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Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members

Originally publishedhttps://doi.org/10.1161/CIRCGENETICS.114.001003Circulation: Cardiovascular Genetics. 2015;8:437–446

Abstract

Background—

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic cohort of 1001 individuals.

Methods and Results—

Clinical and genetic characteristics and follow-up data of ARVD/C index-patients (n=439, fulfilling of 2010 criteria in all) and family members (n=562) were assessed. Mutations were identified in 276 index-patients (63%). Index-patients presented predominantly with sustained ventricular arrhythmias (268; 61%). During a median follow-up of 7 years, 301 of the 416 index-patients presenting alive (72%) experienced sustained ventricular arrhythmias. Sudden cardiac death during follow-up occurred more frequently among index-patients without an implantable cardioverter-defibrillator (10/63, 16% versus 2/335, 0.6%). Overall, cardiac mortality and the need for cardiac transplantation were low (6% and 4%, respectively). Clinical characteristics and outcomes were similar in index-patients with and without mutations, as well as in those with familial and nonfamilial ARVD/C. ARVD/C was diagnosed in 207 family members (37%). Symptoms at first evaluation correlated with disease expression. Family members with mutations were more likely to meet Task Force Criteria for ARVD/C (40% versus 18%), experience sustained ventricular arrhythmias (11% versus 1%), and die from a cardiac cause (2% versus 0%) than family members without mutations.

Conclusions—

Long-term outcome was favorable in diagnosed and treated ARVD/C index-patients and family members. Outcome in index-patients was modulated by implantable cardioverter-defibrillator implantation, but not by mutation status and familial background of disease. One third of family members developed ARVD/C. Outcome in family members was determined by symptoms at first evaluation and mutations.

Introduction

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a hereditary progressive cardiomyopathy characterized by an increased risk of sudden cardiac death (SCD), ventricular arrhythmias (VA), and predominantly right ventricular (RV) dysfunction.1,2 ARVD/C-related mutations in desmosomal and, less commonly, nondesmosomal genes are identified in ≈60% of index-patients.311

Editorial see p 421

Clinical Perspective on p 446

Since the first major disease description, considerable progress has been made in understanding of the genetic substrate, pathogenesis, and clinical diagnosis of ARVD/C.1 However, information on long-term follow-up both in index-patients and in family members is limited. Most previous studies predated the availability of genetic testing, were small, focused on overt index-patients, and used the original less sensitive 1994 Task Force Criteria (TFC) for ARVD/C diagnosis.1222

Although ARVD/C is considered an inherited cardiomyopathy, it is notable that a significant proportion of index-patients have neither an identifiable mutation nor a family history of disease. Whether the disease course differs in this sizable subset of patients remains unknown. Moreover, whether index-patients with what seems to be an isolated disease have yet to be identified mutations or represent a distinct acquired form of ARVD/C, such as exercise-induced RV cardiomyopathy, remains unknown.2325

In this study, we analyzed clinical and genetic characteristics and long-term follow-up data of ARVD/C index-patients and family members in a large transatlantic cohort of >1000 individuals. There were 3 main goals of this study. First, we sought to define the presenting symptoms, clinical characteristics, and long-term outcome of ARVD/C in a large series of index-patients and family members. Importantly, each index-patient underwent molecular-genetic testing, and the revised 2010 TFC were used for ARVD/C diagnosis. Second, we sought to provide insight into determinants of phenotypic and long-term outcome differences among ARVD/C index-patients and family members. Third, we sought to use this analysis as an opportunity to provide insight into the recently proposed hypothesis that isolated ARVD/C may represent exercise-induced RV cardiomyopathy with distinct clinical features and more benign outcomes.

Methods

Study Population

The study population comprised 439 index-patients, fulfilling the 2010 TFC for ARVD/C, and 562 family members enrolled in the ARVD/C registries from the Johns Hopkins University (n=511) and the Dutch Interuniversity Cardiology Institute of the Netherlands (a cardiovascular research institute with collaborative participation of all 8 Dutch University Medical Centers; n=490). Index-patients were defined as the first affected individuals seeking medical attention for ARVD/C in whom the diagnosis was confirmed (ie, ascertained independently of ARVD/C family history). Family members were ascertained by family screening. All family members with a mutation predisposing for ARVD/C were included (regardless of degree of relatedness). Only first-degree relatives of individuals with an ARVD/C diagnosis were included in families in which mutations were not identified. All subjects or their guardians provided informed consent as per individual institutional protocol. The study was approved by an institutional review committee.

