Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated With Mutations in Plakophilin-2

Clinical Features of Arrhythmogenic Right VentricularDysplasia/Cardiomyopathy Associated With

Mutations in Plakophilin-2Darshan Dalal, MD, MPH; Lorraine H. Molin, BS, MS; Jonathan Piccini, MD;

Crystal Tichnell, MGC; Cynthia James, PhD, ScM; Chandra Bomma, MD; Kalpana Prakasa, MD;Jeffrey A. Towbin, MD; Frank I. Marcus, MD; Philip J. Spevak, MD; David A. Bluemke, MD, PhD;

Theodore Abraham, MD; Stuart D. Russell, MD; Hugh Calkins, MD; Daniel P. Judge, MD

Background—Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterizedby right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomalprotein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations inanother large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations.

Methods and Results—DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations inPKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation andthose with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of thepatients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated,families. The mean age at presentation was lower among those with a PKP2 mutation (28�11 years) than in thosewithout (36�16 years) (P�0.05). The age at median cumulative symptom-free survival (32 versus 42 years) andat the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2mutation than among those without a PKP2 mutation (P�0.05). Inducibility of ventricular arrhythmias on anelectrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventriculartachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only amongpatients without a PKP2 mutation (P�0.05).

Conclusions—Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutationexperience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/Cpatients. (Circulation. 2006;113:1641-1649.)

Key Words: arrhythmia � cardiomyopathy � genetics � sudden death � tachyarrhythmias

Arrhythmogenic right ventricular dysplasia/cardiomyopathy(ARVD/C) is an inherited cardiomyopathy characterized

by right ventricular (RV) dysfunction and ventricular arrhyth-mias, which may lead to sudden cardiac death.1–8 Studies haveshown that ARVD/C is present in up to 20% of individuals thatexperience sudden cardiac death and is even more commonamong athletes who die suddenly.9–12 Although fatty or fibro-fatty replacement of the myocardium of the RV is the patholog-ical hallmark of the disease, biopsy of the right ventricle is oflimited value in establishing a clinical diagnosis.11,13 Clinically,the diagnosis of ARVD/C is established by a set of criteria

proposed by a task force based on subjective grading of clinicalfindings associated with the condition.4,14 Molecular diagnosisby identification of genetic mutations may also be an importantscreening tool for predicting risk of ARVD/C in asymptomaticfamily members of an affected individual.

Editorial p 1634Clinical Perspective p 1649

Several genes and genetic loci have been described inassociation with ARVD/C. Mutations in the gene encodingdesmoplakin (DSP) have been described in both dominant

Received June 14, 2005; revision received November 16, 2005; accepted December 16, 2005.From the Division of Cardiology (D.D., L.H.M., J.P., C.T., C.J., C.B., K.P., D.A.B., T.A., S.D.R., H.C., D.P.J.), Department of Radiology

(D.A.B.), and Division of Pediatric Cardiology (P.J.S.), Johns Hopkins University School of Medicine, Baltimore, Md; Section of Cardiology,Sarver Heart Center, University of Arizona, Tucson (F.I.M.); and Department of Pediatrics (Cardiology), Molecular and Human Genetics, BaylorCollege of Medicine, Houston, Tex (J.A.T.).

The online-only Data Supplement, which contains Table I and Table II, can be found at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.105.568642/DC1.

Correspondence to Daniel Judge, MD, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1049, Baltimore, MD 21205.E-mail djudge@jhmi.edu

Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.568642

Arrhythmia/Electrophysiology

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and recessive forms of ARVD/C.15,16 To date, 5 families havebeen described with mutations in DSP resulting in domi-nantly inherited ARVD/C.16,17 Another family has beendescribed with a novel mutation in desmoplakin that results indominantly inherited left ventricular cardiomyopathy.15

Naxos disease, also known as palmoplantar keratoderma witharrhythmogenic RV cardiomyopathy, is an autosomal reces-sive disorder caused by mutations in JUP, encoding junc-tional plakoglobin.18,19 One atypical form of disease, cate-cholaminergic polymorphic ventricular tachycardia (VT), iscaused by mutations in RYR2, encoding a cardiac ryanodinereceptor.20–22 Finally, Beffagna and colleagues23 have asso-ciated the gene encoding transforming growth factor-�3 withARVD/C.

Recently, Gerull and colleagues24 reported mutations inPKP2, encoding the desmosomal protein plakophilin-2,associated with ARVD/C. Mutations in this gene wereshown to be present in 27% of the 120 unrelated ARVD/Cpatients of Western European descent. The purpose of ourstudy was to validate the frequency of mutations in thisgene in another large series of ARVD/C patients and toexamine the phenotypic characteristics associated withmutations in this gene among patients with ARVD/C.

MethodsPatient RecruitmentFifty-eight unrelated ARVD/C patients, who gave written in-formed consent to participate in research genetic screening, wereidentified from the Johns Hopkins ARVD registry, 15 of whomalso enrolled in the National Institutes of Health MulticenterClinical Trial of ARVD. The study protocol was approved by theJohns Hopkins School of Medicine institutional review board.Clinical history and medical records were obtained at enrollment.Subsequent to the initial enrollment, patients were contacted atyearly intervals to determine the occurrence of clinical eventsduring that period.

Patient Evaluation and Clinical TestingThe patients’ medical history was obtained both by review ofmedical records and by patient interview. Information regardingthe presenting symptoms as well as major clinical events, includ-ing implantation of implantable cardioverter/defibrillators (ICD)and ICD interventions, during the follow-up was recorded by agefor each patient. Family history was determined by interviewingpatients and their family members. Palpitations were defined asawareness of one’s own heartbeat, syncope as a transient loss ofconsciousness, near-syncope as an impending loss of conscious-ness associated with lightheadedness or dizziness, diaphoresis asepisodes of profuse sweating, and dyspnea as awareness of one’sown breathing or difficulty in breathing.

