T-wave alternans and the susceptibility to ventricular arrhythmias

T-wave alternans (TWA) reflects beat-to-beat fluctuations in the electrocardiographic T-wave, and is associated with dispersion of repolarization and the mechanisms for sudden cardiac arrest (SCA). This review examines the bench-to-bedside literature that, over decades, has linked alternans of repolarization in cellular, whole-heart, and human studies with spatial dispersion of repolarization, alternans of cellular action potential, and fluctuations in ionic currents that may lead to ventricular arrhythmias. Collectively, these studies provide a foundation for the clinical use of TWA to reflect susceptibility to ventricular arrhythmias in several disease states. This review then provides a contemporary evidence-based framework for the use of TWA to enhance risk stratification for SCA, identifying populations for whom TWA is best established, those for whom further studies are required, and areas for additional investigation.     

T-wave alternans testing for ventricular arrhythmias

T-wave alterans (TWA) measures alternate-beat fluctuations in the ECG T-wave, and has been used to predict the risk for life-threatening ventricular arrhythmias in various clinical populations. This work reviews the traditional literature linking repolarization alternans in cellular and tissue-level studies, with clinical studies that TWA can successfully add to existing clinical risk factors in predicting ventricular arrhythmias. We conclude by providing an evidence-based framework integrating TWA with other risk factors to stratify risk for sudden cardiac arrest.     

Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction.

OBJECTIVES: This study hypothesized that microvolt T-wave alternans (MTWA) improves selection of patients for implantable cardioverter-defibrillator (ICD) prophylaxis, especially by identifying patients who are not likely to benefit. BACKGROUND: Many patients with left ventricular dysfunction are now eligible for prophylactic ICDs, but most eligible patients do not benefit; MTWA testing has been proposed to improve patient selection. METHODS: Our study was conducted at 11 clinical centers in the U.S. Patients were eligible if they had a left ventricular ejection fraction (LVEF) < or =0.40 and lacked a history of sustained ventricular arrhythmias; patients were excluded for atrial fibrillation, unstable coronary artery disease, or New York Heart Association functional class IV heart failure. Participants underwent an MTWA test and then were followed for about two years. The primary outcome was all-cause mortality or non-fatal sustained ventricular arrhythmias. RESULTS: Ischemic heart disease was present in 49%, mean LVEF was 0.25, and 66% had an abnormal MTWA test. During 20 +/- 6 months of follow-up, 51 end points (40 deaths and 11 non-fatal sustained ventricular arrhythmias) occurred. Comparing patients with normal and abnormal MTWA tests, the hazard ratio for the primary end point was 6.5 at two years (95% confidence interval 2.4 to 18.1, p < 0.001). Survival of patients with normal MTWA tests was 97.5% at two years. The strong association between MTWA and the primary end point was similar in all subgroups tested. CONCLUSIONS: Among patients with heart disease and LVEF < or =0.40, MTWA can identify not only a high-risk group, but also a low-risk group unlikely to benefit from ICD prophylaxis.     

T波电交替与室性心律失常

随着心电滤波、放大以及分析技术水平的提高,那些肉眼不能观察到、微伏级水平的T波电交替(TWA)现象得以深入的研究.业已证实,这种微小的TWA与恶性室性心律失常[单形/多形室性心动过速(室速)、尖端扭转型室速、心室颤动(室颤)]、心脏性猝死之间有着极为密切的联系,因而可作为室性心律失常的预测指标,TWA形成机制仍聚焦于心肌动作电位时程,心率(刺激频率)和细胞内钙循环.     

Microvolt T-wave alternans in early repolarization syndrome associated with ventricular arrhythmias: A case report

Despite early repolarization (ER) syndrome being usually considered benign, its association with severe/malignant ventricular arrhythmias (VA) was also reported. Microvolt T-wave alternans (MTWA) is an electrocardiographic marker for the development of VA, but its role in ER syndrome remains unknown. A 90-second 6-lead electrocardiogram from an ER syndrome patient, acquired with the Kardia recorder, was analyzed by the enhanced adaptive matched filter for MTWA quantification. On average, MTWA was 50 μV, higher than what was previously observed on healthy subjects using the same method. In our ER syndrome patient, MTWA plays a potential role in VA development in ER syndrome.     

Diabetes and susceptibility to reperfusion-induced ventricular arrhythmias.