Clinical Analysis

The medical history of each individual was obtained by review of medical records, clinical evaluation, and patient interviews. A detailed family history was obtained through patient interview by genetic counselors with special ARVD/C interest for pedigree analysis. Index-patients and family members were prospectively followed and evaluated for TFC, clinical presentation, clinical course, and outcome. Data on clinical events including sustained VA episodes (defined as sustained ventricular tachycardia, ventricular fibrillation, cardiac arrest, or appropriate implantable cardioverter-defibrillator [ICD] intervention [shock or antitachycardia pacing]), heart failure, cardiac transplantation, SCD, and other causes of death was obtained (Table I, definitions, in the Data Supplement). ARVD/C diagnosis was based on the presence of major and minor diagnostic criteria according to the 2010 TFC.26 All family members had 1 major criterion for family history, ie either for pathogenic mutations or for first-degree relatives with ARVD/C. Noninvasive and invasive diagnostic studies performed are shown in Table II in the Data Supplement. Clinical characteristics of index-patients and family members were compared between subjects with and without identified mutations. In addition, the clinical features of index-patients with familial (defined as fulfillment of any 2010 TFC in the category for family history at last follow-up) and isolated ARVD/C (defined as absence of family history TFC at last follow-up) were compared.

Molecular-Genetic Analysis

Mutation analysis of the desmosomal genes encoding plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2), and plakoglobin (JUP) was performed in all index-patients as reported previously (Table I, definitions, in the Data Supplement).18,27 Nondesmosomal gene analysis included TMEM43 and PLN. Family members were screened for the mutation(s) found in their respective index-patient if any. Subjects who presented with SCD and were either obligate carriers or had ARVD/C on autopsy but did not have genetic screening were assumed to have the same mutation as their first-degree family members.

Statistical Analysis

Continuous variables are summarized as either mean±SD or median (interquartile range [IQR], range) where appropriate and compared across groups using a Student t test. Categorical variables are reported as frequency (%) and compared between groups by the χ2 or Fisher exact test. The cumulative freedom since birth (ie, by age) from the clinical outcome was determined by the Kaplan–Meier method, and differences in survival between groups evaluated with the log-rank test. A value of P≤0.05 was considered significant. SPSS statistical software (version 20; SPSS Inc, Chicago, IL) and STATA 13.1 (Stata Corp, College Station, TX) were used for the analyses.

Results

ARVD/C Cohort

Tables 1 and 2 summarize the demographic features and age at first evaluation of the 1001 subjects (452 unrelated families), including 439 index-patients and 562 family members. Index-patients were followed up for a median of 7 (IQR 12; range 0–37) years. Of 537 family members presenting alive, 364 (68%) had a median follow-up of 5 (IQR 8; range 1–38) years, 173 (32%) were evaluated once.

Table 1. Demographic Characteristics of 439 Index-Patients With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

DemographicsIndex Patients, n (%)Without Identified Mutation, n (%)With Identified Mutation, n (%)With Identified Mutation, n (%)P Value*
Total (n=439)Total Without Mutations (n=163)Total With Mutations (n=276)PKP2 (n=202)Other Desmosomal (n=35)PLN/TMEM43 (n=22)Mult. mut. (n=17)
Men282 (64)103 (63)179 (65)131 (65)26 (74)13 (59)9 (53)0.725
Race
 White432 (98)162 (99)270 (98)200 (99)33 (94)22 (100)15 (88)
 Black1 (0.2)1 (0.6)
 Asian6 (1)6 (2)2 (1)2 (6)2 (12)
Registry
 ICIN198 (45)58 (36)140 (51)99 (49)11 (31)21 (96)9 (53)
 JHU241 (55)105 (64)136 (49)103 (51)24 (69)1 (4)8 (47)
Age at first evaluation, mean±SD, y36±1438±1434±1434±1433±1540±1234±14<0.001
Age at last follow-up, mean±SD, y44±1547±1443±1544±1640±1449±1244±160.015

ICIN indicates Interuniversity Cardiology Institute of The Netherlands; JHU, Johns Hopkins University; PKP2, plakophilin-2; PLN, phospholamban; Mult. mut.: patients with multiple mutations; and TMEM43, transmembrane protein 43.

