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.
•Myocarditis is a distinct presenting phenotype of ARVC.•ARVC diagnostic criteria can make myocarditis phenotype difficult to diagnose.•Genetic testing a subset of myocarditis patients aids in ...diagnosis.•Early and accurate ARVC diagnosis is important for patient and family members.
Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) classically initially present with ventricular arrhythmias or, less commonly, heart failure. Myocardial inflammation has been implicated in pathogenesis, but clinical myocarditis in ARVC is less described. We therefore studied clinical myocarditis as an initial ARVC presentation, and hypothesized that these patients have distinct clinical and genetic characteristics. Using the Johns Hopkins ARVC Registry, we identified 12 patients (all female, median age 20) referred between 2014 and 2019 diagnosed with myocarditis at presentation who were subsequently diagnosed with ARVC by Task Force Criteria. Majority presented with chest pain (n = 7, 58%) or ventricular arrhythmia (n = 3, 25%). All patients had troponin elevations and left ventricular (LV) function was reduced in 5 (42%). Magnetic resonance imaging demonstrated LV delayed gadolinium enhancement and/or pericardial enhancement in 10 (83%); only 3 (25%) patients had right ventricular abnormalities. Pathogenic genetic variants were identified in 11 (92%) patients: 10 desmoplakin (DSP) and 1 desmoglein-2 (DSG2). Thus, nearly 1/3 (10/32, 31%) of overall DSP ARVC patients were originally diagnosed with myocarditis. Patients were diagnosed with ARVC 1.8 years (IQR 2.7 years) after presentation and 8 (75%) patients did not meet Task Force Criteria without genetic testing. ARVC diagnosis led to an additional 5 (42%) patients referred for implantable cardiac defibrillator and 17 family member diagnoses. In conclusion, ARVC may initially present as myocarditis and these patients have distinct characteristics including female gender, LV involvement and DSP gene variants. Genetic testing is key to ARVC diagnosis and should be considered in select myocarditis patients.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease that leads to ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Treating ARVC remains ...challenging due to the complex underlying arrhythmogenic mechanisms, which involve structural and electrophysiological (EP) remodeling. Here, we developed a novel genotype-specific heart digital twin (Geno-DT) approach to investigate the role of pathophysiological remodeling in sustaining VT reentrant circuits and to predict the VT circuits in ARVC patients of different genotypes. This approach integrates the patient's disease-induced structural remodeling reconstructed from contrast-enhanced magnetic-resonance imaging and genotype-specific cellular EP properties. In our retrospective study of 16 ARVC patients with two genotypes: plakophilin-2 (
,
8) and gene-elusive (GE,
8), we found that Geno-DT accurately and non-invasively predicted the VT circuit locations for both genotypes (with 100%, 94%, 96% sensitivity, specificity, and accuracy for GE patient group, and 86%, 90%, 89% sensitivity, specificity, and accuracy for
patient group), when compared to VT circuit locations identified during clinical EP studies. Moreover, our results revealed that the underlying VT mechanisms differ among ARVC genotypes. We determined that in GE patients, fibrotic remodeling is the primary contributor to VT circuits, while in
patients, slowed conduction velocity and altered restitution properties of cardiac tissue, in addition to the structural substrate, are directly responsible for the formation of VT circuits. Our novel Geno-DT approach has the potential to augment therapeutic precision in the clinical setting and lead to more personalized treatment strategies in ARVC.
We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers.
...Pathogenic mutations in desmosomal and non-desmosomal genes were identified in 577 patients (241 families) from USA and Dutch ARVD/C cohorts. Patients with sudden cardiac death (SCD)/ventricular fibrillation (VF) at presentation (n = 36) were younger (median 23 vs. 36 years; P < 0.001) than those presenting with sustained monomorphic ventricular tachycardia (VT). Among 541 subjects presenting alive, over a mean follow-up of 6 ± 7 years, 12 (2%) patients died, 162 (30%) had sustained VT/VF, 78 (14%) manifested left ventricular dysfunction (EF < 55%), 28 (5%) experienced heart failure (HF), and 10 (2%) required cardiac transplantation. Patients (n = 22; 4%) with >1 mutation had significantly earlier occurrence of sustained VT/VF (mean age 28 ± 12 years), lower VT-/VF-free survival (P = 0.037), more frequent left ventricular dysfunction (29%), HF (19%) and cardiac transplantation (9%) when compared with those with only one mutation. Desmoplakin mutation carriers experienced more than four-fold occurrence of left ventricular dysfunction (40%) and HF (13%) than PKP2 carriers. Missense mutation carriers had similar death-/transplant-free survival and VT/VF penetrance (P = 0.137) when compared with those with truncating or splice site mutations. Men are more likely to be probands (P < 0.001), symptomatic (P < 0.001) and have earlier and more severe arrhythmic expression.
Presentation with SCD/VF occurs at a significantly younger age when compared with sustained monomorphic VT. The genotype of ARVD/C mutation carriers impacts clinical course and disease expression. Male sex negatively modifies phenotypic expression.
Endurance exercise is associated with adverse outcomes in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Exercise recommendations for family members remain ...undetermined.
The purposes of this study were to determine if (1) endurance exercise (Bethesda class C) and exercise intensity (metabolic equivalent hours per year MET-Hr/year) increase the likelihood of fulfilling 2010 Task Force Criteria and ventricular arrhythmias/implantable cardioverter-defibrillator shock (ventricular tachycardia/ventricular fibrillation VT/VF), and (2) exercise restriction to the American Heart Association (AHA)-recommended minimum for healthy adults is associated with favorable outcomes of at-risk family members.
Twenty-eight family members of 10 probands inheriting a PKP2 mutation were interviewed about exercise from age 10. Exercise threshold to maintain overall health was based on the 2007 AHA guidelines of a minimum 390 to 650 MET-Hr/year.
