Electrophysiological Mechanisms Underlying T-Wave Alternans and Their Role in Arrhythmogenesis

Abstract

T-wave alternans (TWA) reflects every-other-beat alterations in the morphology of the electrocardiogram ST segment or T wave in the setting of a constant heart rate, hence, in the absence of heart rate variability. It is believed to be associated with the dispersion of repolarization and has been used as a non-invasive marker for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death as numerous studies have shown. This review aims to provide up-to-date review on both experimental and simulation studies in elucidating possible mechanisms underlying the genesis of TWA at the cellular level, as well as the genesis of spatially concordant/discordant alternans at the tissue level, and their transition to cardiac arrhythmia. Recent progress and future perspectives in antiarrhythmic therapies associated with TWA are also discussed.

Keywords: T-wave alternans; arrhythmia; simulation; spatial discordant alternans; sudden cardiac death.

FIGURE 1

AP and CaT alternans at the cellular and tissue level measured by patch-clamp and optical mapping technology. (A) AP alternans of ventricular myocytes in adult guinea pigs, induced by S1S1 stimulation protocol. Stimulus: 1.5-fold threshold; (B) AP and CaT alternans of isolated guinea pig heart, induced by S1S1 stimulation protocol. Stimulus: 2-fold threshold, apex. See the Supplementary Material 1 for detailed experimental methods.

FIGURE 2

Schematic diagram illustrating the mechanisms of cardiac alternans and arrhythmogenesis associated with experimental and simulation studies. I_Na, inward Na⁺ current; I_Na,L, late sodium current; I_NCX, sodium-calcium exchanger current; I_to, outward transient potassium current; I_Ca,L, L-type Ca²⁺ current; I_K1, inward rectifier current; I_Kr, rapid delayed rectifier potassium current; I_Ks, slow delayed rectifier potassium current; RyR_s: ryanodine receptors; SAC_s, stretch-activated channels; SCA/SDA, spatially concordant/discordant alternans; and CV, conduction velocity.

FIGURE 3

Cobweb plots used to indicate the stability of APD alternans. Curve a: APD restitution curve, APD_{n + 1} = f(DI_n); curve b: the fixed relationship of BCL, APD, and diastolic interval (DI), BCL = APD + DI; curve c: the gradient of the APD restitution curve; red star: the equilibrium point (APD_n = APD_n–1), that is the interaction point of the curve a and curve b (modified from Nolasco and Dahlen, 1968). (A) The maximum gradient is less than one and (B) The maximum gradient is greater than or equal to one.

FIGURE 4

At the tissue level, cellular alternans be manifested as spatially concordant and/or discordant alternans. As the red star shows, AP and CaT alternans is in-phase changes in whole tissue, that is, spatially concordant alternans (SCA); as the blue star shows, AP and CaT alternans is out-of-phase changes in different regions, that is, spatially discordant alternans (SDA) (Optical mapping in isolated guinea pig heart by S1S1 stimulation).

FIGURE 5

The schematic diagram of “3R” theory. “3R” theory, in which Ca alternans emerges as collective behavior of Ca sparks, determined by three critical properties of the CRU network from which Ca sparks arise. CRU_s: Ca release units, SR: sarcoplasmic reticulum, and RyR_s: ryanodine receptors.

FIGURE 6

The schematic overview of arrhythmia mechanisms. Purple box: possible electrophysiological mechanism(s) of arrhythmia at the subcellular level; green box: possible electrophysiological mechanism(s) of arrhythmia at the cell level; orange box: possible electrophysiological mechanism(s) of arrhythmia at the tissue level; and brown box: possible mechanism(s) of abnormal myocardial structure leading to arrhythmia. EAD: early afterdepolarization; DAD: delayed atferdepolarization; AP: action potential; CV: conduction velocity; and SDA: spatially discordant alternans.