*P value represents comparison between total with mutations (n=276) and without identified mutations (n=163).

Table 2. Demographic Characteristics of 562 Family Members of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Index-Patients

DemographicsFamily Members, n (%)Without Identified Mutation, n (%)With Identified Mutation, n (%)With Identified Mutation, n (%)P Value*
Total (n=562)Total Without Mutations (n=153)Total With Mutations (n=409)PKP2 (n=342)Other Desmosomal (n=33)PLN/TMEM43 (n=26)Mult. mut. (n=8)
Men260 (46)75 (49)185 (45)160 (47)12 (36)9 (35)4 (50)0.423
Race
 White556 (99)153 (100)403 (99)338 (99)31 (94)26 (100)8 (100)
 Black
 Asian6 (1)6 (1)4 (1)2 (6)
Registry
 ICIN292 (52)62 (41)230 (56)187 (55)13 (39)24 (92)6 (75)
 JHU270 (48)91 (59)179 (44)155 (45)20 (61)2 (2)2 (25)
Age at first evaluation, mean±SD, y36±1938±1936±1935±1934±1845±1443±120.283
Age at last follow-up, mean±SD, y41±1941±1940±1940±1938±1849±1545±110.789

ICIN indicates Interuniversity Cardiology Institute of The Netherlands; JHU, Johns Hopkins University; PKP2, plakophilin-2; PLN, phospholamban; Mult. mut.: patients with multiple mutations; and TMEM43, transmembrane protein 43.

*P value represents comparison between total with mutations (n=409) and without identified mutations (n=153).

Genetic Screening

Molecular-genetic screening identified mutations in 276 of the 439 index-patients (63%; Table III in the Data Supplement). Mutations were predominantly found in PKP2 (202; 46%). Less common were mutations in the other desmosomal genes: DSP (11; 3%), JUP (2; 0.5%), DSG2 (17; 4%), and DSC2 (5; 1%). Mutations in nondesmosomal genes PLN and TMEM43 were identified in 21 (5%) and 1 (0.2%) index-patient(s), respectively. Seventeen (4%) had multiple mutations. In 163 (37%) of 439 index-patients, no mutation could be identified. Notably, although not specifically studied, molecular-genetic screening revealed a de novo PKP2 exon 1 to 14 deletion mutation in 1 Dutch index-patient.

Of 562 family members, 409 (73%) were mutation carriers. Mutations in PKP2 were found in 342 (61%) family members, DSP mutations in 16 (3%), DSG2 mutations in 13 (2%), DSC2 mutations in 4 (0.7%), and PLN mutations in 26 (5%). No family members with JUP or TMEM43 mutations were identified. Eight (1%) had multiple mutations. In 153 (27%) family members, no molecular-genetic screening was performed because no mutation was found in the index-patient.

Presenting Clinical Characteristics, Clinical Course, and Long-Term Outcome in Index-Patients

Figure 1 summarizes the major presenting clinical features, clinical course, and arrhythmia and survival outcomes of each of the 439 index-patients. The mean age at first evaluation was 36±14 years. Of these, 419 (95%) presented with symptoms. The remaining 20 (5%) were asymptomatic but came to medical attention because of abnormal tests in diverse settings. Forty-eight index-patients (11%) presented with a cardiac arrest among whom 25 were resuscitated and 23 died with the diagnosis established at autopsy (median age at cardiac arrest 25 years; IQR 21 years; range 13–70 years). An additional 220 index-patients (50%) presented with a sustained VA.

Figure 1.

Figure 1. Schematic representation of the presentation, clinical course and outcome in arrhythmogenic right ventricular dysplasia/cardiomyopathy index-patients. The majority presented with sustained ventricular arrhythmias (VA) and received an implantable cardioverter-defibrillator (ICD) during follow-up (FU). Of 63 index-patients without an ICD, 11 patients died: 1 of heart failure and 10 of sudden cardiac death (SCD). In 335 patients with an ICD, 10 died: only 2 of SCD, 3 of heart failure, 2 of heart failure/arrhythmias, and 3 of noncardiac causes. Overall even in index-patients, mortality was low with 89% alive at last FU. w/o indicates without.

