HCM. The overrepresentationof males with a clinical diagnosis of HCM in the literature and inthis study could also in part be due to the fact that diagnostic echo-cardiographic criteria are not adjusted for body surface area, whichis in general smaller in females. Disease penetrance in our studywas lower than previously described,10,11 probably becauseaffected relatives and probands were excluded. However, itshows that disease can still become manifest at old age andcardiological evaluations should continue until advanced age.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 2 Clinical parameters at first and last cardiological evaluation of 238 mutation carriers with >1 cardiologicalevaluation and of 208 carriers with only a first evaluation

Clinical parameters Mutation carriers with 1cardiological evaluation(n 5 208) first evaluation

Mutation carriers with >1cardiological evaluation(n 5 238) first evaluation

Mutation carriers with >1cardiological evaluation(n 5 238) last evaluation

Clinical diagnosis of HCM 31 (208, 14.9%)†† 76 (238, 31.8%) 104 (238, 43.7%)*

Risk factors for SCD

Extreme left ventricular hypertrophy 1 (208, 0.5%) 3 (238, 1.3%) 4 (238, 1.7%)

Non-sustained VT 6 (144, 4.2%) 18 (174, 10.3%) 29 (205, 13.7%)

Abnormal blood pressure response 13 (131, 9.9%)† 31 (165, 18.8%) 31 (165, 18.8%)

Unexplained syncope 4 (208, 1.9%)† 15 (238, 6.3%) 15 (238, 6.3%)

Family history of SCD 35 (208, 16.8%) 38 (238, 16.0%) 38 (238, 16.0%)

Previous cardiac arrest or VT 1 (208, 0.5%) 0 (238, 0.0%) 0 (238, 0.0%)

Complete evaluation of all six risk factors 118 (208, 56.7%) 144 (238, 60.5%) 180 (238, 75.2%)***

Cumulative number of risk factors for SCD

0 risk factors 149 (208, 71.6%)†† 149 (238, 62.6%) 131 (238, 55.0%)

1 risk factors 57 (208, 27.4%) 73 (238, 30.7%) 82 (238, 34.5%)

≥2 risk factors 2 (208, 1.0%) 16 (238, 6.7%) 25 (238, 10.5%)

Data are mean+ SD or number and proportion (%). Mean F-U until last cardiological evaluation 2.87+ 1.58 years.HCM, hypertrophic cardiomyopathy; SCD, sudden cardiac death; VT, ventricular tachycardia.Significant differences between carriers with follow-up at first and at last evaluation: *P-value , 0.05, ***P-value , 0.001.Significant differences between carriers without follow-up and carriers with follow-up at first evaluation: †P-value , 0.05, ††P-value , 0.01.


at University L



ownloaded from


Figure 1 Flow chart showing outcomes on a clinical diagnosis of hypertrophic cardiomyopathy and risk factors for sudden cardiac death atfirst and last cardiological evaluation. HCM+, clinical diagnosis of hypertrophic cardiomyopathy; HCM2, no clinical diagnosis of hypertrophiccardiomyopathy; RF0, zero risk factors for sudden cardiac death (SCD); RF1, one risk factor for sudden cardiac death; RF ≥ 2, two or more riskfactors for sudden cardiac death; F-U, follow-up.

Figure 2 Clinical diagnosis of hypertrophic cardiomyopathy and high-risk status for sudden cardiac death (manifest hypertrophic cardiomyo-pathy and ≥2 risk factors) during follow-up.


at University L



ownloaded from


Risk factors for SCD were frequently present in predictivelytested carriers both with and without manifest disease. A majority(53%) of carriers was evaluated cardiologically more than once.

These carriers had significantly longer follow-up—they hadreceived their DNA test longer ago—increasing the likelihood ofan additional evaluation. A recent study of our group, however,

Figure 3 Clinical diagnosis of hypertrophic cardiomyopathy during life in male (F) and female (C) mutation carriers.

