Acute ischemia-induced gap junctional uncoupling and arrhythmogenesis

Sudden cardiac death forms a major cause of mortality. Myocardial ischemia-induced ventricular fibrillation (VF) is frequently the underlying mechanism. Ventricular arrhythmias arise in two distinct phases during the first hour of ischemia. The first, the 1A phase, has been extensively studied, and few studies relate to the 1B phase. The latter is associated with intercellular electrical uncoupling, mediated by decreased conductance of gap junction channels. Although the relation between gap junctional uncoupling and decreased conduction velocity appears clear under normoxic conditions, additional factors contribute to conduction slowing during ischemia, and VF occurs preferentially at moderate levels of uncoupling. A potential mechanism of arrhythmias depends on temporary electrotonic depression of intrinsically viable tissue by the large bulk of the ischemic zone. This causes conduction slowing and conduction block in the surviving layers, leading to arrhythmias. These arrhythmias then resolve with progression of uncoupling. It is unknown whether either accelerated uncoupling or maintenance of gap junctional communication is antiarrhythmic. Ischemic preconditioning postpones both gap junctional uncoupling and occurrence of VF. Given the burden of sudden death and the large number of casualties in the low-risk population, there is, even in the era of implantable cardiac defibrillators, need for further understanding the mechanism of ischemia-induced VF.