During the clinical disease course, an ICD was implanted in 212 (87%) of the 245 index-patients with a sustained VA or resuscitated SCD and in 139 (81%) of the 171 index-patients presenting without sustained VA. Sixty-five index-patients did not have an ICD implanted during follow-up (33 with and 32 without sustained VA at presentation). Sustained VA during follow-up were observed in more than two thirds of index-patients (301; 72%). Of the 65 index-patients without an ICD, 31 (48%) experienced a sustained VA during follow-up.

Among index-patients with an ICD, 10 died (3%; median follow-up 7 years; IQR 11 years; range 0–37 years): 2 of SCD, 3 of heart failure, 2 of a combination of heart failure and arrhythmias, and 3 of noncardiac causes. Among index-patients without an ICD, 11 died (17%; median follow-up 5 years; IQR 12 years; range 0–35 years): 10 of these 11 patients died of SCD and 1 of heart failure. The SCD incidence was remarkably higher in index-patients without an ICD than in those with an ICD (16% versus 0.6%; P<0.001). During long-term follow-up, 54 index-patients (13%) developed symptomatic heart failure and 18 (4%) had a cardiac transplantation. Four patients who underwent transplantation died during follow-up. Overall, 391 of the 416 index-patients (94%) who presented alive were alive at last follow-up.

Table IV in the Data Supplement shows the clinical characteristics of the 416 index-patients presenting alive, as reflected in the 2010 TFC. Figure 2A and 2B shows the results of Kaplan–Meier survival analysis by age for these 416 index-patients for the following outcomes: (1) any ARVD/C-related symptoms, (2) sustained VA, (3) cardiac mortality, and (4) cardiac transplantation. Of particular note is that all patients presented in their teenage years or later (range 10–78 years; only 4 index-patients presented before the age of 13 years, of whom 1 presented with a sustained VA), the development of symptoms correlated closely with the development of a sustained VA, and cardiac mortality and the need for cardiac transplantation were low.

Figure 2.

Figure 2. Survival free from any arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)–related symptoms, sustained ventricular arrhythmias (VA), cardiac death, and cardiac transplantation in ARVD/C index-patients with pathogenic mutations (A) and without identified mutations (B). Symptoms (P=0.005) and sustained VA (P=0.020) occurred significantly more often at younger age in index-patients with mutations. Survival free from cardiac death (P=0.644) and transplantation (P=0.704) was similar in both groups.

Impact of Mutation Status on Presenting Signs and Symptoms and Clinical Outcome

Index-patients with mutations presented at a significantly younger age than index-patients without identified mutations (mean age 34±14 versus 38±14 years; P<0.001; Table 1). ARVD/C TFC did not differ between those with and without identified mutations, except for negative T waves in leads V4 through V6 (4% versus 0.7%; P=0.037; Table IV in the Data Supplement). Index-patients presenting alive with and without identified mutations had similar proportions of symptoms (99% versus 97%; P=0.197) and sustained VA (83% versus 83%; P=0.934) during a median follow-up of 8 versus 6 years (P=0.198). Nonetheless, first symptoms (mean age 33±14 versus 37±15 years; P=0.002) and sustained VA (mean age 36±14 versus 40±14 years; P=0.001) occurred at significantly younger age in index-patients with mutations (log-rank test first symptoms P=0.005; log-rank test sustained VA P=0.020). Mutation status of index-patients did not affect cardiac mortality and transplantation outcomes (Figure 2A and 2B; Table V in the Data Supplement).

Familial Versus Isolated ARVD/C

ARVD/C TFC for family history were met in 295 of 416 index-patients presenting alive (71%). Of these 295 index-patients with familial ARVD/C, 264 had mutations (89%) and 31 did not (11%). In 121 index-patients (29%), family history TFC (including mutation status) were absent. Phenotype comparison of index-patients with familial and isolated ARVD/C showed no clinically relevant phenotypic differences (Table VI in the Data Supplement). Sustained VA, electrocardiographic abnormalities, structural and functional abnormalities, and heart failure occurred similarly in familial and isolated ARVD/C (median follow-up 8 versus 6 years; P=0.294). Cardiac mortality during follow-up was higher in familial ARVD/C (7% versus 0.8%; P=0.013). This difference was mostly because of the 13 index-patients with familial disease who died of SCD during follow-up (median 4 years; IQR 15 years; range 0–35 years). Of these 13 patients (5 with mutations and 8 without), 11 did not have an ICD implanted. Although SCD occurred more often in familial ARVD/C, the incidence of ventricular fibrillation during follow-up was similar (11% versus 15%; P=0.303) in index-patients with familial and isolated disease, respectively.

