Ischemia-induced arrhythmia: the role of connexins, gap junctions, and attendant changes in impulse propagation

Abstract

Sudden cardiac death accounts for more than half of all cardiovascular deaths in the US, and a large proportion of these deaths are attributed to ischemia-induced ventricular fibrillation. As such, the mechanisms underlying the initiation and maintenance of these lethal rhythms are of significant clinical and scientific interest. In large animal hearts, regional ischemia induces two phases of ventricular arrhythmia. The first phase (1A) occurs between 5 and 7 min after arrest of perfusion. This phase is associated with membrane depolarization, a mild intracellular and extracellular acidification and a small membrane depolarization. A second phase (1B) of ventricular arrhythmia occurs between 20 and 30 minutes after arrest of perfusion. This phase occurs at a time when ischemia-induced K+ and pH changes are relatively stable. The arrhythmia is presumed to relate to the process of cell-to-cell electrical uncoupling because a rapid increase of tissue impedance precedes the onset of the arrhythmia. Of note is that tissue resistance is primarily determined by the conductance properties of the gap junctions accounting for cell-to-cell coupling. Impulse propagation in heart is determined by active and passive membrane properties. An important passive cable property that is modulated by ischemia is intercellular resistance and is determined primarily by gap junctional conductance. As such changes in Impulse propagation during myocardial ischemia are determined by contemporaneous changes in active and passive membrane properties. Cellular K loss, intracellular and extracellular acidosis and membrane depolarization are important factors decreasing excitatory currents, while the collapse of the extracellular compartment and cell-to-cell electrical uncoupling increase the resistance to current flow. The time-course of cellular coupling is closely linked to a number of physiological processes including depletion of ATP, and accumulation of intracellular Ca2+. Hence, interventions such as ischemic preconditioning attenuate the effect of subsequent ischemia, delay the onset of cell-to-cell electrical uncoupling and likewise delay the onset of ischemia-induced arrhythmia.