Molecular features and cell composition of left-dominant arrhythmogenic cardiomyopathy reveals key pathways and therapeutic targets.

Background: Arrhythmogenic cardiomyopathy (ACM) is a myocardial disorder characterized by arrhythmias and an increased risk of sudden cardiac death, particularly in left-dominant arrhythmogenic cardiomyopathy (LACM), which primarily affects the left ventricle. This study aims to elucidate the cellular and molecular mechanisms underlying LACM by performing an in-depth single-nucleus RNA sequencing (snRNA-seq) analysis to identify key transcriptional signatures and pathways involved in the disease's pathogenesis.

Method: Human heart samples were collected from five patients undergoing heart transplantation due to ACM and from four healthy donors. Single nuclei were isolated from myocardial tissues and subjected to snRNA-seq using the 10 × Genomics Chromium platform. Data were processed and analyzed to identify distinct cell populations and their differentially expressed genes. Immunofluorescence staining was used to validate key findings.

Result: The snRNA-seq analysis revealed an increased proportion of fibroblasts and adipocytes in the left ventricles of LACM patients, suggesting a cellular basis for the fibrofatty remodeling observed in the disease. Key cell populations, including cardiomyocytes (CMs), fibroblasts (Fbs), and adipocytes (Adipo), were identified with distinct transcriptional profiles. We identified a disease-associated cardiomyocyte subpopulation (CM1) characterized by upregulation of fibrosis-, metabolism-, and stress-related markers, indicating transcriptional remodeling processes involved in LACM. The Fb subgroup Fb1 was characterized by genes involved in the PI3K-AKT signaling pathway. Adipocyte subpopulations exhibited gene expression features reflecting adaptation to the cardiac pathological environment, including markers associated with extracellular matrix remodeling and metabolic stress. Immunofluorescence staining validated the high expression of key markers of LACM patients.

Conclusion: This study provides a cellular and molecular characterization of LACM, identifying key pathways and transcriptional signatures that contribute to the disease's pathogenesis. These findings enhance our understanding of LACM and offer potential targets for therapeutic intervention.