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 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.     

Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death

For nearly 100 years, beat to beat alternation of T wave amplitude, termed T wave alternans (TWA), has been closely linked to electrical instability in the heart. TWA is now established among the strongest markers of susceptibility to sudden cardiac death. Since computer technology allows for detection of very subtle yet clinically significant TWA during standard exercise testing, TWA has been used increasingly as a noninvasive clinical tool for identifying and treating patients at risk for sudden cardiac death. The observation of TWA hastening ventricular tachyarrhythmias in an extraordinary variety of clinical and experimental conditions suggest potential universality of TWA in the pathophysiological mechanism of sudden death. High resolution optical mapping studies have shown that TWA arises from alternans of repolarization at the level of the ventricular myocyte. Cellular alternans is likely due to the actions of one or more ionic currents and is closely related to, if not directly dependent on, the kinetics of intracellular calcium cycling. Impairment in calcium cycling at the cellular and sub-cellular levels has been implicated in the mechanism of cellulcar alternans. Importantly, spatially discordant alternans between cells is most likely a consequence of heterogeneities of electrophysiological properties between cells which span the ventricular wall, serving to amplify spatial heterogeneities of repolarization, and forming a substrate for reentrant excitation. Through this mechanism, TWA is linked directly and mechanistically to the pathogenesis of arrhythmias. Although available data would suggest that TWA is certainly closely related to a mechanism of arrhythmogenesis, and is a strong marker of clinical risk, the precise sequence of events which triggers sudden cardiac death, and the potential role of TWA in this process remains elusive.     

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.     

T波电交替预测心力衰竭病人心源性猝死价值的新分歧

有半数的心力衰竭病AN致命性室性心律失常事件死于心源性猝死。T波电交替是公认的预测心源性猝死的重要指标。早在许多年前就发现T波电交替与心源性猝死有关,近年来新建了频域和时域测量方法。跨室壁复极离散度异常增大是T波电交替的机制。最近研究发布的用微伏级T波电交替进行心肌梗死后危险性分层的初步结果否定心肌梗死后左室射血分数〈30％的病人发生致死性快速室性心律失常的价值。但体内除颤器置入前T波电交替的对心源性猝死一级预防试验和非缺血性心肌病心力衰竭T波电交替的预测价值试验则强有力地支持T波电交替能预测心律失常。     

A comparison of T-wave alternans, signal averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification

OBJECTIVES

The goal of this study was to compare T-wave alternans (TWA), signal-averaged electrocardiography (SAECG) and programmed ventricular stimulation (EPS) for arrhythmia risk stratification in patients undergoing electrophysiology study.

BACKGROUND

Accurate identification of patients at increased risk for sustained ventricular arrhythmias is critical to prevent sudden cardiac death. T-wave alternans is a heart rate dependent measure of repolarization that correlates with arrhythmia vulnerability in animal and human studies. Signal-averaged electrocardiography and EPS are more established tests used for risk stratification.

METHODS

This was a prospective, multicenter trial of 313 patients in sinus rhythm who were undergoing electrophysiologic study. T-wave alternans, assessed with bicycle ergometry, and SAECG were measured before EPS. The primary end point was sudden cardiac death, sustained ventricular tachycardia, ventricular fibrillation or appropriate implantable defibrillator (ICD) therapy, and the secondary end point was any of these arrhythmias or all-cause mortality.

RESULTS

Kaplan-Meier survival analysis of the primary end point showed that TWA predicted events with a relative risk of 10.9, EPS had a relative risk of 7.1 and SAECG had a relative risk of 4.5. The relative risks for the secondary end point were 13.9, 4.7 and 3.3, respectively (p < 0.05). Multivariate analysis of 11 clinical parameters identified only TWA and EPS as independent predictors of events. In the prespecified subgroup with known or suspected ventricular arrhythmias, TWA predicted primary end points with a relative risk of 6.1 and secondary end points with a relative risk of 8.0.

CONCLUSIONS

T-wave alternans is a strong independent predictor of spontaneous ventricular arrhythmias or death. It performed as well as programmed stimulation and better than SAECG in risk stratifying patients for life-threatening arrhythmias.     