Studies using chemically-induced models of diabetes have shown the diabetic myocardium to exhibit abnormalities in cellular ion transport, which may affect susceptibility to reperfusion-induced arrhythmias. We studied the incidence of reperfusion-induced ventricular tachycardia (VT) and fibrillation (VF) in isolated hearts from rats with streptozotocin-induced diabetes and from age-matched and weight-matched control rats (n = 12 per group). Following 5 min of regional ischaemia, reperfusion resulted in a similarly low incidence of arrhythmias in all three groups. Following 10 min of regional ischaemia, the incidence of VT was 92, 100 and 92%, and the incidence of VF was 75, 92 and 92% in diabetic, age-matched control and weight-matched control groups, respectively (NS). However, among those hearts which exhibited VF, the incidence of sustained (greater than or equal to 120 s) VF was 73 and 55% in age-matched and weight-matched control groups, respectively, and 0% in the diabetic group (P less than 0.05 vs both controls). The mean duration of VF in the diabetic group was reduced from 201 +/- 33 and 171 +/- 36 s in age-matched and weight-matched control groups, respectively, to 9 +/- 3 s (P less than 0.05). Thus, streptozotocin-induced diabetes in the rat does not result in an increased susceptibility to reperfusion-induced arrhythmias. To the contrary, hearts from diabetic rats are less susceptible to potentially lethal arrhythmias during reperfusion. Likely contributory factors to this phenomenon include (i) increased myocardial content of free radical scavenging enzymes, (ii) prolonged action potential duration, and (iii) reduced activity of sarcolemmal Na+/H+ and Na+/Ca2+ exchange processes, all of which have previously been reported in similar models of diabetes.     

T-wave alternans in patients with right ventricular tachycardia

Microvolt T-wave alternans has been proposed as a new risk marker for ventricular arrhythmias. However, the clinical significance of T-wave alternans in patients with ventricular tachycardia (VT) originating from the right ventricle has been unknown. The study population consisted of 20 patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic VT. T-wave alternans was measured during bicycle exercise testing using the CH 2000 system. Of the 7 patients with ARVC, 6 (86%) were positive for T-wave alternans. On the other hand, only 1 (8%) of 13 patients with idiopathic VT originating from the right-ventricular outflow tract was positive for T-wave alternans.     

Predictive power of T-wave alternans and of ventricular gradient hysteresis for the occurrence of ventricular arrhythmias in primary prevention cardioverter-defibrillator patients

Background and purpose

Left ventricular ejection fraction lacks specificity to predict sudden cardiac death in heart failure. T-wave alternans (TWA; beat-to-beat T-wave instability, often measured during exercise) is deemed a promising noninvasive predictor of major cardiac arrhythmic event. Recently, it was demonstrated that TWA during recovery from exercise has additional predictive value. Another mechanism that potentially contributes to arrhythmogeneity is exercise-recovery hysteresis in action potential morphology distribution, which becomes apparent in the spatial ventricular gradient (SVG). In the current study, we investigated the performance of TWA amplitude (TWAA) during a complete exercise test and of exercise-recovery SVG hysteresis (SVGH) as predictors for lethal arrhythmias in a population of heart failure patients with cardioverter-defibrillators (ICDs) implanted for primary prevention.

Methods

We performed a case-control study with 34 primary prevention ICD patients, wherein 17 patients (cases) and 17 patients (controls) had no ventricular arrhythmia during follow-up. We computed, in electrocardiograms recorded during exercise tests, TWAA (maximum over the complete test) and the exercise-recovery hysteresis in the SVG. Statistical analyses were done by using the Student t test, Spearman rank correlation analysis, receiver operating characteristics analysis, and Kaplan-Meier analysis. Significant level was set at 5%.

Results

Both SVGH and TWAA differed significantly (P < .05) between cases (mean ± SD, SVGH: −18% ± 26%, TWAA: 80 ± 46 μV) and controls (SVGH: 5% ± 26%, TWAA: 49 ± 20 μV). Values of TWAA and SVGH showed no significant correlation in cases (r = −0.16, P = .56) and in controls (r = −0.28, P = .27). Receiver operating characteristics of SVGH (area under the curve = 0.734, P = .020) revealed that SVGH less than 14.8% discriminated cases and controls with 94.1% sensitivity and 41.2% specificity; hazard ratio was 3.34 (1.17-9.55). Receiver operating characteristics of TWA (area under the curve = 0.699, P = .048) revealed that TWAA greater than 32.5 μV discriminated cases and controls with 93.8% sensitivity and 23.5% specificity; hazard ratio was 2.07 (0.54-7.91).

