Red Flags for Differentiating Desmosomal “Hot‐Phase” Cardiomyopathy From Acute Myocarditis

Background: Desmosomal “hot‐phase” cardiomyopathy (HPC), characterized by bursts of myocardial inflammation mimicking acute myocarditis (AM), carries relevant risks of adverse outcomes. This study aimed to identify diagnostic “red flags” favoring HPC over AM. Methods: Patients (n=134) receiving a first diagnosis of AM, proven by endomyocardial biopsy or cardiac magnetic resonance plus troponin elevation, were retrospectively identified at a referral center. HPC was defined by presence of pathogenic desmosomal gene variants (DGVs). Clinical, imaging, and electrical features were compared between HPC cases and controls with gene‐negative AM to identify red flags. Diagnostic algorithms were derived and tested in an external multicenter cohort of DGV carriers (n=30). Results: Patients with HPC (n=22; 91% DSP +) were more frequently female (73% versus 24%, P 1000/24 hours ventricular ectopy; and recurrent nonsustained ventricular tachycardia. A “first‐contact” algorithm based on female sex and age <30 years achieved 77% accuracy, identifying 63% of DGV carriers in the external cohort. An alternative algorithm incorporating ring‐like late gadolinium enhancement, right ventricular involvement, and family history showed higher accuracy (93%) and yield (93%). Conclusions: Myocarditis in DGV carriers predominantly affects young women. A red flag‐based approach improves recognition of desmosomal HPC over classic AM.