Presenting Clinical Characteristics, Clinical Course, and Long-Term Outcome in Family Members

The 562 family members in the cohort were first evaluated at a median age of 35 (IQR 31; range 1–87) years. Family members were predominantly asymptomatic (463; 82%), but 27 (5%) presented with a cardiac arrest among whom 2 were resuscitated and 25 died (median age 22 years; IQR 25 years; range 14–58 years; 20 autopsy diagnoses and 5 obligate carriers with ARVD/C as probable cause of death). During clinical course, ARVD/C was diagnosed in 207 of 562 family members (37%). Table VII in the Data Supplement shows the clinical characteristics of family members as reflected in the 2010 TFC. Frequent ventricular ectopy and prolonged terminal activation duration/late potentials were the most frequently observed criteria, in 20% and 31%, respectively.

Figure 3 summarizes the clinical evaluation and fulfillment of ARVD/C TFC of the 537 family members presenting alive. In 385 family members, the same mutation(s) as in their respective index-patient was identified. The remaining 152 family members were considered as without mutations because no mutation was identified in their respective index-patient. Symptoms at first evaluation correlated with ARVD/C disease expression. Of the 385 family members with mutations, 61 presented symptomatically (16%) of whom 51 met TFC for diagnosis (84%). Of the 152 family members without mutations, 13 were symptomatic (9%) of whom 10 met TFC for diagnosis (77%). Nevertheless, of 324 asymptomatic family members with mutations and 139 without mutations, 103 (32%) and 18 (13%), respectively, also met TFC for ARVD/C. Overall, family members with mutations had ARVD/C diagnosis twice more often than family members without mutations (154/385; 40% versus 28/152; 18%).

Figure 3.

Figure 3. Schematic representation of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) disease penetrance in 537 family members presenting alive. In 385 family members, the same mutation(s) as in their respective index-patients was identified (mutation +). The remaining 152 family members were considered without mutations because no mutation could be identified in their respective index-patient (mutation −). Fulfillment of Task Force Criteria (TFC) for ARVD/C (indicated by the thick black boxes) correlated with symptoms at first evaluation. Nonetheless, a minority of asymptomatic family members also had ARVD/C diagnosis. This underscores the importance of family screening in ARVD/C.

Figure 4A and 4B shows the results of Kaplan–Meier survival analysis by age for the outcomes: (1) any ARVD/C-related symptoms, (2) sustained VA, (3) cardiac mortality, and (4) cardiac transplantation in the family members presenting alive. Family members had a better clinical event-free survival compared with index-patients. Nonetheless, in those developing symptoms and events, the age of onset was only slightly older than that in index-patients. Family members with mutations had worse clinical outcomes than those without. Of 385 family members with mutations, 42 (11%) experienced sustained VA, whereas only 2 of 152 family members without mutations (1%) had sustained VA (Figure 4A and 4B; P<0.001). Eight family members with mutations (2%) died during follow-up: 4 of SCD (all without ICD), 2 of heart failure, and 2 of noncardiac causes. No deaths during follow-up were observed in family members without mutations. Two family members with (0.5%) and 1 without (0.7%) mutations underwent cardiac transplantation. The difference in sustained VA among family members with and without identified mutations also held when only family members that fulfilled TFC for diagnosis were considered (Supplemental Analysis A in the Data Supplement; detailed analysis of family members with mutations is available in Supplemental Analysis B in the Data Supplement).

Figure 4.

Figure 4. Survival free from any arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)–related symptoms, sustained ventricular arrhythmias (VA), cardiac death, and cardiac transplantation in family members with pathogenic mutations (A) and without mutations (these family members were considered as without mutations because no mutation could be identified in the index-patient; B). Family members without mutations had less symptoms (P=0.004), sustained VA (P<0.001), and cardiac death (no deaths vs 6 deaths: 4 of sudden cardiac death and 2 of heart failure) compared with family members with mutations. Survival free from cardiac transplantation was similar (P=0.812).

An ICD was implanted in 87 of 385 (23%) family members with mutations (appropriate ICD interventions in 18; 21%) compared with 14 of 152 (9%) family members without mutations (appropriate ICD therapy in 2; 14%). However, the percentage of ICDs implanted in family members that fulfilled TFC for ARVD/C diagnosis was not different between those with and without mutations (77/154; 50% versus 12/28; 43%; P=0.429).

