Long-term arrhythmic follow-up and risk stratification of patients with desmoplakin-associated arrhythmogenic right ventricular cardiomyopathy

Background: Patients with likely pathogenic/pathogenic (LP/P) desmoplakin (DSP) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting. Objectives: To characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with DSP LP/P variants fulfilling definite 2010 ARVC Task Force Criteria (DSP-TFC+). Methods: DSP-TFC+ patients were enrolled from twenty institutions across three continents. Ventricular arrhythmias (VA), 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. We tested performance of the ARVC risk calculator for VA prediction, reporting c-statistics. Results: Among 252 DSP-TFC+ patients (39.6±16.9 y.o., 35.3% male), 94 (37.3%) experienced VA over 44.5 [19.6–78.3] months. Patients with LV involvement (n=194) were at higher VA risk (log-rank p=0.0239). History of non-sustained VT (NSVT) (aHR 2.097; p=0.004) showed the strongest association with VA occurrence during the first 5-yr of follow-up. Neither age (p=0.723) nor male sex (p=0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/year). The ARVC Risk Calculator performed poorly overall (c-statistic 0.604 [0.594–0.614]) and very poorly in patients with left ventricular disease (c- statistic 0.558 [0.556–0.560]). Conclusion: DSP-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in DSP-TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, DSP-24 TFC+ patients with NSVT should be considered as high-risk