Role of Substrate and Triggers in the Genesis of Cardiac Alternans, From the Myocyte to the Whole Heart

Electrocardiographic alternans, a phenomenon of beat-to-beat oscillation in electrocardiographic (ECG) waveforms, was first described by Hering in 1908.1 Much of the interest in the alternans phenomenon has focused on alternans during the repolarization phase of the cardiac action potential (AP), also known as repolarization alternans (RA). More specifically, RA has been associated with an increased risk for malignant ventricular arrhythmias and sudden cardiac death (SCD) across a wide range of pathophysiological conditions, including both ischemic and nonischemic congestive heart failure with impaired left ventricular (LV) ejection fraction and recent myocardial infarction.2,3 Cardiac alternans can also be produced in structurally normal hearts under conditions of chronotropic stimulation4,5 or significant metabolic stress.6Given that several comprehensive review papers7–10 have been published on the mechanisms of RA and the clinical risk-stratification aspects of microvolt T-wave alternans (MTWA) testing, in the present report we have attempted to present a novel framework for how an “appropriate” substrate and an “appropriate” trigger event may synergistically contribute to the mechanisms that generate cardiac alternans from the cellular to the whole-heart level, and we propose novel aspects of the use of RA to guide therapy.Two major hypotheses have been developed to explain the alternans phenomenon at the cellular level. The first hypothesis suggests that alternation in sarcolemmal currents, membrane voltage, and AP morphology leads to beat-to-beat fluctuations in intracellular calcium concentration. In support of this hypothesis, it has recently been shown that modulation of sarcolemmal Ca2+11 and K+12,13 currents based on changes in AP morphology14 has a significant effect on the stability of Ca2+ handling processes and the transition to stable alternans15,16 (Figure 1A). In contrast, the second major hypothesis suggests that alternation of …