Connexin‐43 remodelling and arrhythmias: hemichannels as key drivers of cardiac dysfunction

The coordinated and effective contraction of the heart relies on transmission of electrical signals from adjacent myocardial cells, primarily via specialized channels called gap junctions. These junctional channels are formed by the docking of two connexin hemichannels, with each hemichannel contributed by a neighbouring cell. Connexin-43 (Cx43) is the most prominent and studied protein forming gap junction formation in the heart. In various cardiac pathologies Cx43 undergoes remodelling, which involves its displacement from intercalated discs to the lateral sides of cardiomyocytes, internalization and/or reduced levels at intercalated discs. This remodelling predisposes the heart to arrhythmia and dysfunction, but the exact mechanisms remain unclear. Initially it was thought that the decrease in Cx43 protein at the intercalated discs culminated in diminished electrical coupling, enhancing arrhythmias, and heart failure. However despite relevant efforts in clinical trials aimed at enhancing myocardial coupling and improving the outcomes of these cardiac diseases, the results have been unsuccessful. This suggests the existence of other potentially more significant mechanisms involved in the generation of arrhythmias and cardiac dysfunction. Notably a ground-breaking idea has emerged, proposing that Cx43 proteins at the lateral size of cardiomyocytes form active uncoupled hemichannels, whose opening disrupts cardiac excitability and contributes to cardiac disease progression. This review explores the implications of Cx43 remodelling in cardiac diseases, proposing that hyperactive Cx43 hemichannels are the main contributors to cardiac dysfunction. It emphasizes the potential of targeting these hemichannels as a novel and promising therapeutic strategy for treating various cardiac disorders where Cx43 is remodelled. KEY POINTS: The synchronized heartbeat relies on the efficient propagation of electrical impulses through gap junctions, primarily composed of Connexin43 (Cx43). Remodeling and lateralization of Cx43 is a hallmark of various cardiac pathologies and is strongly linked to arrhythmogenesis. While traditional models attribute arrhythmias to the loss of Cx43 at intercalated discs and compromised gap junctional coupling, these changes alone do not fully explain cardiac dysfunction associated with Cx43 remodeling. Emerging evidence indicates that lateralized Cx43 forms hyperactive hemichannels, which disrupt cardiac membrane excitability and exacerbate disease progression. This review highlights aberrant activity of lateralized Cx43 hemichannels as a central contributor in cardiac dysfunction and a promising therapeutic target in heart disease.