Discussion and conclusion

Spatial ventricular gradient hysteresis bears predictive potential for arrhythmias in heart failure patients with an ICD for primary prevention, whereas TWA analysis seems to have lesser predictive value in our pilot group. Spatial ventricular gradient hysteresis is relatively robust for noise, and, as it rests on different electrophysiologic properties than TWA, it may convey additional information. Hence, joint analysis of TWA and SVGH may, possibly, improve the noninvasive identification of high-risk patients. Further research, in a large group of patients, is required and currently carried out by our group.     

T-wave alternans phase following ventricular extrasystoles predicts arrhythmia-free survival

OBJECTIVE: The purpose of this study was to assess the value of T-wave alternans (TWA) following ventricular extrasystoles in predicting arrhythmia-free survival. BACKGROUND: Stratifying risk for sudden death in patients with coronary disease and moderate left ventricular (LV) dysfunction remains a challenge. We hypothesized that, in such patients, a discontinuity in beat-to-beat T-wave alternation (TWA phase reversal) following single ventricular extrasystoles reflects transiently exaggerated repolarization dispersion, and predicts spontaneous ventricular arrhythmias. METHODS: We studied 59 patients with ischemic LV dysfunction (mean LV ejection fraction 38.7 +/- 5.3%) and nonsustained ventricular tachycardia undergoing programmed stimulation. TWA was computed spectrally from the ECG during ventricular pacing, and TWA phase reversal was reflected by a discontinuity in T-wave oscillation after single ventricular extrasystoles. RESULTS: Patients induced into ventricular arrhythmias (n = 36) had greater TWA magnitude (V(alt): 6.60 +/- 6.46 microV vs 2.61 +/- 1.97 microV; P = .001) and more frequent TWA phase reversal (62.1% vs 44.4%; P = .02) than those who were not (n = 23). During a mean follow-up of 36 +/- 12 months, positive TWA (V(alt) > or =1.9 microV) and TWA phase reversal both (P < .05) predicted events (all-cause mortality, ventricular tachycardia, ventricular fibrillation). Univariate predictors of arrhythmia-free survival were TWA phase reversal (P < .005), positive TWA (P < .05), age (P = .008), and LV mass index (P = .043). On multivariate analysis, only TWA phase reversal and age predicted events; if TWA phase was excluded, only positive TWA and age predicted events. CONCLUSION: Phase reversal in TWA following ventricular extrasystoles predicts spontaneous ventricular arrhythmias and all-cause mortality in patients with moderate ischemic LV dysfunction and was a better predictor than positive TWA or programmed ventricular stimulation.     

"Indeterminate" microvolt T-wave alternans tests predict high risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction.

OBJECTIVES: This study tested the hypothesis that an "indeterminate" microvolt T-wave alternans (MTWA) test, when due to ectopy, unsustained MTWA, or low exercise heart rate (HR), has prognostic significance similar to a positive MTWA test. BACKGROUND: MTWA testing, used to stratify risk of sudden or total mortality in patients with structural heart disease, has been limited by a substantial number of "indeterminate" tests. Indeterminate tests are due to patient factors--excessive ventricular ectopy during exercise, unsustained MTWA, or failure to achieve a HR of 105 beats/min for 1 min--or technical factors such as a noisy recording or an exercise protocol that causes an excessively rapid rise in HR. METHODS: Patients in sinus rhythm with left ventricular ejection fraction < or =0.40 underwent MTWA exercise tests, analyzed with the spectral method and classified by a computerized interpretation algorithm. The primary end point was all-cause mortality or documented non-fatal sustained ventricular arrhythmia (SVA). "Indeterminate" tests were reviewed jointly by 2 readers blinded to subsequent events to determine the primary reason for indeterminacy. RESULTS: Participants (N = 549) were 56 +/- 13 years and 71% male; 49% had ischemic cardiomyopathy. There were 40 deaths and 11 non-fatal SVA. Most (94%) indeterminate results were due to patient factors. The 2-year rate for death or SVA was 17.8% in patients with an "indeterminate" MTWA test compared with 12.3% in those with a positive test. CONCLUSIONS: In patients with left ventricular dysfunction, an "indeterminate" MTWA test due to patient factors predicted death or SVA at least as well as a positive test.