Ce-452775-4 long-term arrhythmic follow-up and performance of modern risk stratification tools in large cohort of patients with desmoplakin arrhythmogenic cardiomyopathy

Data describing arrhythmic outcomes of patients harboring a likely pathogenic/pathogenic (LP/P) desmoplakin (DSP) variant and fulfilling a definite diagnosis of arrhythmogenic cardiomyopathy (ACM) is scarce. There has been limited assessment of clinical and demographic variables associated with ventricular arrhythmias (VAs) and the performance of a current risk stratification algorithm (ARVC risk calculator) in this population is uncertain. To characterize arrhythmic outcomes and to test the ARVC risk calculator performance in patients with DSP-associated ACM fulfilling definite 2010 Task Force Criteria over long-term follow-up. Patients with a definite ACM diagnosis and harboring a LP/P DSP variant were enrolled from eighteen ACM/cardiomyopathy registries in North America, Europe, and Australia. VA events, defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow up, were reported as the primary outcome. The performance of the ARVC risk score for VA prediction in eligible patients was tested, reporting c-statistic and calibration plots. Among 252 DSP-ACM patients (39.6±16.9 years old, 35.3% male) enrolled in the study, 94 (37.3%) experienced a VA event over a median follow-up of 44.5 [19.6–78.3] months. History of previous non-sustained VT (aHR 2.249; p=0.001) showed the strongest association with the study outcome, while neither age (p=0.723) nor male sex (p=0.200) were associated. In the 204 patients with no VA at diagnosis and thus eligible for risk stratification with the ARVC risk calculator, overall performance of the algorithm was poor (c-statistic 0.604 [0.594–0.614]). Performance was reasonable in the 58 (28.4%) of DSP-ACM patients without LV involvement (c-statistic 0.691 [0.678–0.704]) but very poor the larger group (N=146, 71.6%) of DSP-ACM patients with LV disease (c-statistic 0.561 [0.558–0.564]). Patients with DSP-ACM are at high risk for VAs, with previous non-sustained VT representing the strongest risk factor. The current ARVC risk calculator showed poor performance in DSP-ACM patients with LV involvement. A gene-specific risk calculator may provide better VA risk stratification for these patients.