Electrophysiology of T-wave alternans: Mechanisms and pharmacologic influences☆
Introduction
TWA refers to a beat-to-beat fluctuation in the morphology and amplitude of the ST-segment and/or T-wave in the electrocardiogram and has long been recognized and linked to arrhythmogenesis.1 Available evidence suggests that TWA reflects spatio-temporal heterogeneity of repolarization, which is sensitive to perturbations in intracellular calcium handling and constitutes a mechanism of arrhythmogenesis.2
This review (a) discusses the cellular mechanisms and insights derived from large animal studies and (b) describes the evidence supporting TWA as a tool for assessing the antiarrhythmic effects of cardiovascular agents.
Section snippets
Basic cellular electrophysiologic mechanisms
The cellular mechanisms underlying TWA have been extensively reviewed.2., 3., 4. To summarize, TWA is a beat-to-beat alternation of action potential duration (APD) at the level of the cardiac myocyte. TWA can be either spatially concordant, when action potentials in neighboring cell regions alternate in phase, or discordant, when they are out-of-phase (Fig. 1).5 The progression from concordant to discordant TWA signals increased risk for malignant arrhythmias.6
Hypotheses involving both APD
Physiologic influences on TWA
Diverse physiologic interventions increase or decrease TWA level consistent with their influence on heterogeneity of repolarization and vulnerability to ventricular tachyarrhythmias.2 Specifically, surges in heart rate, coronary artery occlusion and reperfusion,11., 12., 13. and sympathetic nerve stimulation11 increase TWA level while also increasing arrhythmic risk. Conversely, vagus nerve stimulation, blockade of beta-adrenergic receptors14 or calcium channels,13 inhibition of late INa,15 and
Pharmacologic influences on TWA
Effects of pharmacologic agents on TWA level parallel their antiarrhythmic actions.19
Conclusions
TWA's capacity to assess risk for sustained ventricular tachycardia and fibrillation rests on sound electrophysiological bases, because this phenomenon reflects the degree of heterogeneity of repolarization and the magnitude of perturbations in intracellular calcium handling, key mechanistic factors that are fundamentally linked to triggers of arrhythmia in diverse diseases. Accordingly, TWA is a robust marker that is within the causal pathway of arrhythmogenesis. The evidence cited in this
Disclosures
RLV receives post-market royalties from Georgetown University and Beth Israel Deaconess Medical Center for the Modified Moving Average algorithm for TWA measurement, which is licensed to GE Healthcare. He also receives research grant support from Gilead Sciences, Inc., for experimental investigations on ranolazine.
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Cited by (21)
The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca<sup>2</sup>-ATPase, is a major determinant of Ca<sup>2</sup> alternans in intact mouse hearts
2018, Journal of Biological ChemistryCitation Excerpt :An increasing body of evidence indicates that Ca2+ alternans can occur in the absence of other forms of cardiac alternans, supporting the notion that Ca2+ alternans plays a primary role in the genesis of cardiac alternans (1–11). Despite the well-recognized risk of cardiac alternans in ventricular fibrillation and sudden cardiac arrest (12–19), the molecular mechanisms underlying cardiac alternans are not well understood. Given its crucial role in cardiac alternans, understanding how Ca2+ alternans occurs would be key to the understanding of cardiac alternans.
QRS/T-wave and calcium alternans in a type I diabetic mouse model for spontaneous postmyocardial infarction ventricular tachycardia: A mechanism for the antiarrhythmic effect of statins
2017, Heart RhythmCitation Excerpt :T-wave alternans may be related to APD alternans caused by steep restitution (the relationship between the APD of one beat and the diastolic interval of the proceeding beat)3 or secondary to Ca2+ alternans.8 Ca2+ recycling abnormalities promoting Ca2+ alternans are commonly associated with ischemia, MI, and heart failure.4,5 These data are consistent with our finding that, after coronary artery ligation, Akita mice demonstrate QRS/T-wave alternans without a significant change in heart rate, consistent with an increased propensity of the heart to develop alternans in the setting of MI.21
A T-wave alternans assessment method based on least squares curve fitting technique
2016, Measurement: Journal of the International Measurement ConfederationCardiac myocyte alternans in intact heart: Influence of cell-cell coupling and β-adrenergic stimulation
2015, Journal of Molecular and Cellular CardiologyClinical applications of T-wave alternans assessed during exercise stress testing and ambulatory ECG monitoring
2013, Journal of ElectrocardiologyCitation Excerpt :Multivariate analyses confirm that TWA provides information on risk beyond standard clinical variables for cardiovascular disease, including demographic factors (e.g., age, sex, and race) and contemporary cardiovascular risk markers (e.g., smoking, blood pressure, history, and medications) as well as LVEF. TWA's utility in estimating risk for cardiovascular mortality and SCD is founded on sound electrophysiological principles, as it reflects the degree of heterogeneity of repolarization and perturbations in intracellular calcium handling.3 As TWA is within the causal pathway of arrhythmia generation, it is a target for therapeutic intervention as well as a risk marker.22
RyR2 Serine-2030 PKA Site Governs Ca<sup>2+</sup>Release Termination and Ca<sup>2+</sup>Alternans
2023, Circulation Research
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No funding was received for preparation of this review.