Discussion

Main Findings

The results of this study describe in detail the presentation, clinical and genetic characteristics, and long-term outcomes of >1000 ARVD/C index-patients and family members. These results are important and unique for several reasons. First, this is the largest and most comprehensive report detailing the clinical features and outcomes of patients and family members with ARVD/C. Second, this analysis was performed after the advent of widespread molecular-genetic testing for ARVD/C and after implementation of the revised 2010 ARVD/C TFC. Third, this analysis represents the results of a collaborative transatlantic research effort with nearly equal representation of patients from the United States and Europe. There are 4 main findings of this study. First, long-term outcome was favorable in diagnosed and appropriately treated ARVD/C index-patients and family members. Second, in index-patients phenotype and long-term outcome were modulated by ICD implantation but remarkably not by mutation status and familial background. Third, clinical course and outcome in family members were determined by symptoms at first evaluation and mutation status. Finally, because index-patients with and without mutations or familial and isolated disease had similar clinical features and outcomes, these results challenge the recently proposed concept of an acquired (likely exercise induced) RV cardiomyopathy with unique clinical features and more benign course.

Previous Studies on Long-Term Follow-Up in ARVD/C

Since the first major clinical ARVD/C description in 1982, several studies reported on the long-term follow-up of patients with ARVD/C.1,1222 Although these studies have been invaluable in helping to define the clinical features and outcomes of ARVD/C patients, they also had important limitations that limit their applicability to the management of patients with ARVD/C today. First, most studies included small numbers of patients. Second, most of these studies were reports from single centers outside the United States.1215,17,19–21 Third, more than half of these studies did not include the results of molecular-genetic testing, consistent with the fact that most of these studies included subjects enrolled before the advent of widespread genetic testing.13,17,18,20,22 Fourth, nearly all studies relied on the original TFC for ARVD/C diagnosis established in 1994.1217,19 At present, the revised 2010 TFC are used to evaluate patients for ARVD/C. Finally, almost all of the series focused predominantly on affected patients with ARVD/C. Although family members were included in some of the published series, the number of family members involved was small.17,18,20

Clinical Characteristics, Clinical Presentation, Clinical Course, and Long-Term Outcome in ARVD/C Index-Patients

The results of our study provide many important insights into the clinical characteristics, presentation, clinical course, and long term outcomes of ARVD/C index-patients. First, it is striking that among the 439 index-patients in this study, only 4 presented before the age of 13 years and none presented before the age of 10 years. The onset of the disease from teenage years onward might be related to the completion of intercalated disk maturation, or the need for exposure to a certain amount of exercise before ARVD/C becomes manifest.2831 During postnatal development, the intercellular junctions in the intercalated disk supposedly undergo drastic reorganization and are eventually localized at the end of cardiomyocytes by early adolescence.30,31

Second, the results of our study demonstrate that diagnosis and subsequent treatment are associated with a good long-term outcome in index-patients. The clinical presentation of index-patients was sustained arrhythmia-related in 61%, of whom 11% presented with cardiac arrest. Sustained VA during follow-up occurred in 72% of index-patients. These findings highlight that arrhythmias are the most important and potentially life-threatening ARVD/C manifestation. Moreover, these results stress the importance of early diagnosis of ARVD/C and family member screening for the prevention of SCD. Progression of ARVD/C resulting in symptomatic heart failure was observed in a minority of index-patients (13%), and necessity for cardiac transplantation (4%) or heart failure–associated mortality during follow-up (1%) was even more uncommon. Overall, of our large transatlantic cohort of 439 index-patients, 89% were alive at last follow-up.

Determinants of Phenotypic and Long-Term Outcome Differences in ARVD/C Index-Patients

Our study assessed the impact of several potential determinants of clinical characteristics and long-term outcome in ARVD/C. First, the results of our study call attention to the important role of ICD implantation in patients with ARVD/C. An ICD was implanted in 85% of index-patients in our cohort. There was a remarkably higher incidence of SCD during follow-up in index-patients without an ICD than in those with an ICD (16% versus 0.6%). In addition, none of the 4 family members who died of SCD during follow-up had an ICD. At present, ICD implantation is the only proven life-saving therapy in ARVD/C. In the future, other treatment modalities in ARVD/C might improve disease outcome.32

Second, our study demonstrated for the first time that the presence or absence of identifiable mutations did not affect clinical outcome in ARVD/C index-patients although it did modulate age of disease expression. Phenotypic characteristics and disease course were similar in index-patients with and without identified mutations. Of note, index-patients with mutations had earlier disease onset, with a remarkable 4-year difference in mean age at first symptoms, clinical presentation and sustained VA compared with index-patients without identified mutations.

