BACKGROUND AND AIMS:Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS:This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS:One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS:North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Background: Physical activity (PA) restriction is a recommended intervention for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), due to strong associations of PA history with disease, and the known risk of arrhythmic events in affected patients from tertiary referral centers. However, in patients with secondary findings of genetic risk for ARVC, the association of PA exposure with disease expression is unknown. Hypothesis: Among individuals with incidentally identified pathogenic or likely pathogenic (P/LP) variants in desmosome genes (PKP2, DSP, DSG2, DSC2), clinical evidence of disease will be associated with higher pre-diagnostic PA exposure. Methods: The MyCode (MC) cohort included individuals with P/LP variants in desmosome genes, discovered via population genomic screening of 175,000 individuals; the Johns Hopkins (JH) disease-based cohort included ARVC probands and family members with single P/LP variants enrolled in the JH ARVC Registry. The ARVC task force criteria (TFC) status of each patient was defined based on most recent clinical evaluation. Recreational PA history from age 10 to time of diagnosis (TFC+) or survey (TFC-) was self-reported through structured phone interview and each activity was assigned a metabolic equivalent score. Results: The MC cohort was older, more female-predominant, had a lower proportion of PKP2 variants, and had less disease than the JH cohort (Figure; all p<0.001). As expected, MET-hrs/year of exercise prior to presentation was significantly higher in affected vs. unaffected patients in the JH cohort. In contrast, no association between PA history and disease expression was observed in MC (p=0.42). Conclusions: The MyCode cohort demonstrated both a paucity of clinically evident disease and a lack of obvious association of exercise with disease expression. These findings may be seen as reassuring in the management of patients with secondary ARVC genetic findings, but additional data are needed.

Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), but differences in their utilization across North America and Europe are unknown.

Background: The arrhythmogenic right ventricular cardiomyopathy (ARVC) risk calculator stratifies risk for incident sustained ventricular arrhythmias (VA) at the time of ARVC diagnosis. However, included risk factors change over time, and how well the ARVC risk calculator performs at follow-up is unknown. Methods: This was a retrospective analysis of patients with definite ARVC and without prior sustained VA. Risk factors for VA including age, nonsustained ventricular tachycardia, premature ventricular complex burden, T-wave inversions on electrocardiogram, cardiac syncope, right ventricular function, therapeutic medication use, and exercise intensity were assessed at the time of 2010 Task Force Criteria based ARVC diagnosis and upon repeat evaluations. Changes in these risk factors were analyzed over 5-year follow-up. The 5-year risk of VA was predicted longitudinally using (1) the baseline ARVC risk calculator prediction, (2) the ARVC risk prediction calculated using updated risk factors, and (3) time-varying Cox regression. Discrimination and calibration were assessed in comparison to observed VA event rates. Results: Four hundred eight patients with ARVC experiencing 132 primary VA events were included. Matched comparison of risk factors at baseline versus at 5 years of follow-up revealed decreased burdens of premature ventricular complexes (−1200/day) and nonsustained ventricular tachycardia (−14%). Presence of significant right ventricular dysfunction and number of T-wave inversions on electrocardiogram were unchanged. Observed risk for VA decreased by 13% by 5 years follow-up. The baseline ARVC risk calculator’s ability to predict 5-year VA risk worsened during follow-up (C statistics, 0.83 at diagnosis versus 0.68 at 5 years). Both the updated ARVC risk calculator (C statistics of 0.77) and time-varying Cox regression model (C statistics, 0.77) had strong discrimination. The updated ARVC risk calculator overestimated 5-year VA risk by an average of +6%. ConclusionS: Risk factors for VA in ARVC are dynamic, and overall risk for incident sustained VA decreases during follow-up. Up-to-date risk factor assessment improves VA risk stratification.