Dissertation

Role of gap junctions in the genesis of cardiac arrhythmias

Eloff, Benjamin C

2005

Overview

Gap junctions are principally involved in forming the electrical connections between cardiomyocytes. Gap junction remodeling and underexpression are increasingly thought to play a role in cardiac disease and arrhythmogenesis. Intercellular uncoupling by gating or downregulation of gap junctions has been observed in both chronic and acute cardiac disease. While it is well established that slow conduction and increased gradients of repolarization are important to the initiation of reentrant arrhythmias, the specific role that decreases in intercellular communication play in arrhythmogenesis remains unknown. We used a specialized optical mapping system to study the mechanisms by which reduced intercellular uncoupling contributes to the formation of an arrhythmogenic substrate through the investigation of the following paradigms: (1) Mechanisms of Arrhythmogenesis: Intracellular uncoupling has been shown to slow conduction, and has been theorized to increase both the dispersion of repolarization and the heart rate threshold for discordant alternans, all of which are linked to proarrhythmia in clinically relevant models. (2) Inhibition of Arrhythmogenic Substrate: Previously, cellular uncoupling could be established though a multitude pharmacological agents, transgenes, or disease states, however, it has not been possible to enhance coupling through any means. The novel antiarrhythmic drug, ZP123, specifically targets gap junctions, increasing the conductance between cells, which may reverse the arrhythmogenic effects of cellular uncoupling. We found that Connexin43 (Cx43) downregulation via transgenic techniques slows conduction to an extent that is dependent on the level of downregulation. The properties of gap junctions are not altered by the downregulation process, indicating that there is no protein reserve for the enhancement of coupling under pathophysiologicaI conditions. Closure of gap junctions caused by ischemia may be prevented with the use of the gap junction modifying agent, ZP123. Treatment with this compound preserves conduction and reduces heterogeneities of repolarization during acidosis, the uncoupling component of ischemia. Furthermore, maintenance of coupling during ischemia reduced arrhythmogenic discordant alternans, preventing the generation of arrhythmogenic gradients of repolarization. These findings support gap junctions as an important therapeutic target for antiarrhythmic therapies, and provide several mechanisms through which enhanced gap junction communication may prevent the onset of cardiac arrhythmias.

• Publisher: ProQuest Dissertations & Theses
• Subject: Anatomy & physiology / Animals / Biomedical engineering / Biomedical research / Biophysics / Physiology
• ISBN: 0496932683, 9780496932689