Review
Microvolt T-wave alternans: A review of techniques, interpretation, utility, clinical studies, and future perspectives

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Abstract

Microvolt T-wave alternans (TWA) testing involves measuring variation in the morphology of the T-wave on an every other beat basis. The magnitude of the variation observed is typically on the order of a few microvolts. Thus in order to detect microvolt TWA, specialized recording and signal processing methods must be employed for reliable measurement. Additionally, microvolt TWA is not generally present at rest even in patients at risk of ventricular tachyarrhythmias and therefore exercise stress, pharmacologic stress, or atrial pacing must be utilized in order to elevate the heart rate. A positive MTWA test is one in which sustained TWA is present with an onset heart rate ≤ 110 bpm. With current instrumentation, microvolt TWA represents an inexpensive, convenient non-invasive testing modality. Microvolt TWA has been evaluated prospectively in a variety of patient populations as a means of predicting occurrence of ventricular tachyarrhythmic events and its association with the genesis of ventricular arrhythmias has been demonstrated. Future role of microvolt TWA testing in noninvasive risk stratification is awaiting results of ongoing clinical trials. In this article, we tried to review the techniques, interpretation, indications, clinical studies, and future perspectives of microvolt TWA.

Introduction

Accurate identification of patients at increased risk for sustained ventricular arrhythmias is critical for the development of effective strategies to prevent sudden cardiac death (SCD). Traditionally, left ventricular ejection fraction (LVEF) and measures of ambient arrhythmia were used to identify high-risk individuals and to assess the utility of the prophylactic administration of antiarrhythmic agents [1]. However, this strategy has no survival benefit [2], [3], [4]. Recently, programmed ventricular stimulation (PVS) during electrophysiology study (EPS) identified a cohort with left ventricular dysfunction who had improved survival with implantable cardioverter-defibrillator (ICD) placement [5], [6]. However, programmed stimulation is invasive and costly. Accordingly, improved noninvasive markers of arrhythmia vulnerability are needed. In this regard, T-wave alternans (TWA) is a promising new technique [7].

Microvolt TWA is an every other beat variation in the amplitude and shape of T-wave that is predictive of ventricular tachyarrhythmias associated with SCD [7]. TWA can be used to identify patients requiring further diagnostic testing and treatment, thus increasing the effectiveness of treatment and reducing its cost. The purpose of this review is to describe techniques, interpretation, indications, clinical studies, and future perspectives of microvolt TWA.

Section snippets

Historical aspects of electrical alternans

Electrical alternans is a pattern of variation in the shape of ECG waveform that appears on an every-other-beat basis. Macroscopic electrocardiographic alternans was first reported by Herring in 1909 [8]. Subsequently, Thomas Lewis recognized that cardiac alternans could occur in normal hearts as a result of marked increase in heart rate and also in the diseased myocardium [9]. In 1948, Kalter and Schwartz evaluated ECGs from 6059 patients and described an association between macroscopic TWA

Cellular mechanisms of microvolt T-wave alternans

There are two popular hypotheses concerning the cellular mechanisms of TWA. One states that a spatial (transmural) dispersion of refractoriness gives rise to alternations in propagation and repolarization. According to this hypothesis, repolarization alternans is secondary to propagation alternans which occurs when the time between successive activations is shorter than the refractory period. This hypothesis was supported by an experimental study in which ECG alternans during regional ischemia

Ionic mechanisms of microvolt T-wave alternans

The various mechanisms have been offered to explain the ionic basis for TWA, including beat-to-beat changes in intracellular levels of Ca2+, Ik, K+ accumulation in the extracellular clefts, and Na+/Ca2+ exchange current. Calcium homeostasis is not only important for excitation–contraction coupling but it also significantly influences the action potential (AP) profile and duration (APD) [46]. The change in intracellular Ca2+ during the cardiac cycle or calcium transient has direct and indirect

Mechanisms linking microvolt T-wave alternans to ventricular fibrillation

For more than three quarters of a century, TWA has been closely associated with susceptibility to ventricular arrhythmias in remarkably broad patient populations both with and without structural heart disease. Therefore, an understanding of the mechanisms linking TWA to VF may provide important insights into the pathophysiology of SCD.

