Cardiac Connexin Remodeling and Its Role in Arrhythmogenesis

Cardiac conduction critically depends on gap junctions formed by connexins, with connexin 43 as the predominant ventricular isoform. While traditionally considered solely in the context of reduced coupling at intercalated discs, emerging evidence highlights the arrhythmogenic impact of connexin remodeling through hemichannel activation, altered trafficking, posttranslational modification, and crosstalk with nonmyocyte populations. This review synthesizes current knowledge of connexin biology, the mechanisms of remodeling in ischemic heart disease, heart failure, atrial fibrillation, and inherited cardiomyopathies, and evidence from animal, in vitro, and human studies that implicate connexins as key determinants of arrhythmia susceptibility. We also discuss translational progress, including small-molecule gap junction enhancers, hemichannel-selective inhibitors, and novel gene- and genome-targeted approaches aimed at restoring conduction stability. Clinical integration of connexin biology into electrophysiology practice through risk stratification, imaging, and functional mapping is highlighted, alongside evolving strategies for measuring efficacy across molecular, electrophysiologic, and clinical endpoints. Despite these advances, challenges remain in separating hemichannel from gap junction roles, achieving pharmacological specificity, and translating findings from experimental models to human disease. Future research directions include selective connexin modulators, biomarker development, and clinical validation of targeted therapies. Connexin remodeling thus represents both a hallmark of cardiac disease and a promising therapeutic target for arrhythmia prevention and treatment.