Effect of resistive barrier location on the relationship between T-wave alternans and cellular repolarization alternans: a 1-D modeling study

Structural inhomogeneities in cardiac tissue have been associated with increased cellular repolarization alternans in animal experiments and increased T-wave alternans (TWA) in clinical studies. However, the effect of structural inhomogeneities on the relationship between cellular alternans and TWA has not been thoroughly investigated. We created 1-dimensional multicellular fiber models with and without a resistive barrier in various fiber regions and paced each model to induce cellular alternans. The models demonstrate that a resistive barrier in one fiber region substantially alters cellular repolarization alternans throughout the fiber. A midmyocardial or subepicardial barrier increase both TWA amplitude and maximum cellular alternans magnitude, relative to a fiber without a barrier. In addition, a direct relationship exists between TWA amplitude and maximum cellular alternans magnitude, which was highly dependent on barrier location. These results suggest that the position of a structural inhomogeneity within the myocardium may have substantial effects on dynamic repolarization instability and arrhythmogenicity.     

T-wave alternans: marker,mechanism, and methodology for predicting sudden cardiac death

Sudden cardiac death (SCD) is a leading cause of cardiovascular mortality. Therefore, identifying patients at highest risk for SCD is crucial. Conventional noninvasive markers of SCD are inadequate because of low positive predictive value. The presence of visible T-wave alternans (TWA) on electrocardiogram often predicts the occurrence of lethal ventricular arrhythmias. Signal processing methods have made it possible to detect microvolt-level and visually inapparent TWA on electrocardiogram. TWA is caused by underlying regional inhomogeneities of ventricular repolarization, which predispose patients to have ventricular arrhythmias. Microvolt TWA provoked either by atrial pacing, pharmacological stress, or exercise is a promising marker of arrhythmia vulnerability. Several large trials have shown TWA to be comparable or superior to other noninvasive markers and electrophysiologic study in the prediction of SCD. The patient populations in these trials include post myocardial infarction, both ischemic and nonischemic heart failure, and suspected arrhythmias. Prospective trials regarding benefits of implantation of cardioverter-defibrillator therapy based on TWA results are ongoing.     

健康人微伏级T波电交替试验检测分析

微伏级T波电交替 (MTWA)与器质性心脏病恶性室性心律失常的发生密切相关。T波电交替偶见于正常人运动时。本研究的目的是探讨正常人静息和运动时MTWA的发生情况。用CambridgeHeart.HeartwaveTMsys tem心脏诊断系统 ,以频谱法检测 4 5例健康志愿者MTWA。结果 :所有受试者静息时MTWA阴性。运动负荷试验时 ,非持续性MTWA 5例 (11.11% ) ,持续性MTWA 2例 (4.4 4 % ) ,1例阈值心率 <110次 /分 ,另一例发作心率>110次 /分。 4 5例中 ,MTWA阳性 1例 (2 .2 2 % ) ,但持续时间短暂 (1min) ,不确定性 2例 (4.4 4 % ) ,阴性 4 2例(93.33% )。结论 :健康人MTWA阳性发生率低 (2 .2 2 % ) ,短暂的MTWA无恶性室性心律失常的临床意义。     

T Wave Alternans Does not Assess Arrhythmic Risk in Patients with Brugada Syndrome

Background: Brugada syndrome is associated with a risk for sudden death, but the arrhythmic risk in an individual Brugada syndrome patient is difficult to predict. Pathologic changes in the early repolarization phase of the ventricular action potential probably constitute part of the arrhythmogenic substrate in Brugada syndrome. Microvolt T wave alternans (TWA) assesses dynamic beat‐to‐beat changes in repolarization and has been suggested as a marker for repolarization‐related sudden death. We therefore tested whether TWA is an indicator for arrhythmias in Brugada syndrome with a focus on right precordial ECG leads. Methods: We assessed TWA in nine symptomatic, inducible patients with established Brugada syndrome and in seven healthy controls. TWA was assessed at rest and during exercise using both standard methods and an algorithm that assesses TWA in the early ST segment and the right precordial leads. Results : None of the Brugada patients developed TWA in this study irrespective of analysis at rest or during exercise, neither using standard methods nor when the early ST segment was included in the analysis. When the early ST segment was included in the analysis, nonsustained TWA was found in three out of seven, and sustained TWA in one control. Conclusion: T wave alternans is not an appropriate test to detect arrhythmic risk in patients with Brugada syndrome.     