Currently, there are two prevailing hypotheses regarding the arrhythmogenic mechanisms associated with TWA. One is based on the concept that prolongation of

Techniques

Until now, two main techniques have been applied for measurement of microvolt TWA in clinical setting: fast Fourier Transform (FFT) spectral method and modified moving average (MMA) analysis method. The most widely used procedure, termed FFT spectral method, was developed at Massachusetts Institute of Technology by Dr. Richard J. Cohen [25], [26], [27]. This technique uses 128 measurements taken on corresponding points of 128 consecutive T waves to compute a spectrum. Each T wave is measured at

Effects of antiarrhythmic agents on microvolt T-wave alternans

Because most of patients were treated by the antiarrhythmic agents at the time of microvolt TWA assessment and possible effects of these agents on markers of risk, it would be desirable to know influence of these agents on the results of microvolt TWA test.

Among the sodium channel blockers, disopyramide and lidocaine [61] had no effect on TWA, procainamide [62] reduced TWA amplitude, and flecainide [61] tended to increase alternans.

With regard to effects of potassium channel blockers on TWA,

Indications

The CH2000 is intended for the measurement of microvolt TWA and recording of electrocardiograms and vector cardiograms at rest and during ECG stress testing. The measurement of stress-induced microvolt level TWA has been approved by the United States Food and Drug Administration for the following indication: “The presence of microvolt TWA in patients with known suspected or at risk of ventricular tachyarrhythmia predicts increased risk of a cardiac event (ventricular tachyarrhythmia or sudden

Comparison to other noninvasive markers of arrhythmia risk

Several studies have compared the prognostic value of measured microvolt TWA with other commonly used noninvasive risk-stratifiers in patients referred for EPS. In the studies below, microvolt TWA was demonstrated to be a better predictor of arrhythmia vulnerability and SCD than other available noninvasive means of risk assessment. In addition, in these studies, microvolt TWA compared favorably to EPS in the prediction of arrhythmia-free survival.

Influence of sympathetic nervous system, heart rate, and QRS duration on microvolt T-wave alternans

TWA is significantly dependent on heart rate. This phenomenon has been documented both in animal and human studies [88], [89], [90], [91], [92], [29]. Animal studies demonstrated that induction of AP alternans is dependent on a critically short cycle length [88] and onset heart rate for eliciting of discordant alternans was significantly lower in the presence of a structural barrier [89]. A number of human studies similarly demonstrated that microvolt TWA is strongly heart rate dependent with

TWA assessment in post-MI patients

There are a number of studies evaluating prognostic role of microvolt TWA in patients with prior MI (Table 1). Ikeda et al. [31] prospectively assessed TWA and late potentials (LP) by SAECG and EF in 102 patients with prior MI. In this study, TWA was measured 20 ± 6 days after acute MI. The TWA was present in 50 patients (49%), LP present in 21 patients (21%), and an EF < 40% in 28 patients (27%). During a follow-up period of 13 ± 6 months, symptomatic, sustained VT or VF occurred in 15 patients

Limitations of microvolt TWA testing

There are some technical limitations on use of microvolt TWA testing. These limitations include: (1) TWA could not be measured in patients with AF, which is a common arrhythmia in patients with structural heart disease; (2) the presence of frequent atrial or ventricular ectopy, excessive motion artifacts, and inability to reach the target heart rate would render the results of the microvolt TWA indeterminate. In most of the published studies, indeterminate results were obtained in 25–30% of

Future perspectives

Increasing our ability to select and protect the patients form SCD is the major focus of cardiac electrophysiologists and a number of ongoing clinical trials. At present, there is no single test or a set of tests with high predictive power to separate high-risk from low-risk patients. EPS were limited by its invasive nature, cost, and inadequate predictive power. Noninvasive methods have low specificity and predictive accuracy. On the other hand, ICD implantation for every patient at risk is

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