Identifying individuals at risk for life-threatening arrhythmias remains a major public health challenge, as approximately 400,000 to 450,000 North Americans succumb to sudden cardiac death annually. Although the greatest incidence of sudden cardiac death occurs in the population at highest risk, such as individuals with low LVEF or heart failure, the greatest number of events occurs in healthier subgroups, which constitute the larger population base. Sudden death accounts for at least half of all cardiovascular deaths, and in 20 to 30 percent of cases, it is the first manifestation of underlying cardiovascular disease.
TWA Consensus Guideline Published in JACC
Interest has been sustained over the past decade in the potential for noninvasive risk stratification by T-wave alternans (TWA), a beat-to-beat alternation of the morphology of the ST segment and/or T wave. Recently, the International Society for Holter and Noninvasive Electrocardiology, together with the Japanese Circulation Society, the European Society of Cardiology Working Group on e-Cardiology, and the European Cardiac Arrhythmia Society, charged a panel of international experts with reviewing the topic of microvolt TWA to provide a consensus statement with regard to its physiologic basis, measurement methods, and clinical utility. The TWA Consensus Guideline was recently published in the Journal of the American College of Cardiology.1
The two FDA-cleared techniques reviewed were the frequency-domain Spectral and time-domain Modified Moving Average (MMA) methods. The latter method expands TWA testing from exercise and EP testing to include ambulatory ECG and in-hospital monitoring; it can be performed during the flow of routine clinical evaluation (Figure 1). The authors reviewed evidence from prospective clinical studies that enrolled nearly 14,500 patients and concluded that MMA analysis, which has been tested in more than 4,800 patients, offers prediction that is equivalent to the Spectral Method. They found that hazard ratios for prediction by the Spectral and MMA methods were similar, whether tested in the same population or compared among all studies.
The guideline’s primary conclusion was “Overall, our assessment is that it is reasonable to consider TWA evaluation whenever there is suspicion of vulnerability to lethal cardiac arrhythmias.”1 This conclusion concurs with prior statements by the American Heart Association, the American College of Cardiology, and the National Institutes of Health. The importance of TWA is underscored by the fact that it is present in many pathologic conditions associated with risk for life-threatening arrhythmias, including myocardial ischemia, MI, cardiomyopathy, heart failure, sudden infant death syndrome, drug-induced Torsade de Pointes, and inheritable channelopathies. Thus, the availability of accurate and clinically practical means for assessing TWA is of considerable value.
Analytical Principle of the MMA Method and Comparison to the Spectral Method
The Spectral Method employs the Fast Fourier Transform and utilizes specialized electrodes to minimize noise to detect microvolt levels of TWA. The time-domain MMA algorithm achieves the same demonstrated level of accuracy using standard electrodes by applying the noise-rejection principle of recursive averaging. The algorithm continuously streams odd and even beats into separate bins and creates median complexes for each bin (Figure 2).2 These complexes are then superimposed, and the maximum difference between the odd and even median complexes at any point within the JT segment is averaged for every 10 to 15 seconds and reported as the TWA value. The moving average allows control of the influence of new incoming beats on the median complexes with an adjustable update factor, that is, the fraction of morphology change that an incoming beat can contribute. The recommended rapid update factor of one-eighth provides greater sensitivity and capacity to detect transient but clinically important surges in TWA than one-sixteenth or one-thirty-second. Noise measurements are in part derived from the mismatch of the even or odd median complexes outside the JT segment. The algorithm excludes extrasystoles, noisy beats, and the beats preceding them and filters out effects of noise, movement, and respiration. The inherent noise-rejection features of the MMA design have been enhanced by GE Healthcare’s proprietary algorithms such as Finite Residual Filter and Cubic Spline, which further minimize artifact and reduce the potential for false positive readings.
Inherent Advantages of the Time-Domain MMA Method
- Standard ECG electrodes can be used because noise rejection is accomplished by signal processing.
- TWA can be analyzed from ambulatory ECG recordings.