Lack of noninvasive markers of ventricular repolarization inhomogeneity in patients with idiopathic ventricular tachyarrhythmia

Noninvasive markers reflecting repolarization inhomogeneity have been proposed to be useful indices for identifying patients at risk of ventricular arrhythmias based on organic heart disease. In this study, we clarify whether or not repolarization inhomogeneity markers are useful in patients with idiopathic ventricular tachycardia (VT). We investigated T-wave alternans (TWA) and corrected QT-interval dispersion (QTD) in 84 consecutive patients with idiopathic VT, 90 patients with VT associated with organic heart disease (organic VT), and 87 normal individuals. VT was defined as tachycardia lasting > or =5 consecutive ventricular ectopic beats at a rate of > or =120 beats/min. TWA was positive in 20 of 84 patients (24%) with idiopathic VT, 59 of 90 patients (66%) with organic VT, and 16 of 87 normal individuals (18%). The alternans voltage was 2.6 +/- 3.1 micro V in idiopathic VT patients, 5.6 +/- 6.4 micro V in organic VT patients, and 2.9 +/- 5.7 micro V in normal individuals. QTD were 53 +/- 20 ms in idiopathic VT patients, 92 +/- 20 ms in organic VT patients, 46 +/- 18 ms in normal individuals, respectively. A positive TWA test result was seen more (P <.01) frequently, and QTD was longer (P <.01) in organic VT patients compared to normal individuals, whereas there was no difference between idiopathic VT patients and normal individuals. In addition, in patients with idiopathic VT, neither did any of these measurements differ between patients with sustained VT (lasting for > or =30 s) and those with nonsustained VT. Noninvasive markers of repolarization inhomogeneity, such as TWA and QTD, are not useful for identifying patients with idiopathic VT. Repolarization inhomogeneity may not affect to the pathogenesis of idiopathic VT.     

T-wave alternans in microwave frequency as a new indicator of disordered ventricular repolarization: pathophysiology, methodology, clinical results

Primary prevention of sudden cardiac death is hampered by the inability to accurately identify high risk patients. Various noninvasive methods such as determination of left ventricular function or heart rate variability as well as invasive electrophysiologic testing are currently used for risk stratification. Noninvasive measurement of microvolt T wave alternans (TWA) is a promising new method to assess repolarization abnormalities; in experimental studies, TWA was associated with an increased incidence of ventricular tachyarrhythmias. Since the occurrence of TWA is heart rate-dependent, it is measured either during atrial pacing or during exercise stress testing. The first clinical validation of the method was performed in patients undergoing invasive EP testing to assess prediction of inducibility of ventricular tachyarrhythmias. A first prospective validation of the noninvasive method was performed in patients surviving out-of-hospital cardiac arrest fitted with an ICD. Further studies have shown a good concordance between invasive and noninvasive TWA determination. The occurrence of TWA in this population was of predictive value with respect to arrhythmia recurrence. Recently published data confirm the value of TWA assessment with respect to identification of patients with congestive heart failure at high risk of malignant ventricular tachyarrhythmias. The use of this method in post myocardial infarction risk stratification is currently under prospective evaluation.     

Relation of T-wave alternans to regional left ventricular dysfunction and eccentric hypertrophy secondary to coronary heart disease

Left ventricular (LV) hypertrophy and structural disease are associated with exaggerated repolarization dispersion and risk for cardiac arrest. We hypothesized that T-wave alternans (TWA) from the electrocardiogram, reflecting proarrhythmic repolarization dispersion, would increase with extent of eccentric LV hypertrophy and vary spatially with the distribution of myocardial scar. We studied 28 patients with coronary disease, systolic dysfunction, and nonsustained ventricular tachycardia. On echocardiography, 21 patients had wall motion abnormalities and 20 had LV hypertrophy (mass index > or =100 g/m(2)). TWA magnitude (voltage of alternation), which was computed spectrally during ventricular stimulation, varied linearly with LV mass index (p = 0.003). Spatially, positive TWA (magnitude > or =1.9 microV) in orthogonal electrocardiographic axes overlaid scar or wall motion abnormalities in corresponding echocardiographic segments (p <0.05 in x and y axes). After a follow-up of 35 +/- 13 months, positive TWA predicted the combined end point of death or sustained ventricular arrhythmias in all patients (p = 0.025), with a trend for those with echocardiographic LV hypertrophy (p = 0.058). In conclusion, in patients with systolic dysfunction due to coronary artery disease, TWA may indicate arrhythmic contributions from regional myocardial scar and eccentric LV hypertrophy.     