Results of noninvasive testing, including ECG (n�58), signal-averaged ECG (SAECG) (n�53), Holter monitoring (n�41), andimaging studies (n�58) including echocardiogram and MRI wereobtained. QRS duration (n�56) and the duration of the S-waveupstroke (n�48) on a 12-lead ECG were measured with the imageanalysis software SigmaScan Pro (version 5.0; Systat SoftwareInc, Richmond, Calif).25 The presence of epsilon waves and theextent of T-wave inversion on precordial leads of the standardECG were also determined.25 SAECGs using time-domain anal-ysis with a bandpass filter of 40 Hz were evaluated in patientswho did not have a preexisting complete or incomplete rightbundle-branch block pattern. The SAECG was considered posi-tive for late potentials if any 2 of the following were present: (1)filtered QRS duration �114 ms; (2) low-amplitude signal dura-tion �38 ms; or (3) RMS �20 mV.26 The results of Holter

monitoring and exercise stress test, in addition to the standard12-lead ECGs, were used to determine the presence of sustainedor nonsustained VT as well as the morphology of ventricularectopy and/or VT. The severity and extent of RV dysfunction wasalso determined by imaging studies and was designated as“diffuse” or “mild.” Diffuse disease was defined as global RVdilation and reduced RV ejection fraction.14 Mild disease wasdefined as localized or regional RV abnormalities, such assegmental RV wall motion abnormalities (hypokinetic or akineticareas) without RV dilation or evidence of RV systolicdysfunction.

An electrophysiology study was performed on 53 of the 58patients in the study population and in 45 of the 48 patients whoreceived an ICD. The results of the electrophysiology study weredesignated as “inducible” if 1 or more morphologies of sustainedVT or ventricular fibrillation were induced during the procedureor “not inducible” if no VT or ventricular fibrillation could beinduced during the procedure. Histopathological examinationafter a biopsy was performed in 26 patients. In each case,endomyocardial biopsy was performed through a right internaljugular approach. Biopsies were evaluated for presence or ab-sence of fibrofatty replacement of myocardium as previouslydescribed.11

Diagnosis of ARVD/CThe diagnosis of ARVD/C was established on the basis of thecriteria set by the Task Force of the Working Group of Myocar-dial and Pericardial Disease of the European Society of Cardiol-ogy and of the Scientific Council on Cardiomyopathies of theInternational Society and Federation of Cardiology.14

Genotype AnalysisFor each patient, genomic DNA was extracted from leukocytespresent in whole blood with the use of QIAmp DNA blood maxikits (Qiagen, Inc, Valencia, Calif). Amplification of each exon forPKP2 was performed as previously described, with primer se-quence that was provided by Ludwig Thierfelder.24 Bidirectionalsequence chromatography was performed with the use of AppliedBiosystems (Foster City, Calif) 3730 DNA Analyzer. Analysis ofchromatograms was performed with Sequencher 3.0 (Gene CodesCorp, Ann Arbor Mich) and with MacVector (Accelrys, SanDiego, Calif) for ClustalW alignment. All novel mutations wereanalyzed in a population of 200 individuals (400 chromosomes)from a panel of unrelated unaffected individuals. Control DNAwas obtained from NIGMS Human Genetic Cell Repositorythrough the Coriell Institute for Medical Research, and approxi-mately half of the controls were matched to the mutation carriersby ancestry.

Statistical AnalysisThe study population was divided into 2 groups: those with amutation in the PKP2 gene (n�25) and those with no detectablemutation in the PKP2 gene (n�33). Phenotypic characteristics,including demographics, presenting symptoms, participation inathletics, and clinical characteristics, were compared between the2 groups. Continuous variables were expressed as mean�SD, andcategorical variables were expressed as frequency (percentage).Continuous variables between the 2 groups were compared byunpaired t test, and the categorical variables were compared by �2

test. Kaplan-Meier analysis was used to determine the cumulativesymptom-free and arrhythmia-free survival since birth (ie, age atfirst symptom/arrhythmia), which was compared between the 2groups by log-rank test.

A subgroup of patients with an ICD (n�48) was identified fromthe study population. Kaplan-Meier analysis was used to deter-mine the cumulative rate of appropriate ICD interventions sinceimplantation. The effect of the previously described predictors,including inducibility on an electrophysiology study, severity ofstructural RV disease, and presence of prior spontaneous VT, oncumulative rates of ICD intervention was assessed in each group

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by Kaplan-Meier analysis.27 The Kaplan-Meier curves werecompared by log-rank test.

To eliminate the potential confounding due to presence offamily history suggestive of ARVD/C in our survival analyses, allstatistical analyses were repeated after exclusion of patients whocame to medical attention because of the presence of familyhistory suggestive of ARVD/C. In addition, we also adjusted forpresence of family history in a Cox proportional hazards model.All statistical analyses were performed with the use of STATAstatistical software (version 8.2; College Station, Tex). A proba-bility value �0.05 was considered statistically significant.

The authors had full access to the data and take responsibilityfor its integrity. All authors have read and agree to the manuscriptas written.

ResultsPatient Population and MutationsThe patient population consisted of 58 patients diagnosedwith ARVD/C. Clinical characteristics of the study popu-lation are shown in Data Supplement Table I. Twenty-five(43%) of the 58 patients had a mutation in PKP2, encodingplakophilin-2. Specific information for each mutation islisted in Table 1 and shown schematically in Figure 1.There were 13 different mutations among the 25 individ-uals with mutations in this cohort, with identical mutationsin several apparently unrelated families. Haplotypes weredetermined for probands with recurrent mutations with the

use of polymorphic microsatellite markers that are in closeproximity to PKP2.24 Common haplotypes were not iden-tified in cases of identical mutations. Six mutations wereidentified that have not been reported previously. None ofthese novel mutations was found in a population of 200unrelated, unaffected controls (400 chromosomes). Amongthe 13 mutations identified, 6 were insertion-deletionmutations, 3 altered a critically conserved nucleotide thatforms the intron-exon splice site, 2 were nonsense muta-tions resulting in a premature termination codon, and 2were missense mutations disrupting highly conserved res-idues in functional domains of plakophilin-2. The previ-ously described S140F mutation disrupts a conservedresidue, as reported by Gerull and colleagues.24 The novel

TABLE 1. Types of Mutation in the Study Population

No.* Exon Nucleotide Change Amino Acid Change Reported Previously Type

1 10 2011delC P671fsX683 Novel Deletion

2 5 1368delA N456fsX458 Novel Deletion

3 1 145_148delCAGA S50fsX110 Reported Deletion

5 13 2509delA V837fsX930 Reported Deletion

6 12 2489�1G3A Mutant splice product Reported Splice site

7 5 1171–2A3G Mutant splice product Novel Splice site

8 11 2146–1G3C Mutant splice product Reported Splice site

9 11 2197_2202insGdelCACACC A733fsX740 Novel Deletion

11 7 1613G3A W538X Novel Nonsense

12 5 1271T3C F424S Novel Missense

13 2 235C3T R79X Reported Nonsense

15 7 1642delG V548fsX562 Reported Deletion

21 3 419C3T S140F Reported Missense

*Patient number corresponds to patient numbers in Table I.

Figure 1. Schematic representation of the PKP2 mutations inour study population. *Mutations that have not been previouslyreported.

Dalal et al Clinical Features of PKP2-Induced ARVD 1643

F424S mutation similarly disrupts a highly conservedresidue within a functional armadillo domain.Plakophilin-2 in mouse, dog, cow, chick, frog, puffer fish,zebra fish, and Xenopus all have F (phenylalanine) in thisposition, as does human plakophilin-1.

Demographics and PresentationThe demographics and presenting symptoms of each ofthese patients are listed in Table I and summarized inTable 2. There were 35 men (60%) in the study population.The mean age at presentation was 33�14 years. Thosewith a PKP2 mutation presented at an earlier age (28�11years) than those without (36�16) years (P�0.05). Thirtysubjects (52%) were involved in competitive athletics.There was no statistically significant difference in genderand involvement in athletics between the 2 groups.

Palpitations and syncope were the most common pres-enting symptoms. Fourteen patients were asymptomatic atthe time of first presentation. ARVD/C was suspected inthese patients on the basis of family history suggestive ofARVD/C or premature sudden cardiac death or an abnor-mal ECG pattern at a routine physical examination (TableI). There were no differences in the presenting symptomsbetween the 2 groups.

Clinical Characteristics of PatientsShown in Table I and summarized in Table 3 are the resultsof clinical testing of the 58 patients in the study popula-tion. The diagnosis of ARVD/C was established on thebasis of presence of 2 major criteria (n�24), 1 major plus2 minor criteria (n�27), or 4 minor criteria (n�7). Theresults of clinical testing between the 2 groups were notstatistically different.

Freedom From Symptoms and ArrhythmiaFigure 2 shows Kaplan-Meier analysis for the cumulativesymptom-free survival since birth among ARVD/C pa-

tients with a PKP2 mutation and those without a mutation.The age at median cumulative symptom-free survivalamong those with a PKP2 mutation was lower (32 years)than among those without (42 years) a PKP2 mutation(P�0.05).

Figure 3 shows Kaplan-Meier analysis for the cumula-tive arrhythmia-free survival since birth in ARVD/C pa-tients with a PKP2 mutation and those without. The age atmedian cumulative arrhythmia-free survival among thosewith a PKP2 mutation was lower (34 years) than amongthose without (46 years) a PKP2 mutation (P�0.05).

ICD TherapyLong-term follow-up data of 48 patients with an ICD (21with a PKP2 mutation) were available for analysis. Over amean follow-up of 5�4 years, 28 (58%) of the 48 patientsexperienced an appropriate ICD intervention. The longestevent-free follow up time was 9 years. Among theARVD/C patients with a PKP2 mutation, 11 (52%) expe-rienced an appropriate ICD intervention, whereas amongthose without a PKP2 mutation, 17 (63%) experiencedappropriate ICD interventions during the follow up(P�0.46). The overall incidence rate of appropriate ICDintervention did not differ significantly between patientswith a PKP2 mutation (0.22 intervention per year) andthose without a PKP2 mutation (0.32 intervention peryear) (P�0.22). The cumulative ICD intervention–freesurvival on Kaplan-Meier analysis also did not differbetween patients with a PKP2 mutation and those without(P�0.37).

Figure 4 shows the effect of each of the predictors ofappropriate ICD intervention in ARVD/C patients oncumulative ICD intervention rate separately among pa-tients with PKP2 mutations and those without. As shownin Figure 4, inducibility on an electrophysiology study,

TABLE 2. Demographics and Presentation

CharacteristicNo PKP2 Mutation

(n�33)PKP2 Mutation

(n�25)Total

(n�58)

Demographics

Age at presentation, mean�SD, y* 36�16 28�11 33�14

Gender (male) 18 (55) 17 (68) 35 (60)

Actively involved in athletic activity 15 (45) 15 (60) 30 (52)

Presenting symptoms

Palpitations 9 (27) 9 (36) 18 (31)

Syncope 9 (27) 6 (24) 15 (26)

Dyspnea 5 (15) 3 (12) 8 (14)

Near-syncope 2 (6) 2 (8) 4 (7)

Peripheral edema 1 (3) 0 (0) 1 (2)

Chest pain 1 (3) 0 (0) 1 (2)

Resuscitated from sudden cardiac death 1 (3) 0 (0) 1 (2)

Asymptomatic 7 (21) 7 (28) 14 (24)

Others (eg, nausea, vomiting, diaphoresis,dizziness)

6 (18) 6 (24) 12 (21)

Values are expressed as frequency (%) unless specified otherwise.*P�0.05.

presence of severe RV disease, and presence of priorspontaneous VT were associated with higher rates of ICDintervention among patients with no PKP2 mutation(P�0.05). However, they had no significant effect on theICD firing rate among patients with a PKP2 mutation.

During follow-up, 6 patients developed right-sided heartfailure (2 had a mutation in PKP2), and 2 underwentcardiac transplantation (1 had a mutation in PKP2). Therewere no deaths in the study population. There were nosignificant differences in our results after exclusion of thepatients who came to medical attention because of pres-ence of family history suggestive of ARVD/C or afteradjustment for the presence of family history in a Coxproportional hazards model.

DiscussionOur results confirm and extend the findings by Gerull etal.24 In this US cohort, we found a higher percentage (43%versus 27%) of cases of ARVD/C caused by mutations inPKP2. Possible reasons for this difference in prevalence of

PKP2 mutations include geographic factors, relativelysmall sizes of the populations studied, and selection bias inour cohort of patients referred to a single site perhapshaving a higher chance of dominantly inherited ARVD/C.Multiple mechanisms appear to contribute to these muta-tions, including gene conversion mediated by a nearbyplakophilin-2 pseudogene (PKP2P1) and Cytosine-phospho-Guanine dinucleotide hotspots.

In our analysis, those with a PKP2 mutation manifesttheir disease earlier in life, as determined by age at firstclinical presentation and age at first arrhythmia, even aftercorrection for identification of disease on the basis offamily history. Furthermore, among the patients with aPKP2 mutation who had an implanted ICD, the rate ofappropriate ICD intervention was not affected by thepreviously described predictors of ICD intervention.

Indication for and prevalence of ICD implantation forpatients with ARVD/C varies among different centers.27–30

Traditional risk factors for appropriate ICD interventionsamong ARVD/C patients,27 such as inducibility on elec-

TABLE 3. Clinical Data, International Task Force Criteria, ICD Implantation, and Intervention

Clinical Characteristic and ICD InterventionNo PKP2 Mutation

(n�33)PKP2 Mutation

(n�25)Total

(n�58)

Imaging and cine imaging studies

Severe dilatation and reduction of RVEF with no LV impairment* 9 (27) 9 (36) 18 (31)

Localized ventricular aneurysms (n�56)* 4/32 (13) 6/24 (25) 10/56 (18)

Severe segmental dilatation of RV (n�56)* 3/32 (9) 0/24 (4) 3/56 (5)

Mild dilatation and reduction of RVEF with no LV impairment† 18 (55) 13 (52) 31 (53)

Mild segmental dilatation of RV† 4/32 (13) 5/24 (21) 9/56 (16)

Regional RV hypokinesis† 16/32 (50) 11/24 (46) 27/56 (48)

ECG abnormalities

Prolongation of QRS in leads V1 through V3* 17/31 (55) 15/25 (60) 32/56 (57)

Presence of epsilon waves* 11 (33) 8 (32) 19 (33)

Inverted T waves in leads V1 through V3 or beyond† 25 (76) 21 (84) 46 (79)

S-wave upstroke �55 ms in leads V1 through V3 (n�48) 22/25 (88) 20/23 (87) 42/48 (88)

SAECG abnormalities

Late potentials on SAECG (n�53)† 18/30 (60) 17/23 (74) 35/53 (66)

Arrhythmias

LBBB-type VT documented (n�51)† 20/27 (74) 20/24 (83) 40/51 (78)

Frequent ventricular extrasystoles (n�41)† 14/23 (61) 13/18 (48) 27/41 (66)

Family history

Family history confirmed by biopsy or autopsy* 7 (21) 5 (20) 12 (21)

Sudden cardiac death in family at age �35 y† 2 (6) 3 (12) 5 (9)

Family members diagnosed by the present criteria† 0 (0) 4 (16) 4 (7)

Histopathological study of biopsy/autopsy specimen

Infiltration of RV by fat with presence of surviving strands orcardiomyocytes (n�26)*

9/15 (60) 4/11 (36) 13/26 (50)

ICD implantation and intervention

ICD implantation 27 (82) 21 (84) 48 (83)

Appropriate ICD intervention (n�48) 15/27 (56) 10/21 (48) 25/48 (52)

Values are expressed as frequency (%). EF indicates ejection fraction; LBBB, left bundle branch block. P�NS for all variables.*Major criteria.†Minor criteria.

trophysiology study, presence of a prior VT, or diffuse RVdisease, appear not to influence the rate of appropriate ICDintervention among ARVD/C patients with a PKP2 muta-tion, whereas these risk factors appear to be valid amongthe ARVD/C patients without a PKP2 mutation.

The high percentage of patients with ARVD/C who werefound to have pathogenic mutation in PKP2 highlights thepotential utility of mutation analysis in this gene forfamilies of an individual with ARVD/C. We and others31,32

currently recommend that all first-degree relatives ofpatients with ARVD/C undergo clinical screening forARVD/C. However, for individuals in whom a PKP2mutation is found, more intensive and serial clinicalscreening may be targeted to those who have been shownto inherit a genetic predisposition to ARVD/C within thatfamily. Presently, the penetrance of the ARVD/C pheno-type in families with PKP2 mutations is not known.Accordingly, the presence of a PKP2 mutation alone, inthe absence of clinical criteria for ARVD/C, establishesneither a diagnosis of ARVD/C nor a need for implantationof an ICD. In such cases, inheritance of a genetic predis-position to ARVD/C may lead to alterations in lifestyle,such as avoiding aerobic exercise. In addition, the absenceof a mutation in those at risk of inheritance of a geneticpredisposition can be considered in decisions regardingICD implantation.

Our data emphasize the utility of PKP2 mutation anal-ysis in the diagnosis of ARVD/C. In addition to the 58patients who met clinical criteria for ARVD/C, we ana-lyzed an additional 12 patients who were referred to ourcenter for a second opinion on the diagnosis of ARVD/Cbut did not achieve an adequate number of criteria toestablish the diagnosis (see online-only Data Supplement).None of these individuals were found to have a pathogenicPKP2 sequence variant, lending further support for thecurrent clinical guidelines used to establish a diagnosis ofARVD/C. However, our results support amendment of theclinical criteria established by McKenna and colleagues14

to include demonstration of a known mutation in PKP2 asa minor criterion under family history.

Our conclusions cannot be applied to family members ofARVD/C patients who share a PKP2 mutation but do notmeet clinical criteria for ARVD/C. This disorder is wellrecognized to have both low penetrance and variableexpressivity. Although it is possible that individuals with amutation in PKP2 without apparent structural heart diseasemay be at increased risk for arrhythmia, our analyses didnot address this question.

Presence or absence of a discernible PKP2 mutation inour population of ARVD/C patients does not predictdevelopment of syncope or inducibility for ventriculararrhythmia on electrophysiological analysis. This empha-sizes that ARVD/C is a heterogeneous disorder and that

Figure 2. Kaplan-Meier survival analysis demon-strating cumulative symptom-free survival in thestudy population stratified by presence of PKP2mutation.

Figure 3. Kaplan-Meier survival analysis demon-strating cumulative arrhythmia-free survival in thestudy population stratified by presence of PKP2mutation.

other factors contribute to the development of congestiveheart failure, syncope, and inducibility for ventriculararrhythmia. We do, however, find that ARVD/C patientswith a PKP2 mutation present earlier and have VT at anearlier age than ARVD/C patients without PKP2 mutation.

One limitation in this analysis is that of ascertainmentbias, in that all of the individuals studied came to medicalattention because of a symptomatic and overt clinicaldisorder or a clinical diagnosis of ARVD/C. Our analysismay have been affected by this selection bias and does notapply to other populations in whom mutations in PKP2may be present without resulting in the clinical phenotypeof ARVD/C. Furthermore, because of inability to obtainDNA from individuals who presented with sudden death,in whom the diagnosis of ARVD/C was established atautopsy, our results do not include a cohort of individualswith more severe presentation. On clinical evaluation, werelied on qualitative definitions of RV disease on imagingstudies as recommended by the task force. Thus, we could

only assess parameters such as “dilatation” or “reducedfunction” in our patients as opposed to precise RV diam-eters and ejection fraction. Another limitation in this studyis that the comparison group may have consisted ofpatients with mutations in any of several other genesimplicated in ARVD/C. Although it would have beendesirable to compare the phenotypic characteristics in 2genetically homogeneous groups, the genetic heterogene-ity inherent in this disorder limits such analysis. Finally,although the study sample was large enough to discern theeffect of PKP2 mutation on different outcomes, the samplesize may have been small for subgroup analyses.

Our conclusions should be verified in a second indepen-dent series of ARVD/C patients for validation. Furtherstudies are required to determine the prevalence of PKP2mutations in the general population, the mechanismscausing cellular damage in those with a PKP2 mutation,and the penetrance of this disease among family membersof ARVD/C patients with a PKP2 mutation.

Figure 4. Kaplan-Meier analysis demonstrating cumulative rates of appropriate ICD intervention stratified by presence of PKP2 muta-tion and various previously described predictors of ICD intervention. EP indicates electrophysiology.

AcknowledgmentsWe are grateful to the ARVD patients and families who havemade this work possible.

DisclosuresThe Johns Hopkins ARVD Program is supported by the BogleFoundation, the Campanella family, the Wilmerding Endow-ments, and NIH grant 1-UO1-HL65594-01A1. Drs Towbin,Marcus, and Calkins receive research support from NIH grant1-UO1-HL65594-01A1. Dr Judge receives research support fromthe Donald W. Reynolds Foundation and the W.W. SmithCharitable Trust. There are no other disclosures.

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CLINICAL PERSPECTIVEArrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic disorder resulting in life-threateningventricular arrhythmias. Although rare in the general population, ARVD/C is an important cause of sudden death inapparently healthy, young adults. From this study, there are 3 important points to highlight. First, among the several genesand genetic loci associated with this condition, we confirm a high prevalence of mutations in plakophilin (PKP2) in asecond large cohort of ARVD/C patients. Second, our study shows that ARVD/C patients with a mutation in this genepresent at a younger age and have earlier incidence of ventricular arrhythmias than those without a PKP2 mutation. Third,in our cohort of ARVD/C patients with PKP2 mutations, standard predictors of arrhythmia recurrence were not assuccessful at predicting arrhythmia risk as in our population of ARVD/C patients without PKP2 mutations. As clinicaltesting for PKP2 mutations becomes available, it may also be useful as a screening tool among family members of anindividual with ARVD/C with a PKP2 mutation. At-risk family members who do not share the proband’s PKP2 mutationmay be reassured that they are at lower risk of developing ARVD/C, whereas those who carry the same geneticpredisposition can be counseled and followed up more vigorously. However, many questions remain regarding both geneticand environmental modifiers of this condition. As such, we advocate genetic counseling in a tertiary referral center beforeclinical use of this genetic test. Finally, we propose that genetic testing be considered among the criteria used to establisha diagnosis of ARVD/C.

Bluemke, Theodore Abraham, Stuart D. Russell, Hugh Calkins and Daniel P. JudgeBomma, Kalpana Prakasa, Jeffrey A. Towbin, Frank I. Marcus, Philip J. Spevak, David A.

Darshan Dalal, Lorraine H. Molin, Jonathan Piccini, Crystal Tichnell, Cynthia James, ChandraAssociated With Mutations in Plakophilin-2

Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/CIRCULATIONAHA.105.568642

2006;113:1641-1649; originally published online March 20, 2006;Circulation.

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Online data supplement Clinical characteristics of the study population

Age at events Demographics and presentation Electrical

abnormalities RV imaging LV imaging

no mut pres dia HF HT fu sex race presenting symptoms athlete‡

circumstances at presentation FH

PVC G. dil

Aneurysm location WMA location S. dil, location

WMA, location dil., location HP

1 11 21 - - 22 F W palp, dysp, nau, vom + exercise none - - + + - + nd mild

Infundibular region, RVOT - none 49 - - -

2 15 15 23 - 33 F W dizz + exercise none + - + + + + - severe Ant. wall, apical region -

mild, apical region >55 - - nd

3 15 45 - - 52 F W n. sync + exercise ITFC - + + + + + + mild - - none >55 - - nd 4 16 28 - - 51 M W palp + routine activity none - + + - + + nd severe - RV free wall mild, RVOT >55 - - + 5 16 16 - - 17 M W fam hist + routine activity ITFC - - + + - - + mild - - none >55 - - -

6 18 18 - - 19 M W fam hist + SCD in 1st deg. relative HP, SCD - - + + - + + mild - Inf. aspect of RV

free wall none >55 - - nd 7 20 37 - - 46 M W sync + exercise ITFC + - + + - + + severe - - none >55 - - - 8 20 20 - - 27 M W fam hist + SCD in 1st deg. relative HP, SCD, ITFC + - + + + - + mild - Global none >55 - - nd 9 25 43 43 - 47 M W palp - routine activity none + + + + nd + nd severe - - none >55 - - nd

10 26 26 - - 31 M W dizz, nau, fever - routine activity none + + + + + + + severe - Apical region mild 47 - - +

11 26 26 - - 31 M W palp, nau, vom, dysp + routine activity none + + + + + + nd mild - Global none >55 - - -

12 28 32 - - 32 F W fam hist - death of 2nd deg. relative HP - - - + + + + none -

Apical region, RVOT none >55 - - -

13 28 28 - - 29 F W sync + exertion none - - + - + + + mild - Ant. aspect of RV free wall none - - - nd

14 29 46 - - 46 M W palp, n. sync + exercise none + - + + + + - none - Ant. Aspect of

RVOT none >55 - - - 15 30 30 - - 36 M W fam hist - HP + - + + - - - mild - - none >55 - - nd 16 30 32 - 56 57 M W sync - exercise ITFC - + + nm - + - severe - - none >55 - - + 17 31 31 - - 32 M W fam hist - routine activity HP, SCD, ITFC - - - + + nd nd mild - Global none 46 Global mild, global Nd 18 32 32 - - 32 F W palp, nau, vom - routine activity SCD + - + + + - + mild - - none >55 - - nd

19 33 33 - 34 M W sync + routine activity none + + - + + + + mild Basal region Basal region, mid-cavity mild, RVOT >55 - - nd

20 34 38 - - 49 F W dysp, sweating + exercise none + - + + + + nd severe >55 - - nd 21 37 50 - - 54 M W palp + routine activity SCD - - + - + + nd none RVOT - none 52 - - + 22 39 40 - - 48 F W palp, sync + exercise none + - + + nd + + severe - Apical region none >55 - - -

23 41 59 - - 60 W sync - exercise none + + + + + + - severe RVOT Basal region, mid-cavity none >55 - - nd

24 46 46 - - 49 M W palp - routine activity none + - + + + + + mild - Apical region mild, apical

region >55 - - nd 25

56 56 - - 62 M W VT on ECG - routine exam SCD + - - nm + + + mild + - none >55 - nd

26 13 23 - - 25 M W chest pain, sync - exertion none + + + + + + + severe Tricuspid region Apical region none 47Apical region mild, POFT +

27 13 42 - - 46 F W dizz - routine activity none + - + + + - + mild - Global none >55 mild, POFT nd 28 15 22 - - 26 M W heart murmur + routine activity none - - + + - + + mild - - severe, RVOT >55 - - +

29 16 47 - - 53 F W sync + exercise SCD + + + + - + - severe - -

severe, infundibular

region >55 - - nd

17 17 - - 18 M W VT on ECG + routine exam none + + - + - + + mild - Apical region none - Apical region - nd

31 19 47 - - 49 M W palp - routine activity none - - - + + + - none RVOT RVOT mild, apical

region >55 - mild, global +

32 23 27 - - 40 M W irregular heart beat - routine exam none + - - nm - + nd severe - - none 35 - - nd

33 23 34 - - 35 F W sync + exercise SCD, HP - - + + nd + nd mild - - none >55 - - nd 34 23 24 - - 28 F W dysp, dizz + exertion none - - + - - + - none - Apical region none >55 - - +

35 26 26 - - 28 F W Fam hist -

death of 2nd deg. relative, diag. in 1st deg. relative SCD, ITFC, HP nm - + nm + - - mild RVOT - none >55 - - -

36 26 26 - - 31 F W palp, dizz, n. sync - routine activity none - - + + + + + none - - mild 45 Global - -

37 27 31 - - 35 F W palp, dizz - exertion none - - + + + - + mild - - none >55 - - nd 38 30 30 - - 35 M H RSCD - exertion none + - + + + + nd mild - Global none 32 Global - nd 39 30 64 - - 64 M W VT on ECG - routine exam SCD, HP - - - nm - + + mild - RVOT none >55 - - - 40 31 31 - - 39 M W Fam hist - SCD in 1st deg. relative HP, SCD + + - nm + nd nd none - RV free wall none >55 - - - 41 32 33 - - 33 F W Fam hist - SCD in 1st deg. relative SCD, HP - - - - + nd + mild - - none >55 - - + 42 33 33 - - 33 F W Fam hist + SCD in 1st deg. relative HP, SCD - - + nm + + nd mild - Global none >55 - - nd 43 36 37 - - 40 F W sync pregnant none + - nm - - + mild - Global none >55 - - nd 44 39 39 - - 41 M W sync + running none - - + + + + + mild - - none >55 - - - 45 40 40 40 - 42 M W palp, dysp + symptoms of CHF none + + + nm - + - severe - - none >55 - - + 46 42 42 - - 43 F W palp + routine activity none + - + + + + nd mild - - none >55 mild, global nd 47 44 45 - - 46 F W Fam hist + SCD in 1st deg. relative HP, SCD - - + + + - - mild - - none >55 - - nd 48 44 46 - - 47 M W dizz, dysp, sync - exercise none + + + + - - - mild - - none >55 - - + 49 45 46 - - 55 M W sync + exercise none + - + + + nd + severe - - - nd

50 46 54 56 57 57 M W dizz, several episodes sync + exercise none + + + + + nd nd severe -

Apical region, ant. aspect of RV

free wall severe, apical

region >55 -

mild, global; severe, POFT nd

51 46 46 - - 47 F W asymptomatic + routine exam none - - + + - + + mild RVOT RVOT none >55 - - nd 52 49 49 - - 69 M W palp - routine activity none + - + nm + nd + severe - Global none - - - nd 53 52 52 - - 54 M W palp + emotional stress none + + + + + + nd none - - mild, RVOT >55 - - - 54 53 54 55 - 58 F W dysp - routine activity none - + + + - - - none - Apical region none >55 - - +

55 53 59 - - 61 F W n. sync - routine activity SCD - - + - - + + mild - Apical region mild, apical

region >55 - - nd 56 57 72 - - 73 M W sync + routine activity none + + + + + + - mild - - none >55 - - nd 57 63 64 - - 68 M W palp - routine activity none + - + + nd + nd severe - Global none - - - nd

78 78 78 - 78 M W peripheral edema, dysp - routine activity none + - - + nd nd nd severe - - none 42 - - +

no – Patient number mut – Mutation pres – presentation dia – diagnosis HF – right heart failure HT – heart transplant fu – last follow up ‡

– Participation in individual/team sports/exercise on a regular basis or at a competitive level FH – Family history QRS – Localized QRS prolongation in precordial leads on a 12 lead ECG EW – Presence of Epsilon wave in precordial leads on a 12 lead ECG TWI – T-wave inversions in leads V1 through V3 and beyond on a 12 lead ECG DSW – Delayed S-wave upstroke LP – Late potentials on Signal Averaged ECG LBB – LBBB type VT on ECG, Exercise tolerance test or 24-hour Holter monitor PVC – More than 1000 premature ventricular contractions on a 24-hour Holter monitor G. dil. – Global RV dilatation with no LV impairment Aneurysm – Localized aneurysms (akinetic or dyskinetic areas with diastolic bulging) WMA – Wall motion abnormalities of RV (regional hypokinesia) S. dil. – Segmental dilatation LVEF – Left ventricular ejection fraction dil. – dilatation HP. – Histopathological evidence of ARVD M – Male; F – Female W – White; H – Hispanic palp – palpitations; dysp – dyspnea; nau – nausea; vom – vomiting; dizz – dizziness; n. sync – near syncope; fam hist – family history; VT – Ventricular tachycardia SCD – indicates sudden cardiac death in a family member at an age <35 ; ITFC – indicates diagnosis of ARVD/C in a family member based on International Task force Criteria; HP (under FH) - indicates diagnosis of a family member with ARVD/C based on histopathologic evidence nm – not measurable; nd – test not done RVOT – right ventricular outflow tract; ant. – anterior; RV – right ventricle; inf. – inferior POFT – pulmonary outflow tract + – Indicates presence of a certain characteristic - – Indicates absence of a certain characteristic

Online data supplement Clinical characteristics of the study population

Age at events Demographics and presentation Electrical

abnormalities RV imaging LV imaging

no mut pres dia HF HT fu sex race presenting symptoms athlete‡

circumstances at presentation FH

PVC G. dil

Aneurysm location WMA location S. dil, location

WMA, location dil., location HP

1 11 21 - - 22 F W palp, dysp, nau, vom + exercise none - - + + - + nd mild

Infundibular region, RVOT - none 49 - - -

2 15 15 23 - 33 F W dizz + exercise none + - + + + + - severe Ant. wall, apical region -

mild, apical region >55 - - nd

3 15 45 - - 52 F W n. sync + exercise ITFC - + + + + + + mild - - none >55 - - nd 4 16 28 - - 51 M W palp + routine activity none - + + - + + nd severe - RV free wall mild, RVOT >55 - - + 5 16 16 - - 17 M W fam hist + routine activity ITFC - - + + - - + mild - - none >55 - - -

6 18 18 - - 19 M W fam hist + SCD in 1st deg. relative HP, SCD - - + + - + + mild - Inf. aspect of RV

free wall none >55 - - nd 7 20 37 - - 46 M W sync + exercise ITFC + - + + - + + severe - - none >55 - - - 8 20 20 - - 27 M W fam hist + SCD in 1st deg. relative HP, SCD, ITFC + - + + + - + mild - Global none >55 - - nd 9 25 43 43 - 47 M W palp - routine activity none + + + + nd + nd severe - - none >55 - - nd

10 26 26 - - 31 M W dizz, nau, fever - routine activity none + + + + + + + severe - Apical region mild 47 - - +

11 26 26 - - 31 M W palp, nau, vom, dysp + routine activity none + + + + + + nd mild - Global none >55 - - -

12 28 32 - - 32 F W fam hist - death of 2nd deg. relative HP - - - + + + + none -

Apical region, RVOT none >55 - - -

13 28 28 - - 29 F W sync + exertion none - - + - + + + mild - Ant. aspect of RV free wall none - - - nd

14 29 46 - - 46 M W palp, n. sync + exercise none + - + + + + - none - Ant. Aspect of

RVOT none >55 - - - 15 30 30 - - 36 M W fam hist - HP + - + + - - - mild - - none >55 - - nd 16 30 32 - 56 57 M W sync - exercise ITFC - + + nm - + - severe - - none >55 - - + 17 31 31 - - 32 M W fam hist - routine activity HP, SCD, ITFC - - - + + nd nd mild - Global none 46 Global mild, global Nd 18 32 32 - - 32 F W palp, nau, vom - routine activity SCD + - + + + - + mild - - none >55 - - nd

19 33 33 - 34 M W sync + routine activity none + + - + + + + mild Basal region Basal region, mid-cavity mild, RVOT >55 - - nd

20 34 38 - - 49 F W dysp, sweating + exercise none + - + + + + nd severe >55 - - nd 21 37 50 - - 54 M W palp + routine activity SCD - - + - + + nd none RVOT - none 52 - - + 22 39 40 - - 48 F W palp, sync + exercise none + - + + nd + + severe - Apical region none >55 - - -

23 41 59 - - 60 W sync - exercise none + + + + + + - severe RVOT Basal region, mid-cavity none >55 - - nd

24 46 46 - - 49 M W palp - routine activity none + - + + + + + mild - Apical region mild, apical

region >55 - - nd 25

56 56 - - 62 M W VT on ECG - routine exam SCD + - - nm + + + mild + - none >55 - nd

26 13 23 - - 25 M W chest pain, sync - exertion none + + + + + + + severe Tricuspid region Apical region none 47Apical region mild, POFT +

27 13 42 - - 46 F W dizz - routine activity none + - + + + - + mild - Global none >55 mild, POFT nd 28 15 22 - - 26 M W heart murmur + routine activity none - - + + - + + mild - - severe, RVOT >55 - - +

29 16 47 - - 53 F W sync + exercise SCD + + + + - + - severe - -

severe, infundibular

region >55 - - nd

17 17 - - 18 M W VT on ECG + routine exam none + + - + - + + mild - Apical region none - Apical region - nd

31 19 47 - - 49 M W palp - routine activity none - - - + + + - none RVOT RVOT mild, apical

region >55 - mild, global +

32 23 27 - - 40 M W irregular heart beat - routine exam none + - - nm - + nd severe - - none 35 - - nd

33 23 34 - - 35 F W sync + exercise SCD, HP - - + + nd + nd mild - - none >55 - - nd 34 23 24 - - 28 F W dysp, dizz + exertion none - - + - - + - none - Apical region none >55 - - +

35 26 26 - - 28 F W Fam hist -

death of 2nd deg. relative, diag. in 1st deg. relative SCD, ITFC, HP nm - + nm + - - mild RVOT - none >55 - - -

36 26 26 - - 31 F W palp, dizz, n. sync - routine activity none - - + + + + + none - - mild 45 Global - -

37 27 31 - - 35 F W palp, dizz - exertion none - - + + + - + mild - - none >55 - - nd 38 30 30 - - 35 M H RSCD - exertion none + - + + + + nd mild - Global none 32 Global - nd 39 30 64 - - 64 M W VT on ECG - routine exam SCD, HP - - - nm - + + mild - RVOT none >55 - - - 40 31 31 - - 39 M W Fam hist - SCD in 1st deg. relative HP, SCD + + - nm + nd nd none - RV free wall none >55 - - - 41 32 33 - - 33 F W Fam hist - SCD in 1st deg. relative SCD, HP - - - - + nd + mild - - none >55 - - + 42 33 33 - - 33 F W Fam hist + SCD in 1st deg. relative HP, SCD - - + nm + + nd mild - Global none >55 - - nd 43 36 37 - - 40 F W sync pregnant none + - nm - - + mild - Global none >55 - - nd 44 39 39 - - 41 M W sync + running none - - + + + + + mild - - none >55 - - - 45 40 40 40 - 42 M W palp, dysp + symptoms of CHF none + + + nm - + - severe - - none >55 - - + 46 42 42 - - 43 F W palp + routine activity none + - + + + + nd mild - - none >55 mild, global nd 47 44 45 - - 46 F W Fam hist + SCD in 1st deg. relative HP, SCD - - + + + - - mild - - none >55 - - nd 48 44 46 - - 47 M W dizz, dysp, sync - exercise none + + + + - - - mild - - none >55 - - + 49 45 46 - - 55 M W sync + exercise none + - + + + nd + severe - - - nd

50 46 54 56 57 57 M W dizz, several episodes sync + exercise none + + + + + nd nd severe -

Apical region, ant. aspect of RV

free wall severe, apical

region >55 -

mild, global; severe, POFT nd

51 46 46 - - 47 F W asymptomatic + routine exam none - - + + - + + mild RVOT RVOT none >55 - - nd 52 49 49 - - 69 M W palp - routine activity none + - + nm + nd + severe - Global none - - - nd 53 52 52 - - 54 M W palp + emotional stress none + + + + + + nd none - - mild, RVOT >55 - - - 54 53 54 55 - 58 F W dysp - routine activity none - + + + - - - none - Apical region none >55 - - +

55 53 59 - - 61 F W n. sync - routine activity SCD - - + - - + + mild - Apical region mild, apical

region >55 - - nd 56 57 72 - - 73 M W sync + routine activity none + + + + + + - mild - - none >55 - - nd 57 63 64 - - 68 M W palp - routine activity none + - + + nd + nd severe - Global none - - - nd

78 78 78 - 78 M W peripheral edema, dysp - routine activity none + - - + nd nd nd severe - - none 42 - - +

no – Patient number mut – Mutation pres – presentation dia – diagnosis HF – right heart failure HT – heart transplant fu – last follow up ‡

– Participation in individual/team sports/exercise on a regular basis or at a competitive level FH – Family history QRS – Localized QRS prolongation in precordial leads on a 12 lead ECG EW – Presence of Epsilon wave in precordial leads on a 12 lead ECG TWI – T-wave inversions in leads V1 through V3 and beyond on a 12 lead ECG DSW – Delayed S-wave upstroke LP – Late potentials on Signal Averaged ECG LBB – LBBB type VT on ECG, Exercise tolerance test or 24-hour Holter monitor PVC – More than 1000 premature ventricular contractions on a 24-hour Holter monitor G. dil. – Global RV dilatation with no LV impairment Aneurysm – Localized aneurysms (akinetic or dyskinetic areas with diastolic bulging) WMA – Wall motion abnormalities of RV (regional hypokinesia) S. dil. – Segmental dilatation LVEF – Left ventricular ejection fraction dil. – dilatation HP. – Histopathological evidence of ARVD M – Male; F – Female W – White; H – Hispanic palp – palpitations; dysp – dyspnea; nau – nausea; vom – vomiting; dizz – dizziness; n. sync – near syncope; fam hist – family history; VT – Ventricular tachycardia SCD – indicates sudden cardiac death in a family member at an age <35 ; ITFC – indicates diagnosis of ARVD/C in a family member based on International Task force Criteria; HP (under FH) - indicates diagnosis of a family member with ARVD/C based on histopathologic evidence nm – not measurable; nd – test not done RVOT – right ventricular outflow tract; ant. – anterior; RV – right ventricle; inf. – inferior POFT – pulmonary outflow tract + – Indicates presence of a certain characteristic - – Indicates absence of a certain characteristic

Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated With Mutations in Plakophilin-2

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