Elsevier

Journal of Electrocardiology

Volume 46, Issue 6, November–December 2013, Pages 580-584
Journal of Electrocardiology

Electrophysiology of T-wave alternans: Mechanisms and pharmacologic influences

https://doi.org/10.1016/j.jelectrocard.2013.07.003Get rights and content

Abstract

Extensive experimental evidence indicates a fundamental link between T-wave alternans (TWA) and arrhythmogenesis. Diverse physiologic and pathophysiologic influences alter TWA magnitude in parallel with their effects on vulnerability to ventricular tachyarrhythmias. Specifically, interventions that impede intracellular calcium handling, such as elevated heart rate, heightened adrenergic activity, myocardial ischemia, and heart failure, predispose to greater levels of TWA, reflecting heightened risk for arrhythmias. Conversely, vagus nerve stimulation, blockade of beta-adrenergic receptors and late sodium and L-type calcium channels, and sympathetic denervation decrease TWA magnitude, reflecting the potential of these interventions to reduce risk for ventricular tachycardia and fibrillation. TWA thus appears able to detect the influence of pathophysiologically relevant triggers as well as the efficacy of antiarrhythmic drugs without reducing the predictive capacity of the phenomenon.

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.

References (20)

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    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

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No funding was received for preparation of this review.

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