Prognostic role of myocarditis-like episodes and their treatment in patients with pathogenic Desmoplakin variants

BACKGROUND: Inflammatory, myocarditis-like episodes precede and are associated with higher risk of sustained ventricular arrhythmias and heart failure in patients with pathogenic or likely pathogenic desmoplakin (DSP) variants. Whether the recurrence and treatment of myocarditis-like episodes influence the outcomes in this population is unknown. This study aimed to assess the prognostic impact of the recurrence and treatment of myocarditis-like episodes in patients with pathogenic or likely pathogenic DSP variants. METHODS: The study was designed as an observational cohort study using all patients with pathogenic or likely pathogenic DSP variants in the DSP-ERADOS Network (Desmopakin Specific Effort for a Rare Disease Outcome Study) enrolled at 31 institutions up until April 30, 2024. Survival from ventricular arrhythmia and heart failure end points and recurrent myocarditis-like episodes was evaluated for both first and recurrent documented myocarditis-like episodes and the impact of immunosuppressive treatment on outcomes assessed. RESULTS: A total of 1014 patients with pathogenic or likely pathogenic DSP variants (62.4% female; mean age, 40.4±17.4 years; 47.1% probands) were included. Among them, 177 individuals (17.5%) experienced ≥1 documented myocarditis-like episode, with 63 of them (35.6%) receiving immunosuppressive treatment. Immunosuppressive treatment of the first documented myocarditis-like episode was associated with reduced risk of ventricular arrhythmia and heart failure outcomes (hazard ratio, 0.18 [95% CI, 0.07-0.45]; P<0.001; and hazard ratio, 0.09 [95% CI, 0.02-0.39; P=0.001, respectively) over a median follow-up of 6.4 years (95% CI, 4.0-10.5). This risk was comparable to that of patients with no history of myocarditis-like episode but did not correlate with a reduction in recurrent episodes after completion of initial immunosuppression (hazard ratio, 0.85 [95% CI, 0.47-1.54]; P=0.599). In contrast, nonsteroidal anti-inflammatory drugs or colchicine treatment did not influence outcomes. CONCLUSIONS: Immunosuppressive treatment of myocarditis-like episodes in DSP patients was associated with improved combined ventricular arrhythmia or heart failure outcomes, supporting future prospective evaluation in DSP cohorts.