Comprehensive analysis of desmosomal proteins remodeling identifies DSC2 as a potential biomarker for arrhythmogenic cardiomyopathy

Abstract Background Arrhythmogenic Cardiomyopathy (ACM) is a genetic cardiomyopathy characterized by malignant arrhythmias and sudden cardiac death, particularly in young individuals. Mutations in desmosomal genes are a major cause of ACM, but the role of desmocollin-2 (DSC2) remains understudied. Methods We conducted a multi-cohort study with 52 ACM patients, 29 with dilated cardiomyopathy (DCM), 17 with hypertrophic cardiomyopathy (HCM), and 45 controls. Immunofluorescence, immunohistochemical staining, and Western Blot were used to assess DSC2 expression. Statistical analyses included correlation tests, LASSO regression, ROC analysis and SHapley Additive exPlanation (SHAP) method. Results DSC2 expression was significantly reduced in ACM myocardium compared to controls and other cardiomyopathies (P0.0001), consistent across ACM subtypes and validated in an independent cohort. DSC2 downregulation correlated with clinical characteristics such as age at onset of arrhythmia and heart transplantation. DSC2 reduction in the right ventricle effectively discriminated ACM patients from controls (ROC AUC = 0.8017, P0.0001) and distinguished ACM from other cardiomyopathies (HCM and DCM). Immunohistochemical staining in the Swiss cohort confirmed that 11 out of 12 (91.7%) ACM cases exhibited significantly reduced DSC2 signals compared to normal donors. RNA-Seq analysis revealed significant downregulation of DSC2 genes in ACM tissues. Conclusion DSC2 remodeling is a hallmark of ACM, with significant diagnostic and pathogenic implications. DSC2 reduction is a robust biomarker for ACM, showing high sensitivity and specificity across different disease stages and subtypes. Future research should elucidate the mechanisms underlying DSC2 downregulation.