Gap Junction and Connexin Remodeling in Human Heart Disease

Abstract

Gap junctions, assembled from connexins, form the cell-to-cell pathways for propagation of the precisely orchestrated patterns of current flow that govern the normal rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are co-expressed in the heart; connexin43, connexin40 and connexin45 are found in distinctive combinations and relative quantities in different, functionally-specialized subsets of cardiomyocyte. Alterations of gap junction organization and connexin expression are now well established as a consistent feature of human heart disease in which there is an arrhythmic tendency. These alterations may take the form of structural remodeling, involving disturbances in the distribution of gap junctions, and/or remodeling of connexin expression, involving alteration of the amount or type of connexin(s) expressed. In the diseased ventricle, the most consistent quantitative alteration involves heterogeneous reduction in connexin43 expression. In the atria, features of gap junction organization and connexin expression may contribute to both the initiation and persistence of atrial fibrillation. By correlating data from studies on the human patient with those from animal and cell models, alterations in gap junctions and connexins have emerged as important factors to be considered in understanding the pro-arrhythmic substrate found in a variety of forms of heart disease. Our knowledge of the functional correlates of the specific patterns of connexin co-expression in different subsets of myocyte in the healthy and diseased heart still remains limited, however, and the development of new experimental cell models heralds future advances in this field.