Figure 4 Clinical diagnosis of hypertrophic cardiomyopathy and high-risk status for sudden cardiac death (manifest hypertrophic cardiomyo-pathy and ≥2 risk factors) during follow-up in mutation carriers not diagnosed with manifest hypertrophic cardiomyopathy at first cardiologicalevaluation.


at University L



ownloaded from


showed that a considerable proportion of carriers received nocardiological follow-up because the cardiologist deemed follow-upunnecessary or because first evaluation showed no manifestdisease.20 The present study also demonstrated that carrierswho received additional evaluations more often had manifestdisease and a higher number of risk factors. Likely, the presenceof risk factors and hypertrophy are reasons for the cardiologistfor further evaluation, since they are associated with an unfavour-able prognosis in HCM patients in the literature.

The prognostic impact of risk factors for SCD in HCM patients(i.e. with manifest disease) has been confirmed in many studies, andthey can therefore be used in risk stratification in mutation carrierswith manifest disease. However, it is still unclear whether theserisk factors are also associated with SCD in carriers without mani-fest disease, although SCD has been described in this group.21 Dueto the low incidence of SCD in our study, we were unable toevaluate the prognostic impact of these risk factors on SCD.While our study with medium-term follow-up suggests that therisk of SCD is probably small in this population, a longer follow-upis needed to draw more definite conclusions. The low risk of SCDin our cohort may also be the result of selection bias. Since rela-tives or mutation carriers with an unfavourable prognosis areeither dead or diagnosed with manifest disease because of symp-toms and therefore excluded from this study, predictively testedmutation carriers are probably more likely to be healthy or asymp-tomatic until they were tested at a mean age of 39 years and prob-ably have a relatively favourable prognosis.

Since the risk of SCD in predictively tested carriers is probablyvery low, one could argue that intensive cardiological evaluationincluding risk stratification as recommended in international guide-lines is unnecessary. The guidelines recommend annual evaluationincluding risk stratification for SCD in all carriers. As SCDoccurred only twice, both times in carriers with manifest HCM,our study suggests that risk stratification for SCD may be

omitted as long as HCM is not yet manifest. Our results ondisease penetrance and incidence provide more insight in theoptimal frequency of cardiological evaluations. The incidence of aclinical diagnosis of HCM during follow-up after the first cardiolo-gical evaluation differs with age, with less carriers per year devel-oping HCM under the age of 40 years (Figure 5). It is unlikelythat this is due to the screening interval, since this is not differentin carriers of different ages. Our data suggest that in carriers ,40years without hypertrophy at first evaluation hypertrophy devel-ops more slowly, although the small number of carriers ,15years of age allows no definite conclusions for this age group.Therefore, the frequency of cardiological evaluations in mutationcarriers between 15 and 40 years without manifest disease canpossibly be decreased to, for example, once every 2 years. Ourdata also show that HCM can still become manifest at higher ageand that cardiological evaluations should therefore continue untiladvanced age.

Study limitationsAlthough our group of mutation carriers is of considerable size,distribution of a few characteristics was skewed. Significantly lessmen than women were included. This could be due to the factthat males are more often affected, and affected relatives and pro-bands were excluded from this study. Most carriers had a mutationin the MYBPC3 gene due to the presence of three frequent Dutchfounder mutations in the MYBPC3 gene.22,23 Although there wasno association between the mutated gene and outcome measures,definite genotype–phenotype correlations with respect to age ofdiagnosis and risk factors for SCD cannot be made, and it is uncer-tain if our results can be generalized to predictively tested carriersof a mutation in other sarcomeric genes. Mutations in the MYBPC3gene, however, are worldwide one of the most frequent causesof HCM, accounting for �30% of all identified HCMmutations.7,24– 27

Unfortunately, not all mutation carriers received a Holterrecording and/or exercise test at first cardiological evaluation.Other studies show that complete stratification of all six riskfactors is not customary practice in HCM patients,5,28,29 not tomention the practice in asymptomatic HCM mutation carriers.Because one or more risk factors were less often present in thecarriers without a complete evaluation of risk factors, it seemslikely that the cumulative number of risk factors for SCD asfound in the entire cohort is underestimated. Other clinical charac-teristics were not associated with completeness of risk stratifica-tion making selection bias unlikely.