Finally, in our study, no evidence for impact of familial background on clinical characteristics and long-term outcome among index-patients with established disease was observed. This type of analysis has not been performed among patients with ARVD/C previously. Recently, Heidbüchel et al2325 have proposed a concept of isolated exercise-induced RV cardiomyopathy, mimicking ARVD/C. They hypothesized that these patients with isolated disease, although meeting TFC for ARVD/C diagnosis, have distinct clinical characteristics from inherited and familial forms of ARVD/C. In our cohort, no evidence supporting this hypothesis was found. The isolated form of ARVD/C was clinically identical to familial ARVD/C. Moreover, our data do not suggest that index-patients with familial or isolated ARVD/C should be treated differently. Although cardiac mortality occurred significantly more often in index-patients with familial ARVD/C, this difference was mostly because of the 13 patients, 11 of whom had no ICD, with familial disease who died of SCD during follow-up. Moreover, the incidence of episodes of sustained ventricular tachycardia and ventricular fibrillation and structural and functional abnormalities were similar in familial and isolated disease during a comparable follow-up duration. These results suggest the importance of ICD implantation for both groups of index-patients.

Notably, in 11% of index-patients with familial ARVD/C, no mutation could be identified. Nonetheless, in these families, an unidentified genetic background for ARVD/C can reasonably be assumed. The possible role of de novo mutations in (isolated) ARVD/C, on the contrary, needs yet to be explored.

Clinical Course and Long-Term Outcome in ARVD/C in Family Members

Furthermore, this study provides important insights into the disease course and outcomes of family members of index-patients with ARVD/C. Family members were predominantly asymptomatic at first evaluation. In our cohort, among >500 family members, approximately one third (37%) developed ARVD/C. Sustained VA and cardiac mortality during follow-up occurred in a small minority (8% and 2%, respectively). In the family members who developed disease and sustained VA, the age at onset was comparable with that in index-patients.

Determinants of Phenotypic and Long-Term Outcome Differences in Family Members

The results of our study expose 2 important factors influencing disease course and long-term outcome of family members. First, symptoms at first evaluation corresponded with ARVD/C diagnosis and disease expression. This suggests that particular attention should be paid to symptomatic family members. However, albeit at lower rates, a considerable portion of asymptomatic family members also met 2010 TFC for ARVD/C diagnosis. These results stress the importance of family screening for timely diagnosis and risk management.

Second, in contrast to index-patients, mutation status affected long-term outcome in family members. A 2-fold difference was observed in ARVD/C diagnosis between family members with and without mutations. This is consistent with an autosomal dominant inheritance pattern, assuming that all ARVD/C cases are genetically based. However, sustained VA were observed 8× more often in family members with mutations. This divergence could not be explained by the difference in ARVD/C diagnosis or ICD implantations and subsequent arrhythmia detection because ICD implantation rates were comparable in family members with ARVD/C diagnosis between those with and without mutations. Similarly, cardiac death was observed more often in family members with mutations than in those without mutations. It may be that family members of index-patients without identified mutations are at decreased risk of developing disease, sustained VA, and cardiac death or that they have a higher threshold for development of VA.

Overall, our study in the largest cohort reported to date, demonstrates that family members have excellent long-term outcomes. Most family members did not develop ARVD/C and had better sustained arrhythmia-free survival compared with index-patients. Even in family members with mutations, the major clinical event rate was relatively low. Which family members will develop disease and arrhythmias and what their risk factors are, warrants further study.

Limitations

Not all index-patients and family members underwent all diagnostic tests, as indicated in Table II in the Data Supplement. This reflects diagnostic choices made in daily clinical practice in multiple centers. Index-patients were defined as without mutations when no pathogenic mutation was identified. Particularly among the 11% with familial disease, mutations in new ARVD/C-associated genes may be discovered. The contribution of variants of uncertain significance in index-patients with and without identified mutations was not evaluated. Although founder mutations, which may limit the generalizability of results, were present in the Dutch cohort, outcomes did not differ between the Dutch and US cohort, suggesting that these founder mutations likely had little effect.9,10,33 Only first-degree relatives of patients with ARVD/C without identified mutations were included to limit underestimation of phenotype and outcomes among family members. Although a genetic cause of disease in these families cannot be ruled out, a subset of these family members is possibly unaffected, which might result in an underestimation of the disease outcomes among these individuals.

