Intracellular Ca2+ waves, afterdepolarizations, and triggered arrhythmias

Clinical studies have shown that sudden death is initiated by an ill-timed propagated ectopic beat that leads to fibrillation.1–4 However, the mechanism underlying these focal excitations is not completely understood. Experimental studies have demonstrated that abnormal calcium (Ca2+) cycling is a critical factor in the development of focal excitations.5–9 These excitations can be caused by spontaneous Ca2+ release (SCR) in the form of intracellular Ca2+ waves. These waves are initiated when Ca2+ release from a few Ca2+ release units (CRUs) on the sarcoplasmic reticulum (SR) causes regenerative release in adjoining units via Ca2+-induced Ca2+ release (CICR), causing Ca2+ wave propagation. The resulting depolarizing inward current through the electrogenic Na+–Ca2+ exchanger (NCX) depolarizes the cell membrane to threshold, producing a triggered beat.10–14The relationship between subcellular Ca2+ waves and focal excitations in cardiac tissue is, however, still not completely understood. The basic unanswered question is how Ca2+ release within a population of cardiac cells can induce sufficient inward current to overcome the electrotonic load of the neighbouring cells. In this paper, we will discuss some key ideas that are essential in answering this question, focusing on the probabilistic nature of SCR and the importance of measuring the timing distribution of Ca2+ waves in multicellular populations in tissue. We will also discuss our recent results showing that the likelihood of a triggered beat is determined by the variance of the timing distribution, which is dictated by the time course of SR reloading.15,16 In addition, we will discuss our observations of a form of Ca2+ wave that is distinct from SCR. These Ca2+ waves occur only during rapid pacing and occur with a latency …