Abstract
The heart works as a functional syncytium, which is realized via cell-cell coupling maintained by gap junction channels. These channels connect two adjacent cells, so that action potentials can be transferred. Each cell contributes a hexameric hemichannel (=connexon), formed by protein subuntis named connexins. These hemichannels dock to each other and form the gap junction channel. This channel works as a low ohmic resistor also allowing the passage of small molecules up to 1000 Dalton. Connexins are a protein family comprising of 21 isoforms in humans. In the heart, the main isoforms are Cx43 (the 43 kDa connexin; ubiquitous), Cx40 (mostly in atrium and specific conduction system), and Cx45 (in early developmental states, in the conduction system, and between fibroblasts and cardiomyocytes). These gap junction channels are mainly located at the polar region of the cardiomyocytes and thus contribute to the anisotropic pattern of cardiac electrical conductivity. While in the beginning the cell–cell coupling was considered to be static, similar to an anatomically defined structure, we have learned in the past decades that gap junctions are also subject to cardiac remodeling processes in cardiac disease such as atrial fibrillation, myocardial infarction, or cardiomyopathy. The underlying remodeling processes include the modulation of connexin expression by e.g., angiotensin, endothelin, or catecholamines, as well as the modulation of the localization of the gap junctions e.g., by the direction and strength of local mechanical forces. A reduction in connexin expression can result in a reduced conduction velocity. The alteration of gap junction localization has been shown to result in altered pathways of conduction and altered anisotropy. In particular, it can produce or contribute to non-uniformity of anisotropy, and thereby can pre-form an arrhythmogenic substrate. Interestingly, these remodeling processes seem to be susceptible to certain pharmacological treatment.
Highlights
The cardiac tissue is a complex network of excitable and non-excitable cells, and acellular, electrical passive tissue
The functional architecture is defined by cardiomyocyte cell size, by the number, function, and localization of electrical contacts, the non-excitable areas and their electrical resistance, the ratio between gGJ, longitudinal resistance, transverse resistance, cell capacity, and capacity of the cell, which is to be activated
Since source-sink problems are important for propagation, the direction of conduction may alter the effects of a given tissue architecture: a small, activated area meeting a large sink area may result in conduction failure, while propagation in the opposite direction may be possible
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Recent studies have shown that ephaptic coupling requires an electrical field sufficient for the activation of clusters of sodium channels, and that the clustering of sodium channels potentiates the ephaptic interaction, which is even higher if the gap junction coupling is reduced [8] (Hichri et al 2018) This may contribute to the formation of areas with slow conduction as a typical arrhythmogenic factor [9]. Problematic situations causing source-sink problems are e.g., a high curvature of the propagation wave front, the endings of the Purkinje fibers, the areas in which the activation front passes an isthmus, encircles obstacles, or the border between ischemic (non-excitable tissue; current sink) and non-ischemic tissue (excitable tissue; current source), and the border between cardiac tissue and fibrous strands This all has to be considered together with the cell size of cardiomyocytes, the cell form, and the distribution and density of the gap junction channels with respect to the cell axis. In the atrioventricular node and the bundle of His, Cx45 is most important for conduction, modulated by Cx30.2 and Cx40 (Schrickel et al, 2009) [21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
