Crystal Tichnell

Arrhythmogenic Right Ventricular Dysplasia: A United States Experience

Background— Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. The purpose of our study was to describe the presentation, clinical features, survival, and natural history of ARVD in a large cohort of patients from the United States. Methods and Results— The patient population included 100 ARVD patients (51 male; median age at presentation, 26 [interquartile range {IQR}, 18 to 38; range, 2 to 70] years). A familial pattern was observed in 32 patients. The most common presenting symptoms were palpitations, syncope, and sudden cardiac death (SCD) in 27%, 26%, and 23% of patients, respectively. Among those who were diagnosed while living (n=69), the median time between first presentation and diagnosis was 1 (range, 0 to 37) year. During a median follow-up of 6 (IQR, 2 to 13; range, 0 to 37) years, implantable cardioverter/defibrillators (ICD) were implanted in 47 patients, 29 of whom received an appropriate ICD discharge, including 3 patients who received the ICD for primary prevention. At follow-up, 66 patients were alive, of whom 44 had an ICD in place, 5 developed signs of heart failure, 2 had a heart transplant, and 18 were on drug therapy. Thirty-four patients died either at presentation (n=23: 21 SCD, 2 noncardiac deaths) or during follow-up (n=11: 10 SCD, 1 of biventricular heart failure), of whom only 3 were diagnosed while living and 1 had an ICD implanted. On Kaplan-Meier analysis, the median survival in the entire population was 60 years. Conclusions— ARVD patients present between the second and fifth decades of life either with symptoms of palpitations and syncope associated with ventricular tachycardia or with SCD. Diagnosis is often delayed. Once diagnosed and treated with an ICD, mortality is low. There is a wide variation in presentation and course of ARVD patients, which can likely be explained by the genetic heterogeneity of the disease.

Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers.

OBJECTIVES This study sought to determine how exercise influences penetrance of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) among patients with desmosomal mutations. BACKGROUND Although animal models and anecdotal evidence suggest that exercise is a risk factor for ARVD/C, there have been no systematic human studies. METHODS Eighty-seven carriers (46 male; mean age, 44 ± 18 years) were interviewed about regular physical activity from 10 years of age. The relationship of exercise with sustained ventricular arrhythmia (ventricular tachycardia/ventricular fibrillation [VT/VF]), stage C heart failure (HF), and meeting diagnostic criteria for ARVD/C (2010 Revised Task Force Criteria [TFC]) was studied. RESULTS Symptoms developed in endurance athletes (N = 56) at a younger age (30.1 ± 13.0 years vs. 40.6 ± 21.1 years, p = 0.05); they were more likely to meet TFC at last follow-up (82% vs. 35%, p < 0.001) and have a lower lifetime survival free of VT/VF (p = 0.013) and HF (p = 0.004). Compared with those who did the least exercise per year (lowest quartile) before presentation, those in the second (odds ratio [OR]: 6.64, p = 0.013), third (OR: 16.7, p = 0.001), and top (OR: 25.3, p < 0.0001) quartiles were increasingly likely to meet TFC. Among 61 individuals who did not present with VT/VF, the 13 subjects experiencing a first VT/VF event over a mean follow-up of 8.4 ± 6.7 years were all endurance athletes (p = 0.002). Survival from a first VT/VF event was lowest among those who exercised most (top quartile) both before (p = 0.036) and after (p = 0.005) clinical presentation. Among individuals in the top quartile, a reduction in exercise decreased VT/VF risk (p = 0.04). CONCLUSIONS Endurance exercise and frequent exercise increase the risk of VT/VF, HF, and ARVD/C in desmosomal mutation carriers. These findings support exercise restriction for these patients.

Electrocardiographic features of arrhythmogenic right ventricular dysplasia/cardiomyopathy according to disease severity: A need to broaden diagnostic criteria

Background—The purpose of this study was to systematically study diagnostic and prognostic electrocardiographic (ECG) characteristics of arrhythmogenic right ventricle dysplasia/cardiomyopathy (ARVD/C). Methods and Results—The patient population included 50 patients with ARVD/C (27 males, 23 females; mean age 38±15 years). We also analyzed the ECG of 50 age- and gender-matched normal control subject and 28 consecutive patients who presented with right ventricular outflow tract (RVOT) tachycardia. Right bundle-branch block (RBBB) was present in 11 patients (22%). T-wave inversions in V1 through V3 were observed in 85% of ARVD/C patients in the absence of RBBB compared with none in RVOT and normal controls, respectively (P<0.0001); epsilon waves were seen in 33%, and a QRS duration ≥110 ms in V1 through V3 was present in 64% of patients. Among those without RBBB, our newly proposed criterion of “prolonged S-wave upstroke in V1 through V3” ≥55 ms was the most prevalent ECG feature (95%) and correlated with disease severity and induction of VT on electrophysiological study. This feature also best distinguished ARVD/C (diffuse and localized) from RVOT. Conclusions—A prolonged S-wave upstroke in V1 through V3 is the most frequent ECG finding in ARVD/C and should be considered as a diagnostic ECG marker.

