Clinical applications of T-wave alternans assessed during exercise stress testing and ambulatory ECG monitoring

Analytical methods to measure T-wave alternans (TWA), a beat-to-beat fluctuation in the morphology of the ST-segment and T wave in the electrocardiogram (ECG), have been developed to address the unmet challenge of identifying individuals at increased risk for sudden cardiac death. Conventional noninvasive markers including left ventricular ejection fraction have significant limitations as many individuals who die suddenly have relatively preserved ventricular mechanical function. TWA is an attractive marker as it is closely linked to ECG heterogeneity and abnormalities in calcium handling, key factors in arrhythmogenesis. The objectives of this review are to summarize the clinical evidence supporting use of TWA in risk stratification and to discuss its current and potential applications in guiding device and medical therapy.     

Quantitative assessment of microvolt T-wave alternans in patients with congestive heart failure

INTRODUCTION: T-wave alternans has been shown to be linked to the genesis of ventricular tachyarrhythmias. Currently, only qualitative assessment of microvolt T-wave alternans (MTWA) is recommended in clinical practise. Whether quantitative assessment of MTWA yields complementary information is unknown. METHODS AND RESULTS: Noninvasive MTWA determination was performed in 204 consecutive patients with ischemic or nonischemic cardiomyopathy. Of those, 100 tested MTWA positive. In these recordings, MTWA magnitude was quantitatively assessed (alternans voltage, V(alt)). Patients were followed for a mean of 17 months. Ventricular tachyarrhythmic events constituted the study endpoint. Patients with nonischemic cardiomyopathy had a higher V(alt) than patients with ischemic cardiomyopathy (10.3 +/- 9.2 [median 7.2] vs 6.2 +/- 3.2 [median 4.6] microV; P = 0.007). The number of MTWA-positive ECG leads was also higher in patients nonischemic cardiomyopathy (7.3 +/- 2.4 [median 8] vs 6.0 +/- 2.5 [median 6]; P = 0.016). Patients who suffered an arrhythmic event during follow-up had higher MTWA voltages (10.8 +/- 10.0 [median 8.8] vs 7.4 +/- 5.7 [median 6.4] microV; P = 0.05) a higher number of MTWA-positive ECG leads (7.6 +/- 2.4 [median 8] vs 6.4 +/- 2.5 [median 6]; P = 0.05) compared to patients with an uncomplicated course. CONCLUSION: Patients with nonischemic cardiomyopathy and patients with tachyarrhythmic complications have more extensive MTWA possibly reflecting more extensive myocardial damage and a higher arrhythmia propensity.     

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.     

Effect of bundle branch block on microvolt T-wave alternans and electrophysiologic testing in patients with ischemic cardiomyopathy

BACKGROUND: T-wave alternans (TWA) and electrophysiology study (EPS) are used for risk stratification for sudden death. OBJECTIVE: The purpose of the study was to determine the effect of bundle branch block or intraventricular conduction delay on TWA and EPS. METHODS: 386 patients with coronary artery disease, nonsustained ventricular tachycardia, and left ventricular ejection fraction < or =40% underwent TWA and EPS, and were followed for 40 +/- 19 months. RESULTS: Patients with wide QRS were more likely than narrow QRS patients to have nonnegative TWA (77% vs 63%, P <.01) or positive EPS (60% vs 48%, P = .03). Nonnegative TWA predicted the combined endpoint of ventricular tachyarrhythmia or death in narrow QRS (HR = 1.64, P = .04) but not wide QRS patients (HR = 1.04, P = .91). Similarly, positive EPS predicted the combined endpoint in narrow QRS (HR = 2.28, P <.001) but not wide QRS patients (HR = 0.94, P = .84). In multivariate analysis, QRS width and TWA, as well as QRS width and EPS, were independent predictors of events. There was no TWA- or EPS-based difference in arrhythmia-free survival within any specific wide QRS morphology. CONCLUSION: TWA and EPS are more often abnormal in patients with a wide QRS than in those with a narrow QRS. In patients with narrow QRS, both TWA and EPS stratify patients according to their risk of ventricular tachyarrhythmia or death. However, among patients with a wide QRS, regardless of specific QRS morphology, the risk is high and comparable regardless of TWA or EPS results. Therefore, the only truly low-risk group consists of those patients with negative test results and a narrow QRS.     

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.     

The many faces of repolarization instability: which one is prognostic?

