The Role of Altered Calcium-Handling in Mechanically-Induced Arrhythmias During Acute Regional Ischemia

Abstract

Sudden Cardiac Death, a leading cause of death in Canada, commonly occurs as a result of arrhythmias occurring in the first hour of acute regional ischemia (ARI) after coronary artery occlusion. The mechanisms by which ARI leads to arrhythmias are unclear, with mechanically-induced alterations in electrical activity implicated as a contributing factor. The goal of this thesis was to investigate the role of altered calcium (Ca2+)-handling in mechanically-induced arrhythmias during ARI. ARI was induced via coronary artery ligation in isolated, mechanically-loaded, Langendorff-perfused rabbit hearts. Four studies were conducted, which investigated: i) ischemia-induced alterations in Ca2+ handling (in the absence of mechanical effects); ii) the role of Ca2+ as a driver of arrhythmias; and the effects of iii) cytosolic Ca2+ buffering, and iv) ryanodine receptor (RyR) stabilization, on arrhythmias. This involved optical mapping (single or dual parametric, of voltage and/or Ca2+) and pharmacological manipulation. It was found that shortening of Ca2+ transient duration (CaT) occurred more slowly than action potential duration (APD) during ARI, giving rise to a potential window of vulnerability for Ca2+-driven afterdepolarizations. In contrast, depression in the rate of cellular depolarization and of Ca2+ release, as well as the increase in the magnitude of APD and CaT alternans, displayed similar temporal changes. Ca2+-driven arrhythmias were not observed, however application of the Ca2+ dye resulted in a near elimination of arrhythmias, thought to be a result of Ca2+ buffering. This was confirmed by direct cytosolic Ca2+ buffering with BAPTA, which, along with RyR stabilization with the clinically-approved drug Dantrolene, also reduced the incidence of arrhythmias. These findings suggest that during ARI there is a necessary contribution of changes in Ca2+ handling to mechanically-dependent arrhythmias.