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: =0.007). When matched 1:1 by age, sex, and presentation, DGV carriers showed distinctive red flags: family history of cardiomyopathy/AM/sudden death; recurrent troponin peaks; persistent left ventricular systolic dysfunction; right ventricular involvement; ring-like late gadolinium enhancement; late gadolinium enhancement persistence or extension; low QRS voltages; life-threatening ventricular arrhythmias at 1000/24 hours ventricular ectopy; and recurrent nonsustained ventricular tachycardia. A "first-contact" algorithm based on female sex and age