Gap junctions and conduction of cardiac excitation

Abstract

c p t t o i Gap junction remodeling and cardiac disease Changes in function and/or remodeling of connexins occur in almost all major arrhythmogenic cardiac disorders. However, since these diseases are often associated with alterations in all major components of cell and tissue function, potentially involving changes in hundreds of genes and proteins, it is often difficult, if not impossible, to delineate a specific arrhythmogenic role for connexin remodeling. In cardiac failure and ischemic heart disease, remodeling of cell-to-cell coupling is likely to play a significant role in arrhythmogenesis. It is generally agreed that cardiac failure leads to a decrease in Cx43 immunosignals and an increase in Cx45 immunosignals in gap junctions, associated with a decrease in cell-to-cell coupling and propagation velocity. Studies associating the pattern and intensity of Cx43 immunosignals in humans with the occurrence of ventricular arrhythmias have suggested that the inhomogeneity of connexin expression in gap junctions rather than its average decrease may represent an arrhythmogenic mechanism in heart failure. In cardiac ischemia, dephosphorylation of onnexins and the associated cell-to-cell uncoupling occur ithin approximately 15 minutes after acute oxygen withrawal, and tissue surviving from myocardial infarction xhibits marked connexin remodeling. The role of connexin remodeling in atrial fibrillation is more disputed. Experimental studies have shown a relatively large variety of changes without delineating a clear picture. However, somatic mutations in both major atrial onnexins, Cx43 and Cx40, have recently been associated ith lone atrial fibrillation. Although these cases seem to e rare, they may help to explain the role of connexin emodeling in atrial propagation. Whether the association etween mutations in atrial connexins and arrhythmogensis reflects a direct effect of changed cell-to-cell coupling r whether additional changes contribute to the disturbed lectrical function remains to be shown.