- Specialized exercise protocols to raise and fix heart rate are not necessary, as the data stationarity requirements are considerably less than with spectral methods. As a result, MMA analysis can be performed during standard symptom-limited exercise protocols in the flow of routine clinical assessment.
- Transient, physiologically significant surges in TWA can be detected as a result of MMA’s rapid computational dynamics.
- ECG morphology is retained and TWA templates are generated in the time domain to permit overreading of the waveforms.
- The indeterminate rate for MMA-based TWA analysis is low (3–5 percent).
- TWA level is stated in terms of microvolts with reference to specific recommended cutpoints.
MMA’s QRS-Aligned TWA Templates Facilitate Overreading and Verification
A unique design feature of the MMA method is the generation and display of high-resolution QRS-aligned templates of superimposed ECG complexes, which are available for analysis of both ambulatory ECGs and exercise stress test ECGs (Figure 3).
These templates permit the operator to inspect the ECGs and to verify the TWA pattern and its magnitude, validating the automated analyses.
Classification of MMA-Based TWA Test Results
TWA represents a continuum of risk, and higher levels indicate greater risk. With the recommended update factor of one-eighth, TWA levels greater than 60 μV during routine exercise testing and ambulatory ECG monitoring indicate severely elevated risk for sudden cardiac death and/or cardiovascular mortality. In patients during the early post-MI phase with or without heart failure, a TWA level greater than 47 μV also predicted sudden cardiac death. Each 20 μV of TWA increases risk of cardiovascular and sudden cardiac death by 55 and 58 percent, respectively.
Quantitative assessment of the level of TWA, which is standard for MMA analysis, may add to its prognostic accuracy beyond qualitative categorization of a test as “positive,” “negative,” or “indeterminate.” For many clinical measures, such as blood pressure, cholesterol levels, LVEF, and others, knowing an individual patient’s values within a range can be important in evaluating urgency of intervention and effectiveness of therapy. Essentially, quantification of TWA level by MMA enables this technology to fulfill the contemporary need to develop methods for personalized medical care.
Evidence Supporting the Predictive Capacity of MMA-Based T-Wave Alternans Analysis
Predictivity by the MMA method has been demonstrated in more than 4,800 patients, including those with coronary artery disease, recent or old MI, congestive heart failure, or cardiomyopathy. Sudden cardiac death was witnessed or judged by physician review or an events committee. In the FINnish CArdioVAscular Study (FINCAVAS), the largest investigation of TWA to date, TWA predicted sudden cardiac death and cardiovascular and total mortality in a general population of nearly 3,600 low-risk patients referred for routine, symptom-limited exercise testing. MMA-based TWA is also predictive when monitored during immediate post-exercise recovery3 or from ambulatory ECG recordings,4 when it reflects the influences of daily activity, mental stress, sleep states, and sleep apnea. For a detailed summary of the MMA studies, see Table 2 in the TWA Consensus Guideline published in JACC.1
Role of TWA in Guiding ICD Therapy
The consensus guideline reported on important areas for further investigation. Foremost is the need for interventional trials to test the utility of TWA to guide ICD implantation. Recently, the Spectral Method exhibited limited capacity to identify patients who received appropriate ICD therapy. Specifically, in the Microvolt T Wave Alternans Testing for Risk Stratification of Post-MI Patients (MASTER) trial and TWA substudy of Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), TWA did not predict appropriate ICD therapy, sudden cardiac death, and/or ventricular tachycardia/fibrillation. As discussed in the TWA Consensus Guideline, there are plausible explanations for this departure from the confirmatory results of most prospective studies. Specifically, withdrawal of beta-adrenergic blockade before TWA testing diminishes its predictive strength by nearly four-fold.
By contrast, the Alternans Before Cardioverter Defibrillator (ABCD) trial provided evidence that TWA testing is comparable to electrophysiologic study in guiding ICD implantation and that the two methods are complementary.