After adjustment for age, sex, and family membership, both participation in endurance athletics (odds ratio OR 7.4, P = .03) and higher-intensity exercise (OR = 4.2, P = .004) were associated with diagnosis (n = 13). Endurance athletes were also significantly more likely to develop VT/VF (n = 6, P = .02). Family members who restricted exercise at or below the upper bound of the AHA goal (≤650 MET-Hr/year) were significantly less likely to be diagnosed (OR = 0.07, P = .002) and had no VT/VF. At diagnosis and first VT/VF, family members had accumulated 2.8-fold (P = .002) and 3.5-fold (P = .03), respectively, greater MET-Hr exercise than the AHA-recommended minimum. Those who developed VT/VF had performed particularly high-intensity exercise in adolescence compared to unaffected family members (age 10-14: P = .04; age 14-19: P = .02).
The results of this study suggest restricting unaffected desmosomal mutation carriers from endurance and high-intensity athletics but potentially not from AHA-recommended minimum levels of exercise for healthy adults.
Variable success rates have been reported after epicardial radiofrequency catheter ablation (RFA) in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The details of the ...electroanatomic substrate are limited to a few studies, and the characteristics of the recurrent ventricular tachycardia (VT) in ARVD/C remain largely unknown.
The purpose of this study was to report procedural strategy, safety, and efficacy of epicardial RFA at a tertiary single center with a focus on the characteristics of the substrate and recurrent VT.
We included 30 ARVD/C patients (mean age 33.1 ± 11.1 years, 53% male) who underwent endocardial/epicardial mapping and epicardial catheter ablation of VT at the Johns Hopkins Hospital. Implantable cardioverter-defibrillator interrogations were evaluated for VT recurrence.
The majority of critical VT circuits (69%) were on the epicardial surface, mostly in the subtricuspid region. Eight patients (27%) experienced VT recurrence after epicardial RFA, and the VT-free survival was 83%, 76%, and 70% at 6,12, and 24, months respectively. A significant reduction of VT burden was observed (P <.001), even among those with VT recurrence. No complications occurred except for acute pericarditis in 1 patient. The majority of VT recurrences occurred during the first year after RFA, during exercise, had fast cycle lengths, and required implantable cardioverter-defibrillator shock for termination.
The vast majority of critical VT circuits were epicardial, mostly in the subtricuspid region. Epicardial RFA of VT appears to be both safe and effective in achieving arrhythmia control in ARVD/C. The features of the recurrent VT suggest a possible catecholamine-mediated mechanism with an origin in a region not targeted for ablation.
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.
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.
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.
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.
BACKGROUND—Prior studies evaluating the efficacy of catheter ablation of ventricular tachycardia (VT) among patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) have ...reported varied outcomes. More recently, studies have suggested that an epicardial ablation is necessary for improved outcomes after catheter ablation of VT. The overall objective of the present study was to assess the efficacy of radiofrequency catheter ablation (RFA) of VT in ARVD/C, with particular focus on newer ablation strategies, including epicardial catheter ablation.
METHODS AND RESULTS—The study population included 87 patients with ARVD/C who underwent a total of 175 RFA procedures between 1992 and 2011 at 80 different electrophysiology centers. Recurrence of VT following RFA and effect of RFA on the burden of VT were assessed. The mean age of the cohort was 38 ± 13 years. Over a mean follow-up of 88.3 ± 66 months, the overall freedom from VT of the 175 procedures was 47%, 21%, and 15%, at 1, 5, and 10 years, respectively. The cumulative freedom from VT following epicardial RFA was 64% and 45% at 1 and 5 years, respectively, which was significantly longer than endocardial RFA (P=0.021). Survival free of VT among procedures with 3D electroanatomic mapping was significantly longer compared to those without (P=0.016). Burden of VT was reduced irrespective of the ablation strategy (P<0.001).
CONCLUSIONS—Although VT recurrences are common, RFA results in a significant reduction in the burden of VT in patients with ARVD/C. Further, although the use of 3D electroanatomic mapping systems and epicardial ablation strategies are associated with longer survival free of VT, recurrence rates remain considerable.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy, characterized by right ventricular dysfunction and ventricular arrhythmias. Limited information is ...available concerning atrial arrhythmias in ARVD/C.
The purpose of this study was to characterize spontaneous atrial arrhythmias in a large registry population of ARVD/C patients.
Patients (n = 248) from the Johns Hopkins ARVD/C registry who met the diagnostic criteria and had undertaken genotype analysis were included. Medical records of each were reviewed to ascertain incidence and characteristics of atrial arrhythmia episodes. Detailed demographic, phenotypic, and structural information was obtained from registry data.
Thirty-five patients with ARVD/C (14%) experienced one or more types of atrial arrhythmia during median follow-up of 5.78 (interquartile range 8.52) years. Atrial fibrillation was the most common atrial arrhythmia, occurring in 80% of ARVD/C patients with atrial arrhythmias. Patients developed atrial arrhythmias at a mean age of 43.0 ± 14.0 years. Atrial arrhythmia patients obtained a total of 22 inappropriate implantable cardioverter-defibrillator shocks during follow-up. Older age at last follow-up (P <.001) and male gender (P = .044) were associated with atrial arrhythmia development. Patients with atrial arrhythmias had a higher occurrence of death (P = .028), heart failure (P <.001), and left atrial enlargement on echocardiography (P = .004).
Atrial arrhythmias are common in ARVD/C and present at a younger age than in the general population. They are associated with male gender, increasing age, and left atrial enlargement. Atrial arrhythmias are clinically important as they are associated with inappropriate implantable cardioverter-defibrillator shocks and increased risk of both death and heart failure.
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