Since 24% of the carriers already had a clinical diagnosis of HCMat the time of the first cardiological evaluation and DNA diagnosis,the HCM diagnosis-free survival times estimated in the presentsample are biased upwards. Due to the presence of asymptomaticHCM, more precise estimates can be only be obtained by regularscreening of mutation carriers that were HCM free at the firstevaluation, preferably starting at a young age to prevent bias dueto selection.

Predictive genetic screening occurred in tertiary care centres.Because this is the only setting where genetic testing for HCM ispossible in the Netherlands, we do not expect selection biasbased upon the type of centre.

Figure 5 Mutation carriers diagnosed with hypertrophic cardi-omyopathy per 100 person-years during follow-up in mutationcarriers not diagnosed with manifest hypertrophic cardiomyopa-thy at first cardiological evaluation and standard deviation.


at University L



ownloaded from


ConclusionsOf the mutation-carrying relatives, 107 (24%) had manifest HCM atfirst cardiological evaluation, which increased to 30% duringfollow-up. Older age and male gender were independent riskfactors for manifest disease. Manifest HCM appears to developmore slowly in carriers ,40 years, possibly allowing less frequentcardiological evaluations (for example once every 2 years insteadof annually) in carriers between 15 and 40 years as long as hyper-trophy is absent.

One or more risk factors for SCD were present in 33% of car-riers at first evaluation. Seventeen (3.8%) carriers had a high-riskstatus at first evaluation or during follow-up. The low SCD eventrate suggests that the risk of SCD is very low in predictivelytested mutation carriers especially when disease is not manifestyet. Risk stratification for SCD could therefore probably beomitted in HCM mutation carriers as long as manifest disease isabsent.

Our results suggest that the SCD event rate in predictivelytested mutation-carrying relatives is lower than in probands, andthat the ACC/ESC recommendations need revision to accommo-date for mutation-carrying relatives, i.e. the recommended screen-ing policy appears unnecessary intensive and frequent. More recentguidelines already have adapted the screening frequency inmutation carriers without manifest disease; however, they stilladvise intensive screening including risk stratification for SCD.30,31

Prolonged follow-up is needed to (i) evaluate the prognosticimpact of risk factors for SCD, and (ii) to determine the optimalscreening policy (risk stratification, screening interval) in asympto-matic mutation-carrying relatives with a wide spectrum of genemutations. Including probands and affected relatives could alsoprovide more insight in the natural history of HCM.

AcknowledgementsWe would like to thank Michael Tanck for statistical support.

FundingThis work was supported by ZonMw (grant number 62000010); andthe Netherlands Heart Foundation (grant number 2003 D302). Thefunding organizations have had no involvement in study design, collec-tion, analysis, and interpretation of data; in the writing of this paper andin the decision to submit the paper for publication.

Conflict of interest: none declared.

References1. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE,

Shah PM, Spencer WH III, Spirito P, Ten Cate FJ, Wigle ED. American College ofCardiology/European Society of Cardiology clinical expert consensus documenton hypertrophic cardiomyopathy. A report of the American College of Cardiol-ogy Foundation Task Force on Clinical Expert Consensus Documents and theEuropean Society of Cardiology Committee for Practice Guidelines. J Am CollCardiol 2003;42:1687–1713.

2. Cannan CR, Reeder GS, Bailey KR, Melton LJI, Gersh BJ. Natural history of hyper-trophic cardiomyopathy. A population-based study, 1976 through 1990. Circula-tion 1995;92:2488–2495.

3. Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, Graham KJ,Burton DA, Cecchi F. Epidemiology of hypertrophic cardiomyopathy-relateddeath: revisited in a large non-referral-based patient population. Circulation2000;102:858–864.