Instabilities of the STT segment's magnitude, and particularly the 0.5 beat/cycle oscillations (T-wave alternans, or TWA), have been linked to the heightened risk of ventricular tachyarrhythmias (VTA) and sudden cardiac death (SCD). During the last decade theoretical, experimental and clinical research efforts have focused primarily on TWA, examining its mechanisms and predictive value using time-invariant cutoff values. However, recent evidence suggests that such a single-snapshot test of a single-frequency (TWA) oscillation using a constant cutoff value might be suboptimal for risk stratification because of several reasons.First, it is well known that the risk of VTA/SCD evolves over time with changes in electrophysiologic substrate, environmental and physiologic triggers, and the impact of other physiologic (eg, circadian) rhythmicity. Hence, the outcome of TWA testing might depend on the time of day, as Holter-based TWA studies have demonstrated. Furthermore, currently used single-snapshot testing with a binary cutoff value may not coincide with the periods of heightened risk for VTA/SCD and may not yield prognostic information, as a recent TWA substudy of the sudden cardiac death in heart failure trial has showed. Second, the analysis focused on TWA alone ignores the existence of multiple (alternating and nonalternating) forms of repolarization instability that have been shown to arise or increase before the onset of VTA/SCD.Summarizing, recent studies have identified multiple forms of repolarization instabilities modulated by distinct mechanisms, which might have different prognostic values. Therefore, the assessment of TWA needs to be dynamic and personalized to take into account the time evolution of risk and individual history.     

Microvolt-level T-wave alternans determination using the spectral method in patients with QT prolongation: value of adjusting the T-wave window

Background

Microvolt-level T-wave alternans (MTWA) measured by the spectral method is a useful risk predictor for sudden cardiac death because of its high negative predictive value. MTWA analysis software selects a segment of the ECG that encompasses the T-wave in most individuals, but may miss the T-wave end in patients with QT prolongation.

Hypotheses

(1) In patients with QT prolongation, adjustment of the T-wave window will increase the sensitivity of MTWA detection. (2) The extent of T-wave window adjustment needed will correspond to the degree of QT prolongation.

Methods

Using data from long-QT syndrome patients, including QTc < 0.45s (normal), 0.45–0.49s (moderate prolongation), and ≥ 0.50s (severe prolongation), MTWA analysis was performed before and after T-wave window adjustment.

Results

Of 119 patients, 74% required T-wave window adjustment. There was a stronger association between the magnitude of the T-wave offset and the unadjusted QT than between the magnitude of the T-wave offset and QTc (Spearman correlation coefficient 0.690 vs. 0.485 respectively, P<.05). Of 99 initially negative MTWA results, 4 became non-negative after adjustment of the T-wave window (P<.05). All 8 initially positive studies and 12 initially indeterminate studies remained positive and indeterminate, respectively.

Conclusions

T-wave window adjustment can enable detection of abnormal MTWA that otherwise would be classified as “negative” or “normal.” Newly developed T-wave window adjustment software may further improve the negative predictive value of MTWA testing and should be validated in a structural heart disease population.     

Biventricular pacing does not affect microvolt T-wave alternans in heart failure patients

BACKGROUND: Microvolt T-wave alternans (MTWA) is a valuable tool for stratification of patients at risk for sudden death and has recently been approved for this purpose by Medicare. Although right atrial (RA) pacing has been applied for MTWA testing, the effects of other pacing modalities on MTWA have not been systematically studied. Accordingly, it is unknown whether biventricular (BiV) pacing might influence MTWA test results. OBJECTIVE: This study sought to investigate effects of BiV pacing in comparison with other pacing modalities. METHODS: Congestive heart failure patients (n = 30) receiving cardiac resynchronization therapy were included, and a systematic step-up pacing protocol was performed via the implanted cardioverter-defibrillator. RESULTS: Of the overall 120 MTWA tests performed, 67 (56%) were nonnegative. Nonnegative MTWA test results were observed in 18 patients (60%) during RA stimulation, whereas 17 (57%), 15 (50%), and 17 test results (57%) were nonnegative during right ventricular (RV), left ventricular (LV), and BiV pacing, respectively. Seven (23%) patients were MTWA negative for all pacing sites. Results of MTWA assessment during RA pacing were concordant with results obtained with RV pacing in 25 (83%) patients (kappa = 0.66, P = .0003), to LV pacing in 21 (70%) patients (kappa = 0.4, P = .025), and to BiV pacing in 25 (83%) patients (kappa = 0.66, P = .0003). Positive and negative predictive values of nonnegative MTWA test results obtained during RA pacing for a similar result obtained with RV pacing were 88% and 76%. Respective values were similar for other pacing modalities (80% and 60% for LV; 88% and 76% for BiV pacing). CONCLUSION: There is a high level of concordance between MTWA test results obtained during RA pacing and other pacing modalities, and MTWA assessment seems not to be influenced by BiV stimulation in congestive heart failure patients. In general, BiV pacing does not seem to affect an arrhythmogenic substrate as detected by MTWA testing.     