The ongoing REFINE-ICD (Risk Estimation Following Infarction Noninvasive Evaluation - ICD Efficacy) trial is designed to shed further light on MMA’s potential to stratify mortality risk. REFINE-ICD is an ongoing randomized trial of ICD implantation versus usual care in patients with recent MI and LVEF between 36 and 49 percent. The MMA method will be used to assess TWA on ambulatory ECGs during 24 hours and a six-minute walk test. Autonomic activity will be assessed by heart rate turbulence.
Role of TWA in Evaluating the Effects of Medical Therapy
Withdrawal of medications, such as beta-blockade therapy, before the TWA test, can impact negatively on its predictivity. Thus, it is recommended that TWA testing be performed during chronic medical therapy. Many TWA studies have been conducted while patients were taking standard medical therapy, including all four classes of antiarrhythmic agents as well as angiotensin-converting enzyme inhibitors and angiotensin II receptor blocking agents. Thus, medications do not interfere with TWA’s predictive capacity although they alter TWA level. An important corollary is that TWA can detect the antiarrhythmic effect of a wide variety of medications.5 Specifically, beta-blockers can convert a positive TWA test to a negative test in about 50 percent of cases. This reduction in TWA level by beta-blockade is consistent with its known capacity to reduce incidence of sudden cardiac death.
The adverse, proarrhythmic effects of both cardiac and noncardiac agents can be detected by an increase in TWA level.5 Drug-induced Torsade de Pointes elicited by a variety of agents including amiodarone, almokalant, and erythromycin and other antibacterials may be preceded by high levels of TWA, indicating an adverse reaction.
Collectively, this evidence suggests that TWA is a promising marker for anti- and pro-arrhythmic effects of therapeutic agents. However, randomized clinical trials will be required to establish this point with certainty.
TWA’s Clinical Utility: Conclusions
Overall, the current evidence indicates that microvolt TWA testing is potentially of clinical value, whether it is performed using the Spectral or Modified Moving Average methods. The data reviewed in the TWA Consensus Guideline clearly demonstrate that patients with higher TWA levels carry 2- to 23-fold greater risk of serious outcomes as compared with individuals with lower TWA levels. Elevated TWA provides risk information independent of LVEF, standard clinical variables (e.g., age and sex) and important cardiovascular risk markers (e.g., smoking, diabetes, hypertension, and medications).
Cardiac arrhythmia risk assessment with TWA should not be a solely automatic process devoid of clinical judgment. TWA test results provide additional information that contributes to the overall assessment of risk and should be viewed in the context of the patients’ clinical history and other clinical indicators. The appropriate course of action should be based on the physician’s clinical judgment.
Availability of MMA Software for TWA analysis
MMA software is available as an option or upgrade on the CASE exercise testing and MARS Holter analysis systems produced by GE Healthcare. It leverages the same user interfaces that are employed to view standard ST-segment analysis and offers immediate, visual assessment of TWA level. Trend plots and superimposed beats are reviewable using the full disclosure function.
- Verrier RL, Klingenheben T, Malik M, et al. Microvolt T-wave alternans physiological basis, methods of measurement, and clinical utility — Consensus guideline by International Society for Holter and Noninvasive Electrocardiology. J Am Coll Cardiol 2011;58:1309–1324.
- Nearing BD, Verrier RL. Modified moving average method for T-wave alternans analysis with high accuracy to predict ventricular fibrillation. J Appl Physiol 2002;92:541–549.
- Slawnych MP, Nieminen T, Kahonen M, et al. Post-exercise assessment of cardiac repolarization alternans in patients with coronary artery disease using the modified moving average method. J Am Coll Cardiol 2009;53:1130–1137.
- Sakaki K, Ikeda T, Miwa Y, et al. Time-domain T-wave alternans measured from Holter electrocardiograms predicts cardiac mortality in patients with left ventricular dysfunction: A prospective study. Heart Rhythm 2009;6:332–337.
- Verrier RL, Nieminen T. T-wave alternans as a therapeutic marker for antiarrhythmic agents. J Cardiovasc Pharmacol 2010;55:544–554.