Arrhythmogenic consequences of intracellular calcium waves

Abstract

Intracellular Ca2+ (Cai2+) waves are known to cause delayed afterdepolarizations (DADs), which have been associated with arrhythmias in cardiac disease states such as heart failure, catecholaminergic polymorphic ventricular tachycardia, and digitalis toxicity. Here we show that, in addition to DADs, Cai2+ waves also have other consequences relevant to arrhythmogenesis, including subcellular spatially discordant alternans (SDA, in which the amplitude of the local Cai2+ transient alternates out of phase in different regions of the same cell), sudden repolarization changes promoting the dispersion of refractoriness, and early afterdepolarizations (EADs). Cai2+ was imaged using a charge-coupled device-based system in fluo-4 AM-loaded isolated rabbit ventricular myocytes paced at constant or incrementally increasing rates, using either field stimulation, current clamp, or action potential (AP) clamp. Cai2+ waves were induced by Bay K 8644 (50 nM) + isoproterenol (100 nM), or low temperature. When pacing was initiated during a spontaneous Cai2+ wave, SDA occurred abruptly and persisted during pacing. Similarly, during rapid pacing, SDA typically arose suddenly from spatially concordant alternans, due to an abrupt phase reversal of the subcellular Cai2+ transient in a region of the myocyte. Cai2+ waves could be visualized interspersed with AP-triggered Cai2+ transients, producing a rich variety of subcellular Cai2+ transient patterns. With free-running APs, complex Cai2+ release patterns were associated with DADs, EADs, and sudden changes in AP duration. These findings link Cai2+ waves directly to a variety of arrhythmogenic phenomena relevant to the intact heart.