4. Epstein AE, Dimarco JP, Ellenbogen KA, Estes NA III, Freedman RA, Gettes LS,Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK,Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormal-ities: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Commit-tee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation ofCardiac Pacemakers and Antiarrhythmia Devices). Circulation 2008;117:e350–e408.

5. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE,Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NAM, Favale S,Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G,Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention ofsudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405–412.

6. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M,Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA,Roden DM, Silka MJ, Tracy C, Smith SC Jr, Jacobs AK, Adams CD, Antman EM,Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B,Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J,McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhyth-mias and the prevention of sudden cardiac death: a report of the AmericanCollege of Cardiology/American Heart Association Task Force and the EuropeanSociety of Cardiology Committee for Practice Guidelines (Writing Committee toDevelop Guidelines for Management of Patients With Ventricular Arrhythmiasand the Prevention of Sudden Cardiac Death): developed in collaboration withthe European Heart Rhythm Association and the Heart Rhythm Society. Circula-tion 2006;114:e385–e484.

7. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A,Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K,Hainque B, Komajda M. Hypertrophic cardiomyopathy: distribution of diseasegenes, spectrum of mutations, and implications for a molecular diagnosis strategy.Circulation 2003;107:2227–2232.

8. Charron P, Carrier L, Dubourg O, Tesson F, Desnos M, Richard P, Bonne G,Guicheney P, Hainque B, Bouhour JB, Mallet A, Feingold J, Schwartz K,Komajda M. Penetrance of familial hypertrophic cardiomyopathy. Genet Couns1997;8:107–114.

9. Christiaans I, Birnie E, van Langen IM, van Spaendonck-Zwarts KY, van Tintelen JP,van den Berg MP, Atsma DE, Helderman-van den Enden ATJM, Pinto YM,Hermans-van Ast JF, Bonsel GJ, Wilde AAM. The yield of risk stratification forsudden cardiac death in hypertrophic cardiomyopathy myosin-binding proteinC gene mutation carriers: focus on predictive screening. Eur Heart J 2010;31:842–848.

10. Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, Seidman CE.Development of left ventricular hypertrophy in adults in hypertrophic cardiomyo-pathy caused by cardiac myosin-binding protein C gene mutations. J Am CollCardiol 2001;38:315–321.

11. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W,Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE. Mutationsin the gene for cardiac myosin-binding protein C and late-onset familial hyper-trophic cardiomyopathy. N Engl J Med 1998;338:1248–1257.

12. Olivotto I, Maron MS, Adabag AS, Casey SA, Vargiu D, Link MS, Udelson JE,Cecchi F, Maron BJ. Gender-related differences in the clinical presentation andoutcome of hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;46:480–487.

13. Lekanne Deprez RH, Muurling-Vlietman JJ, Hruda J, Baars MJ, Wijnaendts LC,Stolte-Dijkstra I, Alders M, van Hagen JM. Two cases of severe neonatal hyper-trophic cardiomyopathy caused by compound heterozygous mutations in theMYBPC3 gene. J Med Genet 2006;43:829–832.

14. Christiaans I, Birnie E, Bonsel GJ, Wilde AAM, van Langen IM. Uptake of geneticcounselling and predictive DNA testing in hypertrophic cardiomyopathy. Eur JHum Genet 2008;16:1201–1207.

15. McKenna WJ, Spirito P, Desnos M, Dubourg O, Komajda M. Experience fromclinical genetics in hypertrophic cardiomyopathy: proposal for new diagnostic cri-teria in adult members of affected families. Heart 1997;77:130–132.

16. Elliott PM, Gimeno Blanes JR, Mahon NG, Poloniecki JD, McKenna WJ. Relationbetween severity of left-ventricular hypertrophy and prognosis in patients withhypertrophic cardiomyopathy. Lancet 2001;357:420–424.

17. Elliott PM, Gimeno JR, Tome MT, Shah J, Ward D, Thaman R, Mogensen J,McKenna WJ. Left ventricular outflow tract obstruction and sudden death riskin patients with hypertrophic cardiomyopathy. Eur Heart J 2006;27:1933–1941.

18. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an indepen-dent marker of sudden death risk in young patients. J Am Coll Cardiol 2003;42:873–879.


at University L



ownloaded from


19. Michels M, Soliman OI, Phefferkorn J, Hoedemaekers YM, Kofflard MJ, Dooijes D,Majoor-Krakauer D, Ten Cate FJ. Disease penetrance and risk stratification forsudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutationcarriers. Eur Heart J 2009;30:2593–2598.

20. Christiaans I, van Langen IM, Birnie E, Bonsel GJ, Wilde AA, Smets EM. Geneticcounseling and cardiac care in predictively tested hypertrophic cardiomyopathymutation carriers: the patients’ perspective. Am J Med Genet A 2009;149A:1444–1451.

21. Christiaans I, Deprez RHLD, van Langen IM, Wilde AAM. Ventricular fibrillation inMYH7-related hypertrophic cardiomyopathy before onset of ventricular hyper-trophy. Heart Rhythm 2009;6:1366–1369.

22. Alders M, Jongbloed R, Deelen W, van den Wijngaard A, Doevendans P, tenCate F, Regitz-Zagrosek V, Vosberg HP, van Langen I, Wilde A, Dooijes D,Mannens M. The 2373insG mutation in the MYBPC3 gene is a founder mutation,which accounts for nearly one-fourth of the HCM cases in the Netherlands. EurHeart J 2003;24:1848–1853.

23. Christiaans I, Nannenberg EA, Dooijes D, Jongbloed RJ, Michels M, Postema PG,Majoor-Krakauer D, van den WA, Mannens MM, van Tintelen JP, van LI,Wilde AA. Founder mutations in hypertrophic cardiomyopathy patients in theNetherlands. Neth Heart J 2010;18:248–254.

24. Andersen PS, Havndrup O, Bundgaard H, Larsen LA, Vuust J, Pedersen AK,Kjeldsen K, Christiansen M. Genetic and phenotypic characterization of mutationsin myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophiccardiomyopathy: total or partial haploinsufficiency. Eur J Hum Genet 2004;12:673–677.

25. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, Ackerman MJ.Myosin binding protein C mutations and compound heterozygosity in hyper-trophic cardiomyopathy. J Am Coll Cardiol 2004;44:1903–1910.

26. Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopa-thy: from bench to the clinics. J Cardiovasc Electrophysiol 2008;19:104–110.

27. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic impli-cations of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol 2009;54:201–211.

28. Biagini E, Coccolo F, Ferlito M, Perugini E, Rocchi G, Bacchi-Reggiani L, Lofiego C,Boriani G, Prandstraller D, Picchio FM, Branzi A, Rapezzi C. Dilated-hypokineticevolution of hypertrophic cardiomyopathy: prevalence, incidence, risk factors,and prognostic implications in pediatric and adult patients. J Am Coll Cardiol2005;46:1543–1550.

29. Kofflard MJ, Ten Cate FJ, van der Lee C, van Domburg RT. Hypertrophic cardi-omyopathy in a large community-based population: clinical outcome and identifi-cation of risk factors for sudden cardiac death and clinical deterioration. J Am CollCardiol 2003;41:987–993.

30. Charron P, Arad M, Arbustini E, Basso C, Bilinska Z, Elliott P, Helio T, Keren A,McKenna WJ, Monserrat L, Pankuweit S, Perrot A, Rapezzi C, Ristic A,Seggewiss H, van LI, Tavazzi L. Genetic counselling and testing in cardiomyopa-thies: a position statement of the European Society of Cardiology WorkingGroup on Myocardial and Pericardial Diseases. Eur Heart J 2010;31:2715–2726.

31. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA.Genetic evaluation of cardiomyopathy—a Heart Failure Society of America prac-tice guideline. J Card Fail 2009;15:83–97.


at University L



ownloaded from


Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide...

Documents

Transcript of Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide...