Published online before print March 20, 2006, doi: 10.1161/CIRCULATIONAHA.105.568642
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(Circulation. 2006;113:1641-1649.)
© 2006 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated With Mutations in Plakophilin-2
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, Baylor College of Medicine, Houston, Tex (J.A.T.).
Correspondence to Daniel Judge, MD, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1049, Baltimore, MD 21205. E-mail djudge{at}jhmi.edu
Received June 14, 2005; revision received November 16, 2005; accepted December 16, 2005.
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Abstract |
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Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another 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 in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. 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 those without (36±16 years) (P<0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (P<0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P<0.05).
Conclusions— Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.
Key Words: arrhythmia • cardiomyopathy • genetics • sudden death • tachyarrhythmias
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Introduction |
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Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular (RV) dysfunction and ventricular arrhythmias, which may lead to sudden cardiac death.1–8 Studies have shown that ARVD/C is present in up to 20% of individuals that experience sudden cardiac death and is even more common among athletes who die suddenly.9–12 Although fatty or fibrofatty replacement of the myocardium of the RV is the pathological hallmark of the disease, biopsy of the right ventricle is of limited 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 clinical findings associated with the condition.4,14 Molecular diagnosis by identification of genetic mutations may also be an important screening tool for predicting risk of ARVD/C in asymptomatic family members of an affected individual.
Editorial p 1634
Clinical Perspective p 1649
Several genes and genetic loci have been described in association with ARVD/C. Mutations in the gene encoding desmoplakin (DSP) have been described in both dominant and recessive forms of ARVD/C.15,16 To date, 5 families have been described with mutations in DSP resulting in dominantly inherited ARVD/C.16,17 Another family has been described with a novel mutation in desmoplakin that results in dominantly inherited left ventricular cardiomyopathy.15 Naxos disease, also known as palmoplantar keratoderma with arrhythmogenic RV cardiomyopathy, is an autosomal recessive disorder caused by mutations in JUP, encoding junctional plakoglobin.18,19 One atypical form of disease, catecholaminergic polymorphic ventricular tachycardia (VT), is caused by mutations in RYR2, encoding a cardiac ryanodine receptor.20–22 Finally, Beffagna and colleagues23 have associated the gene encoding transforming growth factor-ß3 with ARVD/C.
Recently, Gerull and colleagues24 reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. Mutations in this gene were shown to be present in 27% of the 120 unrelated ARVD/C patients of Western European descent. The purpose of our study was to validate the frequency of mutations in this gene in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with mutations in this gene among patients with ARVD/C.
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Methods |
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Patient Recruitment
Fifty-eight unrelated ARVD/C patients, who gave written informed consent to participate in research genetic screening, were identified from the Johns Hopkins ARVD registry, 15 of whom also enrolled in the National Institutes of Health Multicenter Clinical Trial of ARVD. The study protocol was approved by the Johns Hopkins School of Medicine institutional review board. Clinical history and medical records were obtained at enrollment. Subsequent to the initial enrollment, patients were contacted at yearly intervals to determine the occurrence of clinical events during that period.
Patient Evaluation and Clinical Testing
The patients’ medical history was obtained both by review of medical records and by patient interview. Information regarding the presenting symptoms as well as major clinical events, including implantation of implantable cardioverter/defibrillators (ICD) and ICD interventions, during the follow-up was recorded by age for each patient. Family history was determined by interviewing patients and their family members. Palpitations were defined as awareness of one’s own heartbeat, syncope as a transient loss of consciousness, near-syncope as an impending loss of consciousness associated with lightheadedness or dizziness, diaphoresis as episodes of profuse sweating, and dyspnea as awareness of one’s own breathing or difficulty in breathing.
Results of noninvasive testing, including ECG (n=58), signal-averaged ECG (SAECG) (n=53), Holter monitoring (n=41), and imaging studies (n=58) including echocardiogram and MRI were obtained. QRS duration (n=56) and the duration of the S-wave upstroke (n=48) on a 12-lead ECG were measured with the image analysis software SigmaScan Pro (version 5.0; Systat Software Inc, Richmond, Calif).25 The presence of epsilon waves and the extent of T-wave inversion on precordial leads of the standard ECG were also determined.25 SAECGs using time-domain analysis with a bandpass filter of 40 Hz were evaluated in patients who did not have a preexisting complete or incomplete right bundle-branch block pattern. The SAECG was considered positive for late potentials if any 2 of the following were present: (1) filtered QRS duration >114 ms; (2) low-amplitude signal duration >38 ms; or (3) RMS <20 mV.26 The results of Holter monitoring and exercise stress test, in addition to the standard 12-lead ECGs, were used to determine the presence of sustained or nonsustained VT as well as the morphology of ventricular ectopy and/or VT. The severity and extent of RV dysfunction was also determined by imaging studies and was designated as "diffuse" or "mild." Diffuse disease was defined as global RV dilation and reduced RV ejection fraction.14 Mild disease was defined as localized or regional RV abnormalities, such as segmental RV wall motion abnormalities (hypokinetic or akinetic areas) without RV dilation or evidence of RV systolic dysfunction.
An electrophysiology study was performed on 53 of the 58 patients in the study population and in 45 of the 48 patients who received an ICD. The results of the electrophysiology study were designated as "inducible" if 1 or more morphologies of sustained VT or ventricular fibrillation were induced during the procedure or "not inducible" if no VT or ventricular fibrillation could be induced during the procedure. Histopathological examination after a biopsy was performed in 26 patients. In each case, endomyocardial biopsy was performed through a right internal jugular approach. Biopsies were evaluated for presence or absence of fibrofatty replacement of myocardium as previously described.11
Diagnosis of ARVD/C
The diagnosis of ARVD/C was established on the basis of the criteria set by the Task Force of the Working Group of Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology.14
Genotype Analysis
For each patient, genomic DNA was extracted from leukocytes present in whole blood with the use of QIAmp DNA blood maxi kits (Qiagen, Inc, Valencia, Calif). Amplification of each exon for PKP2 was performed as previously described, with primer sequence that was provided by Ludwig Thierfelder.24 Bidirectional sequence chromatography was performed with the use of Applied Biosystems (Foster City, Calif) 3730 DNA Analyzer. Analysis of chromatograms was performed with Sequencher 3.0 (Gene Codes Corp, Ann Arbor Mich) and with MacVector (Accelrys, San Diego, Calif) for ClustalW alignment. All novel mutations were analyzed in a population of 200 individuals (400 chromosomes) from a panel of unrelated unaffected individuals. Control DNA was obtained from NIGMS Human Genetic Cell Repository through the Coriell Institute for Medical Research, and approximately half of the controls were matched to the mutation carriers by ancestry.
Statistical Analysis
The study population was divided into 2 groups: those with a mutation in the PKP2 gene (n=25) and those with no detectable mutation in the PKP2 gene (n=33). Phenotypic characteristics, including demographics, presenting symptoms, participation in athletics, and clinical characteristics, were compared between the 2 groups. Continuous variables were expressed as mean±SD, and categorical variables were expressed as frequency (percentage). Continuous variables between the 2 groups were compared by unpaired t test, and the categorical variables were compared by 
2 test. Kaplan-Meier analysis was used to determine the cumulative symptom-free and arrhythmia-free survival since birth (ie, age at first symptom/arrhythmia), which was compared between the 2 groups by log-rank test.
A subgroup of patients with an ICD (n=48) was identified from the study population. Kaplan-Meier analysis was used to determine the cumulative rate of appropriate ICD interventions since implantation. The effect of the previously described predictors, including inducibility on an electrophysiology study, severity of structural RV disease, and presence of prior spontaneous VT, on cumulative rates of ICD intervention was assessed in each group by Kaplan-Meier analysis.27 The Kaplan-Meier curves were compared by log-rank test.
To eliminate the potential confounding due to presence of family history suggestive of ARVD/C in our survival analyses, all statistical analyses were repeated after exclusion of patients who came to medical attention because of the presence of family history suggestive of ARVD/C. In addition, we also adjusted for presence of family history in a Cox proportional hazards model. All statistical analyses were performed with the use of STATA statistical software (version 8.2; College Station, Tex). A probability value <0.05 was considered statistically significant.
The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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Patient Population and Mutations
The patient population consisted of 58 patients diagnosed with ARVD/C. Clinical characteristics of the study population are shown in Data Supplement Table I. Twenty-five (43%) of the 58 patients had a mutation in PKP2, encoding plakophilin-2. Specific information for each mutation is listed in Table 1 and shown schematically in Figure 1. There were 13 different mutations among the 25 individuals with mutations in this cohort, with identical mutations in several apparently unrelated families. Haplotypes were determined for probands with recurrent mutations with the use of polymorphic microsatellite markers that are in close proximity to PKP2.24 Common haplotypes were not identified in cases of identical mutations. Six mutations were identified that have not been reported previously. None of these novel mutations was found in a population of 200 unrelated, unaffected controls (400 chromosomes). Among the 13 mutations identified, 6 were insertion-deletion mutations, 3 altered a critically conserved nucleotide that forms the intron-exon splice site, 2 were nonsense mutations resulting in a premature termination codon, and 2 were missense mutations disrupting highly conserved residues in functional domains of plakophilin-2. The previously described S140F mutation disrupts a conserved residue, as reported by Gerull and colleagues.24 The novel F424S mutation similarly disrupts a highly conserved residue within a functional armadillo domain. Plakophilin-2 in mouse, dog, cow, chick, frog, puffer fish, zebra fish, and Xenopus all have F (phenylalanine) in this position, as does human plakophilin-1.
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Demographics and Presentation
The demographics and presenting symptoms of each of these patients are listed in Table I and summarized in Table 2. There were 35 men (60%) in the study population. The mean age at presentation was 33±14 years. Those with a PKP2 mutation presented at an earlier age (28±11 years) than those without (36±16) years (P<0.05). Thirty subjects (52%) were involved in competitive athletics. There was no statistically significant difference in gender and involvement in athletics between the 2 groups.
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Palpitations and syncope were the most common presenting symptoms. Fourteen patients were asymptomatic at the time of first presentation. ARVD/C was suspected in these patients on the basis of family history suggestive of ARVD/C or premature sudden cardiac death or an abnormal ECG pattern at a routine physical examination (Table I). There were no differences in the presenting symptoms between the 2 groups.
Clinical Characteristics of Patients
Shown in Table I and summarized in Table 3 are the results of clinical testing of the 58 patients in the study population. The diagnosis of ARVD/C was established on the basis of presence of 2 major criteria (n=24), 1 major plus 2 minor criteria (n=27), or 4 minor criteria (n=7). The results of clinical testing between the 2 groups were not statistically different.
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Freedom From Symptoms and Arrhythmia
Figure 2 shows Kaplan-Meier analysis for the cumulative symptom-free survival since birth among ARVD/C patients with a PKP2 mutation and those without a mutation. The age at median cumulative symptom-free survival among those with a PKP2 mutation was lower (32 years) than among those without (42 years) a PKP2 mutation (P<0.05).
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Figure 3 shows Kaplan-Meier analysis for the cumulative arrhythmia-free survival since birth in ARVD/C patients with a PKP2 mutation and those without. The age at median cumulative arrhythmia-free survival among those with a PKP2 mutation was lower (34 years) than among those without (46 years) a PKP2 mutation (P<0.05).
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ICD Therapy
Long-term follow-up data of 48 patients with an ICD (21 with a PKP2 mutation) were available for analysis. Over a mean follow-up of 5±4 years, 28 (58%) of the 48 patients experienced an appropriate ICD intervention. The longest event-free follow up time was 9 years. Among the ARVD/C patients with a PKP2 mutation, 11 (52%) experienced an appropriate ICD intervention, whereas among those without a PKP2 mutation, 17 (63%) experienced appropriate ICD interventions during the follow up (P=0.46). The overall incidence rate of appropriate ICD intervention did not differ significantly between patients with a PKP2 mutation (0.22 intervention per year) and those without a PKP2 mutation (0.32 intervention per year) (P=0.22). The cumulative ICD intervention-free survival on Kaplan-Meier analysis also did not differ between patients with a PKP2 mutation and those without (P=0.37).
Figure 4 shows the effect of each of the predictors of appropriate ICD intervention in ARVD/C patients on cumulative ICD intervention rate separately among patients with PKP2 mutations and those without. As shown in Figure 4, inducibility on an electrophysiology study, presence of severe RV disease, and presence of prior spontaneous VT were associated with higher rates of ICD intervention among patients with no PKP2 mutation (P<0.05). However, they had no significant effect on the ICD firing rate among patients with a PKP2 mutation.
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During follow-up, 6 patients developed right-sided heart failure (2 had a mutation in PKP2), and 2 underwent cardiac transplantation (1 had a mutation in PKP2). There were no deaths in the study population. There were no significant differences in our results after exclusion of the patients who came to medical attention because of presence of family history suggestive of ARVD/C or after adjustment for the presence of family history in a Cox proportional hazards model.
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Discussion |
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Our results confirm and extend the findings by Gerull et al.24 In this US cohort, we found a higher percentage (43% versus 27%) of cases of ARVD/C caused by mutations in PKP2. Possible reasons for this difference in prevalence of PKP2 mutations include geographic factors, relatively small sizes of the populations studied, and selection bias in our cohort of patients referred to a single site perhaps having a higher chance of dominantly inherited ARVD/C. Multiple mechanisms appear to contribute to these mutations, including gene conversion mediated by a nearby plakophilin-2 pseudogene (PKP2P1) and Cytosine-phospho-Guanine dinucleotide hotspots.
In our analysis, those with a PKP2 mutation manifest their disease earlier in life, as determined by age at first clinical presentation and age at first arrhythmia, even after correction for identification of disease on the basis of family history. Furthermore, among the patients with a PKP2 mutation who had an implanted ICD, the rate of appropriate ICD intervention was not affected by the previously described predictors of ICD intervention.
Indication for and prevalence of ICD implantation for patients with ARVD/C varies among different centers.27–30 Traditional risk factors for appropriate ICD interventions among ARVD/C patients,27 such as inducibility on electrophysiology study, presence of a prior VT, or diffuse RV disease, appear not to influence the rate of appropriate ICD intervention among ARVD/C patients with a PKP2 mutation, whereas these risk factors appear to be valid among the ARVD/C patients without a PKP2 mutation.
The high percentage of patients with ARVD/C who were found to have pathogenic mutation in PKP2 highlights the potential utility of mutation analysis in this gene for families of an individual with ARVD/C. We and others31,32 currently recommend that all first-degree relatives of patients with ARVD/C undergo clinical screening for ARVD/C. However, for individuals in whom a PKP2 mutation is found, more intensive and serial clinical screening may be targeted to those who have been shown to inherit a genetic predisposition to ARVD/C within that family. Presently, the penetrance of the ARVD/C phenotype in families with PKP2 mutations is not known. Accordingly, the presence of a PKP2 mutation alone, in the absence of clinical criteria for ARVD/C, establishes neither a diagnosis of ARVD/C nor a need for implantation of an ICD. In such cases, inheritance of a genetic predisposition to ARVD/C may lead to alterations in lifestyle, such as avoiding aerobic exercise. In addition, the absence of a mutation in those at risk of inheritance of a genetic predisposition can be considered in decisions regarding ICD implantation.
Our data emphasize the utility of PKP2 mutation analysis in the diagnosis of ARVD/C. In addition to the 58 patients who met clinical criteria for ARVD/C, we analyzed an additional 12 patients who were referred to our center for a second opinion on the diagnosis of ARVD/C but did not achieve an adequate number of criteria to establish the diagnosis (see online-only Data Supplement). None of these individuals were found to have a pathogenic PKP2 sequence variant, lending further support for the current clinical guidelines used to establish a diagnosis of ARVD/C. However, our results support amendment of the clinical criteria established by McKenna and colleagues14 to include demonstration of a known mutation in PKP2 as a minor criterion under family history.
Our conclusions cannot be applied to family members of ARVD/C patients who share a PKP2 mutation but do not meet clinical criteria for ARVD/C. This disorder is well recognized to have both low penetrance and variable expressivity. Although it is possible that individuals with a mutation in PKP2 without apparent structural heart disease may be at increased risk for arrhythmia, our analyses did not address this question.
Presence or absence of a discernible PKP2 mutation in our population of ARVD/C patients does not predict development of syncope or inducibility for ventricular arrhythmia on electrophysiological analysis. This emphasizes that ARVD/C is a heterogeneous disorder and that other factors contribute to the development of congestive heart failure, syncope, and inducibility for ventricular arrhythmia. We do, however, find that ARVD/C patients with a PKP2 mutation present earlier and have VT at an earlier age than ARVD/C patients without PKP2 mutation.
One limitation in this analysis is that of ascertainment bias, in that all of the individuals studied came to medical attention because of a symptomatic and overt clinical disorder or a clinical diagnosis of ARVD/C. Our analysis may have been affected by this selection bias and does not apply to other populations in whom mutations in PKP2 may be present without resulting in the clinical phenotype of ARVD/C. Furthermore, because of inability to obtain DNA from individuals who presented with sudden death, in whom the diagnosis of ARVD/C was established at autopsy, our results do not include a cohort of individuals with more severe presentation. On clinical evaluation, we relied on qualitative definitions of RV disease on imaging studies as recommended by the task force. Thus, we could only assess parameters such as "dilatation" or "reduced function" in our patients as opposed to precise RV diameters and ejection fraction. Another limitation in this study is that the comparison group may have consisted of patients with mutations in any of several other genes implicated in ARVD/C. Although it would have been desirable to compare the phenotypic characteristics in 2 genetically homogeneous groups, the genetic heterogeneity inherent in this disorder limits such analysis. Finally, although the study sample was large enough to discern the effect of PKP2 mutation on different outcomes, the sample size may have been small for subgroup analyses.
Our conclusions should be verified in a second independent series of ARVD/C patients for validation. Further studies are required to determine the prevalence of PKP2 mutations in the general population, the mechanisms causing cellular damage in those with a PKP2 mutation, and the penetrance of this disease among family members of ARVD/C patients with a PKP2 mutation.
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Acknowledgments |
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We are grateful to the ARVD patients and families who have made this work possible.
Disclosures
The Johns Hopkins ARVD Program is supported by the Bogle Foundation, the Campanella family, the Wilmerding Endowments, and NIH grant 1-UO1-HL65594-01A1. Drs Towbin, Marcus, and Calkins receive research support from NIH grant 1-UO1-HL65594-01A1. Dr Judge receives research support from the Donald W. Reynolds Foundation and the W.W. Smith Charitable Trust. There are no other disclosures.
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Footnotes |
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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.
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