Arrhythmogenesis of T wave alternans associated with surface QRS complex alternans and the role of ventricular prematurity: observations from a canine model of LQT3 syndrome

INTRODUCTION: T wave alternans (TWA) is characterized by cycle-to-cycle changes in the QT interval and/or T wave morphology. It is believed to amplify the underlying dispersion of ventricular repolarization. The aim of this study was to examine the mechanisms and arrhythmogenesis of TWA accompanied by QRS complex and/or blood pressure (BP) waveform alternans, using transmural ventricular electrogram recordings in an anthopleurin-A model of long QT syndrome. METHODS AND RESULTS: The cardiac cycle length was gradually shortened by interruption of vagal stimulation, and TWA was induced in six canine hearts. Transmural unipolar electrograms were recorded with plunge needle electrodes from endocardial (Endo), mid-myocardial (Mid), and epicardial (Epi) sites, along with the surface ECG and BP. The activation-recovery interval (ARI) was measured to estimate local refractoriness. During TWA, ARI alternans was greater at the Mid than the Epi/Endo sites, and it was associated with the development of marked spatial dispersion of ventricular repolarization. As TWA increased, ventricular activation of the cycles associated with shorter QT intervals displayed delayed conduction at the Mid sites as a result of a critically longer ARI of the preceding cycle and longer QT interval, while normal conduction was preserved at the Epi site. Delayed conduction at the Mid sites manifested as surface ECG QRS and BP waveform alternans, and spontaneous ventricular tachyarrhythmias developed in absence of ventricular prematurity. In other instances, in absence of delayed conduction during TWA, ventricular premature complexes infringed on a prominent spatial dispersion of ventricular repolarization of cycles with long QT intervals and initiated ventricular tachyarrhythmia. CONCLUSION: TWA accompanied by QRS alternans may signal a greater ventricular electrical instability, since it is associated with intramural delayed conduction, which can initiate ventricular tachyarrhythmia without ventricular premature complexes.     

Mechanism linking T-wave alternans to the genesis of cardiac fibrillation

BACKGROUND: Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear. METHODS AND RESULTS:-T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209+/-46 bpm) that was significantly lower (by 57+/-36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation. CONCLUSIONS: Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG. Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death.     

Cellular and ionic basis for T-wave alternans under long-QT conditions

BACKGROUND: T-wave alternans (TWA), an ECG phenomenon characterized by beat-to-beat alternation of the morphology, amplitude, and/or polarity of the T wave, is commonly observed in the acquired and congenital long-QT syndromes (LQTS). This study examines the cellular and ionic basis for TWA induced by rapid pacing under conditions mimicking the LQT3 form of the congenital LQTS in an arterially perfused canine left ventricular wedge preparation. METHODS AND RESULTS: Transmembrane action potentials from epicardial, M, and endocardial cells and 6 to 8 intramural unipolar electrograms were simultaneously recorded together with a transmural ECG and isometric tension development. In the presence of sea anemone toxin (ATX-II; 20 nmol/L), an increase in pacing rate (from a cycle length [CL] of 500 to 400 to 250 ms) produced a wide spectrum of T-wave and mechanical alternans. Acceleration to CLs of 400 to 300 ms produced mild to moderate TWA principally due to beat-to-beat alternation of repolarization of cells in the M region. Transmural dispersion of repolarization during alternans was exaggerated during alternate beats. Acceleration to CLs of 300 to 250 ms caused more pronounced beat-to-beat alternation of action potential duration (APD) of the M cell, resulting in a reversal of repolarization sequence across the ventricular wall, leading to alternation in the polarity of the T wave. The peak of the negative T waves coincided with repolarization of the M region, whereas the end of the negative T wave coincided with the repolarization of epicardium. In almost all cases, electrical alternans was concordant with mechanical alternans. Torsade de pointes occurred after an abrupt acceleration of CL, which was associated with marked TWA. Both ryanodine and low [Ca2+]o completely suppressed alternans of the T wave, APD, and contraction, suggesting a critical role for intracellular Ca2+ cycling in the maintenance of TWA. CONCLUSIONS: Our results suggest that TWA observed at rapid rates under long-QT conditions is largely the result of alternation of the M-cell APD, leading to exaggeration of transmural dispersion of repolarization during alternate beats, and thus the potential for development of torsade de pointes. Our data also suggest that unlike transient forms of TWA that damp out quickly and depend on electrical restitution factors, the steady-state electrical and mechanical alternans demonstrated in this study appears to be largely the result of beat-to-beat alternans of [Ca2+]i.     

T-wave alternans for risk stratification and prevention of sudden cardiac death

Despite considerable progress in the management of ischemic heart disease, a substantial proportion of patients continue to experience life-threatening arrhythmic events. The Multicenter Automatic Defibrillator Implantation Trial 2 has recently shown the superiority of implantable cardioverter defibrillators (ICDs) over conventional strategies to prevent sudden death in patients with reduced ejection fraction, but at the expense of potentially unnecessary ICD implantation in a large percentage of patients. T-wave alternans (TWA), which reflects alternation of cellular repolarization, results in a substantial increase in dispersion of repolarization, a prerequisite for reentrant arrhythmias. Recent trials, cumulating close to 3000 patients, have established TWA analysis as a powerful tool for arrhythmia prevention. Based on the most recent estimates, at least one third of post-myocardial infarction patients are expected to be tested negative. With a negative predictive value greater than 90%, TWA might allow for targeting of patients most likely to benefit from ICD therapy. Accurate identification of high-risk patients by noninvasive TWA may allow for improved widespread screening for sudden death prevention in the general population.     

