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: 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 DSP-ERADOS Network with no sustained VA prior to or at first assessment and that 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 by c-statistic in both the overall cohort and stratifying by history of prior myocarditis-like episodes. Results: 450 DSP patients from 30 centers were enrolled (mean age 42.2±17.6, 40.4% female, 18.4% with prior myocarditis-like episode). Over a median of 4.3 [1.6-10.0] years, 60 sustained VAs were observed. The DSP Risk Score yielded good discrimination both overall (C statistic: 0.719 (95% C.I.: 0.706-0.733]) and for patients with (C statistic 0.719 (95% C.I: 0.702-0.737)) and without (C statistic 0.749 (95% C.I.: 0.740-0.759)) prior myocarditis-like episodes. 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 ICD implantation in the primary prevention of VAs in patients harboring DSP P/LP variants.