Cutaneous ultrastructure reveals potential biomarkers of ventricular arrhythmias in inflammatory cardiomyopathy

Inflammatory cardiomyopathy (ICM), resulting from persistent myocardial inflammation, is associated with life-threatening ventricular arrhythmias (VA). Recent studies suggested overlap between ICM-associated VA and desmosomal diseases affecting the intercalated discs (ID), which are critical for electromechanical coupling. Genetic variants in desmosomal genes cause arrhythmogenic cardiomyopathies and genodermatoses, supporting a potential link between desmosomal dysfunction and arrhythmic risk. This single-center pilot study explored cutaneous abnormalities in patients with ICM complicated by VA, focusing on desmosomal alterations in skin tissue. Four patients (mean age 56 ± 6 years, 50% male) with cardiac magnetic resonance- and endomyocardial biopsy-proven ICM, documented VA, and available myocardial and cutaneous tissue were retrospectively evaluated. Two patients carried genetic variants (DSP and FLNC), while two had systemic autoimmune diseases. Transmission electron microscopy revealed consistent ultrastructural abnormalities in cardiac biopsies, including widened intercellular cleft width (ICW), a marker associated with arrhythmic risk. Similar abnormalities were observed in cutaneous biopsies, including small, narrow, or clustered desmosomes and dermal-epidermal junction detachments. Patients with greater cutaneous desmosomal coupling variability exhibited more complex VA, lower left ventricular ejection fraction, and a genetic etiology. These findings suggest that cutaneous desmosomal abnormalities may mirror cardiac changes and represent a potential biomarker for arrhythmic risk stratification.