Prognostic value of average T-wave alternans and QT variability for cardiac events in MADIT-II patients

Background

Identifying which patients might benefit the most from ICD therapy remains challenging. We hypothesize that increased T-wave alternans (TWA) and QT variability (QTV) provide complementary information for predicting appropriate ICD therapy in patients with previous myocardial infarction and reduced ejection fraction.

Methods

We analyzed 10-min resting ECGs from MADIT-II patients with baseline heart rate > 80 beats/min. TWA indices IAA and IAA₉₀ were computed with the multilead Laplacian Likelihood ratio method. QTV indices QTVN and QTVI were measured using a standard approach. Cox proportional hazard models were adjusted considering appropriate ICD therapy and sudden cardiac death (SCD) as endpoints.

Results

TWA and QTV were measured in 175 patients. Neither QTV nor TWA predicted SCD. Appropriate ICD therapy was predicted by combining IAA₉₀ and QTVN after adjusting for relevant correlates.

Conclusion

Increased TWA and QTV are independent predictors of appropriate ICD therapy in MADIT-II patients with elevated heart rate at baseline.     

Analysis of T-wave alternans using the dominant T-wave paradigm

The dominant T wave (DTW) reflects the derivative of the repolarization phase of the transmembrane potential of myocytes. T-wave alternans (TWA) is defined as an alteration of this repolarization that repeats every other beat. We investigate if the DTW can offer new insight on TWA.We first proved that the DTW estimate obtained through singular value decomposition is optimal, because it minimizes the norm of the residuals. Then we suggested an optimal estimate of the vector of lead factors, in the case in which the DTW is given. Finally, we derived a mathematical relationship between observable TWA on electrocardiogram and DTW morphology. The relationship depends on the slope of the repolarization phase of the myocytes' transmembrane potentials and on the dispersion of the repolarization times. Based on this finding, a new index meant to quantify TWA was defined and termed amplitude of dominant T-wave alternans (ADTWA).A preliminary validation of the index was performed using the synthetic records contained in the Computers in Cardiology 2008 data set. They were obtained from 5 electrocardiogram models to which TWA was added at different extents. We found a linear relationship between the TWA amplitude and the ADTWA metric (R² = 0.9898 ± 0.100 across all models). Moreover, the root mean square error between actual and estimated TWA amplitudes was 10.9 μV (ADTWA) vs 12.9 μV obtained with the classical spectral method.     

Implantable cardioverter-defibrillator shocks increase T-wave alternans

Introduction: While implantable defibrillator shocks save lives, shock can lead to ventricular arrhythmias. However, the mechanism of shock-related proarrhythmia remains unclear. We evaluated the impact of ICD shock on repolarization instability, a factor associated with ventricular arrhythmogenesis.
Methods and Results: Sixty-five patients with ICDs underwent ambulatory ECG monitoring during defibrillation testing 3 months postimplant. TWA was analyzed continuously in the time domain during baseline, sedated, and post-shock states. RR, QRS, and QT intervals and catecholamines were also measured continuously. Adequate pre- and post-shock Holter data were recorded in 55 patients, 48 male, mean 64 ± 12 years, 50 with coronary disease, 48 with prior spontaneous or induced arrhythmia. TWA significantly increased after shock, from 9.6 ± 0.5 to 11.9 ± 0.6 μV, as did QRS duration, epinephrine, and norepinephrine levels, compared with sedated and baseline states. RR intervals decreased minimally. TWA changes with shock were not associated with RR or QRS duration changes, but were associated with changes in epinephrine.
Conclusions: ICD shock, even in the sedated state, increases repolarization instability as measured by TWA, an effect mediated in part by sympathetic stimulation. This association between shock and TWA may have important mechanistic and clinical implications for optimization of defibrillation therapy.     