Conclusions

This study of an extensive transatlantic ARVD/C cohort of 1001 individuals, including large numbers of index-patients and family members, provides insights in clinical course and long-term outcome with important clinical implications for current patient management strategies in ARVD/C. Long-term outcome was favorable in diagnosed and appropriately treated index-patients and family members. ICD implantation importantly reduced SCD incidence during follow-up and improved long-term outcome. Index-patients with and without identified mutations had a similar disease course and outcome although disease onset was earlier in index-patients with mutations. No phenotypic and clinical outcome differences, except for cardiac mortality, were observed between ARVD/C index-patients with familial and isolated disease. Approximately one third of family members developed ARVD/C during clinical course. Long-term outcome in family members was negatively influenced by symptoms at first evaluation and the presence of mutations.

Acknowledgments

We are grateful to the patients who have made this work possible.

Appendix

From the Division of Cardiology, Department of Medicine (A.B., C.A.J., A.S.t.R., C.T., B.M., A.C.S., B.K., S.D.R., R.J.T., H.T., D.P.J., H.C.) and Department of Radiology (S.L.Z., I.R.K.), Johns Hopkins University School of Medicine, Baltimore, MD; Departments of Cardiology (J.A.G., A.S.t.R., J.F.v.d.H., M.J.C., P.A.D., R.N.H.), Genetics (D.D.), and Medical Physiology (T.A.v.V.), University Medical Center Utrecht, Utrecht, The Netherlands; ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.A.G., J.P.v.T., R.N.H.); Departments of Cardiology (A.C.P.W.) and Genetics (J.P.v.T.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (D.E.A.); Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands (P.G.V.); Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands (N.M.d.G.); Department of Cardiology, VU Medical Center, Amsterdam, The Netherlands (K.d.B.); Department of Cardiology, AMC Heart Center, Academic Medical Center, Amsterdam, The Netherlands (A.A.W.); and Durrer Center for Cardiogenetic Research, Utrecht, The Netherlands (J.P.v.T.).

Footnotes

*Drs Groeneweg and Bhonsale contributed equally to this work.

The Data Supplement is available at http://circgenetics.ahajournals.org/lookup/suppl/doi:10.1161/CIRCGENETICS.114.001003/-/DC1.

Correspondence to Hugh Calkins, MD, Division of Cardiology, Johns Hopkins Hospital, Sheikh Zayed Tower 7125R, 1800 Orleans St, Baltimore, MD 21287. E-mail

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CLINICAL PERSPECTIVE

Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a progressive cardiomyopathy (ARVD/C), characterized by ventricular arrhythmias and predominantly right ventricular involvement. Information on long-term follow-up of ARVD/C is limited. In addition, ARVD/C is considered a hereditary disease. However, in a significant subset of patients, no mutation can be identified. It is unknown whether the presence of a mutation influences disease course in ARVD/C. We aimed to define long-term outcome and determinants of outcome in a large transatlantic cohort of ARVD/C index-patients and family members. These results provide important insights into clinical presentation, clinical course, and disease outcomes of ARVD/C. Our study showed that in index-patients arrhythmias are the most important and potentially life-threatening ARVD/C manifestation. In accordance, long-term outcome was improved by ICD implantation. In index-patients mutation status and familial background of disease did not influence outcomes. Nonetheless, index-patients with mutations had earlier onset of symptoms and arrhythmias. Overall, index-patients had favorable long-term outcomes; cardiac mortality and the need for cardiac transplantation were low. Family members also had favorable long-term outcomes. Approximately one third developed ARVD/C, and ventricular arrhythmia and cardiac mortality rates were lower than index-patients. Symptoms at first evaluation correlated with disease expression. Nevertheless, a subset of asymptomatic family members also developed the disease. These results emphasize the importance of timely family screening to identify family members at risk. In contrast to index-patients, mutation status did influence outcomes in family members. Family members with mutations had more symptoms, ventricular arrhythmias, and ARVD/C diagnosis than in those without mutations.

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