Connexins in the heart

Abstract

Gap junctions form the cell-cell pathways for propagation of the precisely orchestrated patterns of current flow that govern the regular rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are expressed in the heart; Cx43, Cx40, and Cx45 are found in distinctive combinations and relative quantities in different, functionally specialized subsets of cardiac myocyte. Cardiac development is marked by major alterations in the spatiotemporal patterns of expression of these connexins, and studies on transgenic animals, in which specific connexins are ablated or substituted, help differentiate their roles in regional tuning of impulse propagation and in morphogenesis. Mutations in genes that encode connexins have only rarely been identified as a cause of human cardiac disease, but remodeling of connexin expression and gap junction organization are well documented in acquired adult heart disease, notably coronary heart disease. Remodeling may take the form of alterations in the distribution of gap junctions and the amount and type of connexin(s) expressed. The evidence that these alterations can contribute to the development of arrhythmia in the diseased human heart is now substantial. It is well established that heterogeneous reduction in Cx43 expression and disordering in gap junction distribution occur in defined forms of ventricular disease and correlate with electrophysiologically identified arrhythmic changes and contractile dysfunction in animal models. Features of gap junction organization and connexin expression may also contribute to the most common form of atrial arrhythmia, atrial fibrillation, though conclusions in this area are less well founded. A major task ahead is to define the precise functional properties conferred by the distinctive connexin coexpression patterns of different myocyte types in health and disease.