Detection of T-wave alternans using an implantable cardioverter-defibrillator

BACKGROUND: Microvolt T-wave alternans (TWA) increases acutely prior to ventricular tachycardia (VT) or ventricular fibrillation (VF) in computer simulations and animal models, suggesting that TWA may provide a warning for VT/VF in patients with an implantable cardioverter-defibrillator (ICD). OBJECTIVES: The purposes of this study were to develop a method for analyzing TWA recorded from ICD electrograms (EGMs) and to evaluate the degree of concordance between EGM TWA and TWA recorded from the surface ECG. METHODS: We developed a software program to measure EGM TWA in the frequency domain and then used simulated EGMs to determine the effects of ICD signal processing, electrical noise, and variation in the EGM fiducial point on the recorded amplitude and K score (signal-to-noise ratio) of TWA. We then applied this method to analyze TWA simultaneously using both surface ECGs and ICD EGMs during incremental pacing in 25 ICD patients. Pacing modes and EGM sources were varied in repeated trials. EGMs with dynamic range adjusted to achieve a large T wave were telemetered to a digital Holter recorder and measured offline. ECG TWA was analyzed using a commercial system. A positive (+) ECG test had sustained alternans >or=1.9 microV with K score >or=3. Stored EGMs were reviewed for VT/VF during a 6-month follow-up period. RESULTS: Simulations demonstrated that the EGM method accurately identified TWA >or=10 microV. Overall, 10 (40%) patients had at least one ECG TWA+ test and 15 patients (60%) had no ECG TWA+ tests. The maximum value of TWA was greater in EGMs than in ECGs (median 64 microV vs 2.2 microV, P <.0001). EGM TWA was greater in ECG TWA+ tests than in ECG TWA- tests (169 +/- 175 microV vs 71 +/- 61 microV, P <.001). Using a sustained EGM TWA threshold of 30 microV, EGM TWA was concordant with ECG TWA in 63 (84%) of 75 analyzed tests (P <.0001) and predicted ECG TWA results with 85% sensitivity and 84% specificity. Both ECG and EGM TWA predicted VT/VF during follow-up (ECG: P = .006; EGM: P = .035). CONCLUSION: The amplitude of TWA is at least 10 times greater on ICD EGMs than on surface ECGs. EGM and ECG TWA have substantial concordance and comparable predictive value for spontaneous VT/VF. These observations support the hypothesis that ECG and EGM TWA detect the same electrical alternans phenomenon.     

Exercise-induced quantitative microvolt T-wave alternans in hypertrophic cardiomyopathy

Background/Purpose

Patients with hypertrophic cardiomyopathy (HCM) have elevated risk for sudden cardiac death (SCD). Our study aimed to quantitatively characterize microvolt T-wave alternans (TWA), a potential arrhythmia risk stratification tool, in this HCM patient population.

Relationship between extracellular T-wave height, T-wave alternans amplitude, and tissue action potential alternans: a 1-dimensional computer modeling study

T-wave alternans (TWA) is a useful marker of cardiac instability, but not much is known about the factors that affect its measurement, such as electrode placement. We used a 1-dimensional myocardial fiber computer model of alternans to investigate the effect of electrode position on TWA measurement. Results demonstrated that TWA amplitude and T-wave amplitude change proportionally if both recording electrodes are symmetrically moved toward or away from the tissue. However, TWA amplitude and T-wave amplitude change out of proportion to one another when one electrode is moved while the other electrode remains stationary. These disproportionate changes result from beatwise alternation in the asymmetric potential field around the tissue. In summary, nonlinear changes in tissue repolarization during alternans result in nonlinear changes in T-wave amplitude and TWA amplitude.     

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.     

Optimizing ambulatory ECG monitoring of T-wave alternans for arrhythmia risk assessment

Considerable scientific data support the potential value of T-wave alternans (TWA) as anindex of vulnerability to ventricular fibrillation. This chapter summarizes our state of knowledge regardingthe use of routine ambulatory ECGs to evaluate TWA and discusses recent methodologic approaches designed tooptimize AECG-based TWA analysis for arrhythmia risk stratification. Newer methods, including the nonspectraltechnique of Modified Moving Average analysis, appear promising in detecting TWA during the changingconditions associated with daily activities. The Modified Moving Average approach does not requirespecialized electrodes and is not encumbered by the need to achieve target heart rates, as is the case forconventional spectral-based methods. Guidelines are provided for evaluating latent cardiac electricalinstability using AECG-based TWA testing. These recent developments make possible the TWA analysis ofambulatory ECGs not only in prospective trials but also in vast stores of archival data.     

Electrophysiology of T-wave alternans: Mechanisms and pharmacologic influences

Extensive experimental evidence indicates a fundamental link between T-wave alternans (TWA) and arrhythmogenesis. Diverse physiologic and pathophysiologic influences alter TWA magnitude in parallel with their effects on vulnerability to ventricular tachyarrhythmias. Specifically, interventions that impede intracellular calcium handling, such as elevated heart rate, heightened adrenergic activity, myocardial ischemia, and heart failure, predispose to greater levels of TWA, reflecting heightened risk for arrhythmias. Conversely, vagus nerve stimulation, blockade of beta-adrenergic receptors and late sodium and L-type calcium channels, and sympathetic denervation decrease TWA magnitude, reflecting the potential of these interventions to reduce risk for ventricular tachycardia and fibrillation. TWA thus appears able to detect the influence of pathophysiologically relevant triggers as well as the efficacy of antiarrhythmic drugs without reducing the predictive capacity of the phenomenon.     

Evaluation of T-wave alternans in pediatric patients with chronic renal failure

Introduction

Microvolt T-wave alternans (TWA) is known to be useful in prediction of ischemia and sudden death in high-risk populations and there are no studies in children with chronic renal failure (CRF). Cardiac problems seem to be responsible for an important part of death in children and young adults with CRF. The aim of this study is to evaluate Holter microvolts TWA measurements in children with CRF comparing to the control group.