External validation of the DSP-risk score for prediction of clinically significant ventricular arrhythmias in primary prevention patients with desmoplakin cardiomyopathy-associated genetic variants

BACKGROUND: Patients harboring pathogenic/likely pathogenic (P/LP) variants in the desmoplakin (DSP) gene are at risk of ventricular arrhythmias (VAs). In this population, a risk prediction model estimating the 5-year risk of VAs has been recently developed. OBJECTIVE: This study aimed to provide external validation of this prediction model in a new large, international, multicenter cohort and to test its reliability in patients with and without a history of myocarditis-like episodes. METHODS: All patients with a P/LP pathogenic DSP variant enrolled in the Desmoplakin Specific Effort for a Rare Disease Outcome Study Network with no sustained VA before or at first assessment and who were not used for the development of the DSP-risk score (www.DSP-risk.com) were used to test its performance. Model performance was assessed using the c-statistic in both the overall cohort and stratifying by history of myocarditis-like episodes. RESULTS: 450 DSP patients from 30 centers were enrolled (mean age 42.2 ± 17.6; 40.4% female; 18.4% with previous myocarditis-like episode). Over a median of 4.3 years (1.6-10.0), 60 sustained VAs were observed. The DSP-risk score yielded good discrimination both overall (c-statistic, 0.719; 95% confidence interval [CI], 0.706-0.733) and for patients with (c-statistic, 0.719; 95% CI, 0.702-0.737) and without previous myocarditis-like episodes (c-statistic, 0.749; 95% CI, 0.740-0.759). CONCLUSION: In a large independent cohort of DSP patients, this study showed external validity of the DSP-risk score. These findings support the use of the DSP-risk score to facilitate shared decision making regarding implantable cardioverter-defibrillator implantation in the primary prevention of VAs in patients harboring DSP P/LP variants.