T-wave alternans and arrhythmogenesis in cardiac diseases

Zhilin Qu

doi:10.3389/fphys.2010.00154

Abstract

T-wave alternans, a manifestation of repolarization alternans at the cellular level, is associated with lethal cardiac arrhythmias and sudden cardiac death. At the cellular level, several mechanisms can produce repolarization alternans, including: (1) electrical restitution resulting from collective ion channel recovery, which usually occurs at fast heart rates but can also occur at normal heart rates when action potential is prolonged resulting in a short diastolic interval; (2) the transient outward current, which tends to occur at normal or slow heart rates; (3) the dynamics of early after depolarizations, which tends to occur during bradycardia; and (4) intracellular calcium cycling alternans through its interaction with membrane voltage. In this review, we summarize the cellular mechanisms of alternans arising from these different mechanisms, and discuss their roles in arrhythmogenesis in the setting of cardiac disease.

Highlights

Alternans resulting from Early afterdepolarizations (EADs) Despite the various complex ionic mechanisms, we showed recently that EADs are caused by dynamical instabilities and can exhibit many complex temporal patterns including action potential duration (APD) alternans under periodic pacing (Sato et al, 2009, 2010; Tran et al, 2009)
Summary and conclusions Numerous clinical and basic studies investigating T-wave alternans (TWA) have greatly advanced our understanding of this dynamical phenomenon and its relation to lethal arrhythmias
We summarized different dynamical mechanisms of alternans and their possible arrhythmogenic consequences in different diseases

Summary

Introduction

T-wave alternans (TWA), a precursor of lethal cardiac arrhythmias and sudden death (Rosenbaum et al, 1994; Armoundas et al, 2002; Narayan, 2006; Verrier and Nieminen, 2010b), has been associated with many cardiac diseases, such as heart failure (Luomanmaki et al, 1975), long QT syndromes (Zareba et al, 1994; Shimizu and Antzelevitch, 1999; Armoundas et al, 2000; Kroll and Gettes, 2002; Wegener et al, 2008; Verrier and Nieminen, 2010a), ischemia (Nakashima et al, 1978; Giudici and Savage, 1990), Brugada syndrome (Chinushi et al, 2001; Morita et al, 2002, 2006; Takagi et al, 2002; Nishizaki et al, 2005; Fish and Antzelevitch, 2008; Tada et al, 2008), etc. In addition to its arrhythmogenic effects at fast heart rates, APD alternans may be applicable to arrhythmogenesis when APD is substantially prolonged, such as in the long QT syndromes or heart failure, so that DI becomes short enough to engage the steep slope range of the APD restitution curve, even at normal heart rates Another example is ischemia, in which the Na channel conductance is reduced and recovery slowed (Joyner et al, 1991; Pu and Boyden, 1997), causing postrepolarization refractoriness. When we took into account the memory effects by constructing a restitution relation in which APD depends on DIs over a longer history, i.e., APDn+1 = f(DIn, DIn−1, ..., DIn−k), we accurately predicted the bifurcation leading to APD alternans (unpublished results) In this case, instead of using the slope of the APD restitution curve to predict the occurrence of alternans, we followed the standard linear stability analysis by calculating the eigenvalues of the system to determine the stability of the system (Strogatz, 2000). APD alternans induced by Ito or TWA in Brugada syndrome, it occurs at slow or normal heart rate, may still have a causal relationship to arrhythmogenesis

Alternans resulting from early afterdepolarization dynamics

Alternans arising from instabilities of intracellular Ca cycling