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

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.

DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a disorder characterized by fibrofatty replacement of cardiac myocytes that typically manifests in the right ventricle. It is inherited as an autosomal dominant disease with reduced penetrance, although autosomal recessive forms of the disease also occur. We identified four probands with ARVD/C caused by mutations in DSG2, which encodes desmoglein-2, a component of the cardiac desmosome. No association between mutations in this gene and human disease has been reported elsewhere. One of these probands has compound-heterozygous mutations in DSG2, and the remaining three have isolated heterozygous missense mutations, each disrupting known functional components of desmoglein-2. We report that mutations in DSG2 contribute to the development of ARVD/C.

Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited disorder typically caused by mutations in components of the cardiac desmosome. The prevalence and significance of desmosome mutations among patients with ARVD/C in North America have not been described previously. We report comprehensive desmosome genetic analysis for 100 North Americans with clinically confirmed or suspected ARVD/C. Methods and Results— In 82 individuals with ARVD/C and 18 people with suspected ARVD/C, DNA sequence analysis was performed on PKP2, DSG2, DSP, DSC2, and JUP. In those with ARVD/C, 52% harbored a desmosome mutation. A majority of these mutations occurred in PKP2. Notably, 3 of the individuals studied have a mutation in more than 1 gene. Patients with a desmosome mutation were more likely to have experienced ventricular tachycardia (73% versus 44%), and they presented at a younger age (33 versus 41 years) compared with those without a desmosome mutation. Men with ARVD/C were more likely than women to carry a desmosome mutation (63% versus 38%). A mutation was identified in 5 of 18 patients (28%) with suspected ARVD. In this smaller subgroup, there were no significant phenotypic differences identified between individuals with a desmosome mutation compared with those without a mutation. Conclusions— Our study shows that in 52% of North Americans with ARVD/C a mutation in one of the cardiac desmosome genes can be identified. Compared with those without a desmosome gene mutation, individuals with a desmosome gene mutation had earlier-onset ARVD/C and were more likely to have ventricular tachycardia.

Misdiagnosis of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Introduction: Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) has major implications for the management of patients and their first‐degree relatives. Diagnosis is based on a set of criteria proposed by the International Task Force for Cardiomyopathies. We report our experience in providing a re‐evaluation for patients who previously have been diagnosed with ARVD/C.

Incidence and Predictors of Implantable Cardioverter-Defibrillator Therapy in Patients With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Undergoing Implantable Cardioverter-Defibrillator Implantation for Primary Prevention

OBJECTIVES The purpose of this study was to define the incidence and predictors of implantable cardioverter-defibrillator (ICD) therapy in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) after placement of an ICD for primary prevention. BACKGROUND Patients with a diagnosis of ARVD/C often receive an ICD for prevention of sudden cardiac death. METHODS Patients (n = 84) from the Johns Hopkins registry with definite or probable ARVD/C who underwent ICD implantation for primary prevention were studied. Detailed phenotypic, genotype, and ICD event information was obtained and appropriate ICD therapies were adjudicated based on intracardiac electrograms. RESULTS Over a mean follow-up of 4.7 ± 3.4 years, appropriate ICD therapy was seen in 40 patients (48%), of whom 16 (19%) received interventions for potentially fatal ventricular fibrillation/flutter episodes. Proband status (p < 0.001), inducibility at electrophysiologic study (p = 0.005), presence of nonsustained ventricular tachycardia (p < 0 .001), and Holter premature ventricular complex count >1,000/24 h (p = 0.024) were identified as significant predictors of appropriate ICD therapy. The 5-year survival free of appropriate ICD therapy for patients with 1, 2, 3, and 4 risk factors was 100%, 83%, 21%, and 15%, respectively. Inducibility at electrophysiologic study (hazard ratio: 4.5, 95% confidence interval: 1.4 to 15, p = 0.013) and nonsustained ventricular tachycardia (hazard ratio: 10.5, 95% confidence interval: 2.4 to 46.2, p = 0.002) remained as significant predictors on multivariable analysis. CONCLUSIONS Nearly one-half of the ARVD/C patients with primary prevention ICD implantation experience appropriate ICD interventions. Inducibility at electrophysiologic study and nonsustained ventricular tachycardia are independent strong predictors of appropriate ICD therapy. An increase in ventricular ectopy burden was associated with progressively lower event-free (appropriate ICD interventions) survival. Incremental risk of ventricular arrhythmias and ICD therapy was observed with the presence of multiple risk factors.

Magnetic Resonance Imaging Findings in Patients Meeting Task Force Criteria for Arrhythmogenic Right Ventricular Dysplasia

Introduction: Magnet resonance imaging (MRI) findings in patients meeting Task Force criteria for the diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) have not been systematically described. We report qualitative and quantitative MRI findings in ARVD using state‐of‐the‐art MRI.

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

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.