Clinical value of T-wave alternans assessment

Microvolt-level T-wave alternans (TWA) is a new arrhythmia risk marker to assess subtle changesin repolarization that has been introduced for arrhythmia risk stratification. Recent experimental studies havedemonstrated that it reflects a heartrate dependent increased spatial dispersion of repolarization associated withunidirectional conduction block, and reentry that may result in the occurrence of ventricular fibrillation.Clinical studies have convincingly demonstrated that TWA is closely related to arrhythmia induction in theelectrophysiology (EP) laboratory as well as to the occurrence of spontaneous ventriculartachyarrhythmias in patients undergoing EP study. Subsequent studies showed that TWA—assessednoninvasively—is predictive of future arrhythmic events in patients with implanted ICDs as well as forventricular tachyarrhythmias in patients with congestive heart failure without a prior history of arrhythmias.There is still controversy, however, about the predictive value of TWA in patients following acute myocardialinfarction (MI). Several studies which differ in patient selection, pharmacologic treatment of thepatients, and endpoint definitions, have reported conflicting results. Therefore, studies with a large number ofunselected patients after acute MI on optimal treatment according to contemporary therapeutic guidelines as wellas of patients with reduced left ventricular ejection fraction following MI are needed to define its role withregard to identifying patients who may benefit from primary preventive ICD therapy. Future research should alsofocus on evaluation of alternative methods to increase heart rate (i.e., pharmacological stimulation) inan attempt to reduce the proportion of incomplete tests in patients with insufficient increase in heart rateduring exercise testing.     

Noninvasive Sudden Death Risk Stratification by Ambulatory ECG‐Based T‐Wave Alternans Analysis: Evidence and Methodological Guidelines

Extensive experimental and clinical evidence supports the utility of T‐wave alternans (TWA) as a marker of risk for ventricular fibrillation. This entity appears to reflect the fundamental arrhythmogenic property of enhanced dispersion of repolarization. This relationship probably accounts for its relative ubiquity in patients with diverse types of cardiac disease, as has been recognized with the development of analytical tools. A basic premise of this review is that ambulatory ECG monitoring of TWA as patients experience the provocative stimuli of daily activities can expose latent electrical instability in individuals at heightened risk for arrhythmias. We will discuss the literature that supports this concept and summarize the current state of knowledge regarding the use of routine ambulatory ECGs to evaluate TWA for arrhythmia risk stratification. The dynamic, nonspectral modified moving average analysis method for assessing TWA, which is compatible with ambulatory ECG monitoring, is described along with methodological guidelines for its implementation. Finally, the rationale for combined monitoring of autonomic markers along with TWA will be presented.     

Effects of psychologic stress on repolarization and relationship to autonomic and hemodynamic factors

INTRODUCTION: Psychological stress can precipitate ventricular arrhythmias in patients with ICDs, as well as sudden death. However, the physiologic pathways remain unknown. We sought to determine whether psychological stress induced in the laboratory setting alters indices of repolarization associated with arrhythmogenesis. METHODS AND RESULTS: Patients with ICDs and a history of ventricular arrhythmia underwent ambulatory ECG monitoring during a laboratory mental stress protocol (anger recall and mental arithmetic). Continuous changes in repolarization indices which have correlated with temporal and spatial myocardial heterogeneity of repolarization, including T-wave alternans (TWA), T-wave amplitude (Tamp), and T-wave area (Tarea) were analyzed in the time domain. In the 33 patients (85% male, 88% with coronary artery disease, mean ejection fraction 30%), norepinephrine, epinephrine, BP, and HR increased during mental stress. TWA increased from 22 (interquartile range 16-27) at baseline to 29 (21-38) uV during mental stress (P < 0.001). Changes in TWA correlated with changes in HR, systolic BP, and catecholamines. Tamp and Tarea also increased with mental stress (P < 0.01) but did not correlate with changes in other variables. CONCLUSION: Psychological stress increased TWA, Tamp, and Tarea. Autonomically mediated repolarization changes may be a pathophysiologic link between emotion and arrhythmia in susceptible patients.