T wave alternans

Editors-In-Chief: Richard L. Verrier, PhD, FACC, and Tuomo Nieminen, MD, PhD

Assistant Editors-in-Chief: Jose Roberto Pegler and Caio Tavares, Medical Students, University of São Paulo, Brazil, in research program at Beth Israel Deaconess Medical Center

Overview
T-wave alternans is a beat-to-beat alternation in the repolarization cycle of the heartbeat. It can be observed in the electrocardiogram (ECG) as a difference in the amplitude and morphology of the ST-segment and/or the T wave among successive odd and even beats in an ABAB pattern (Figure).

(Reprinted with permission from John Wiley & Sons, Inc., from Minkkinen et al, “Enhanced predictive power of quantitative TWA during routine exercise testing in the Finnish Cardiovascular Study,” published in J Cardiovasc Electrophysiol 2009; 20: 408-415.)(1)

Interest is focused on this phenomenon because of its promise in identifying individuals with elevated risk for lethal heart rhythm disturbances and sudden cardiac death, the leading cause of death in the industrially developed world. The video of the ABAB pattern of TWA heralds the onset of ventricular fibrillation during myocardial ischemia. The arrhythmia was successfully terminated by defibrillation countershock.



History of T Wave Alternans
Hering, in 1908, was the first to observe and describe visible macroscopic TWA and its association with increased susceptibility to ventricular tachyarrhythmias.(2) The advent of digital signal processing techniques allowed identification and measurement of nonvisible levels of TWA.

Influence of Physiological Interventions on TWA
TWA is a reflection of spatial gradients in repolarization among neighboring myocardial regions, provoking heterogeneity of repolarization.(3) Its occurrence indicates that the myocardial substrate is altered by pathophysiological processes or pharmacologic agents. At a cellular level, impaired calcium cycling (4) and action potential duration restitution (5,6) are implicated.

TWA magnitude is amplified in parallel with elevated risk of arrhythmias caused by increased heart rate, coronary artery occlusion and reperfusion,(7-9) sympathetic nerve stimulation,(7) mental stress in patients with implantable cardioverter defibrillators (ICDs),(10) and proarrhythmic agents.(11) Heart rate is not the sole determinant of TWA, as raising heart rate by fixed rate pacing does not induce the same levels of TWA as imposing adrenergic factors or myocardial ischemia to reach the same heart rate.(12)  Vagus nerve stimulation, pharmacologic blockade of beta-adrenergic receptors,(13) sodium channels,(14, 15) or the angiotensin II receptor,(16) sympathetic denervation,(7) and spinal cord stimulation (17) decrease TWA levels and reduce risk of arrhythmia.

Microvolt TWA and Test Methods
In the 1980’s, Drs. Richard J. Cohen, Joseph M. Smith, David S. Rosenbaum, and colleagues at Massachusetts Institute of Technology and Massachusetts General Hospital (18, 19) and Drs. Richard L. Verrier and Bruce D. Nearing at Georgetown University School of Medicine and later at Beth Israel Deaconess Medical Center, Harvard Medical School,(7-9) applied signal processing techniques to detect visually indiscernible levels of TWA and established that at a microvolt level, TWA discloses risk for lethal cardiac arrhythmias and sudden cardiac death. TWA monitoring can provide valuable information to support overall decision-making to implant an ICD.(20) Recently, Verrier and Nieminen reviewed the body of evidence that indicates the potential value of TWA in guiding medical therapy and detecting risk for proarrhythmia.(11)

Two techniques for TWA analysis currently cleared by the United States Food and Drug Administration for risk stratification for arrhythmic death are the Spectral Method, which emanated from Dr. Cohen’s laboratory and is commercialized by Cambridge Heart, Inc. and Cardiac Sciences, Inc. and the Modified Moving Average method, which resulted from Drs. Verrier and Nearing’s collaboration and is commercialized by GE Healthcare, Inc. and in Europe by Getemed AG.

Spectral Method (SM)
The Fast Fourier Transform is employed to analyze 128 consecutive beats from the J-point to the end of the T wave and produces a power spectrum at 0.5 cycle/beat (on every other beat), which is defined as the alternans power. Since the Spectral Method requires a graded heart-rate increase to a target heart rate, it is usually performed during bicycle ergometry or treadmill exercise. Specialized electrodes are required for noise reduction.

Interpreting Results of Spectral Method
If the TWA level calculated by the Spectral Method exceeds 1.9µV, then the test is considered positive.(21) These patients should be referred to a cardiac electrophysiologist for further evaluation. Results below 1.9µV are interpreted as negative. Several prospective studies have demonstrated that a negative TWA test result with the Spectral Method confirms a low level of risk for an arrhythmic episode, since the test displays a negative predictive value ≥97%,(20, 22) indicating that a negative test correctly identifies ≥97% of patients with diminished risk of developing a lethal cardiac arrhythmia or sudden cardiac death during the next year to two years. Test results may be indeterminate for technical reasons (noise from muscle, respiration, or movement artifact) or because of patient factors (inability to reach a target heart rate of 105-110 beats/min, excessive ectopy, or nonsustained TWA). Indeterminate test results due to patient factors indicate a level of the risk that is equivalent to or greater than a positive test result,(23) and these patients should be immediately retested.

Prognostic Value of the Spectral Method
While the usefulness of the test has been demonstrated in patients with congestive heart failure, ischemic cardiomyopathy, or previous myocardial infarction, its utility in patients with nonischemic dilated cardiomyopathy, in the early post-myocardial infarction period, or in hereditary channelopathies remains unclear.(24)

Modified Moving Average (MMA) Method
This approach employs the noise-rejection principle of recursive averaging.(9) It was designed to allow TWA measurement during routine exercise stress testing and ambulatory ECG monitoring, as it circumvents the requirement of heart-rate stabilization and uses standard precordial leads. The algorithm continuously streams odd and even beats into separate bins and creates median complexes for each bin. The complexes are then superimposed and the peak difference between the odd and even median complexes at any point from the J point to the end of the T wave is defined as the TWA value and is updated every 10 to 15 seconds. The influence of new incoming beats is controlled through use of an adjustable update factor; the sensitive 1/8 update factor is recommended. Artifacts due to respiration and motion are reduced by software.

The MMA method reports TWA values in microvolts and presents high-resolution templates of superimposed beats to display the alternation pattern and permit visual overreading to verify the automated TWA measurement. Watch the video "TWA Analysis in Ambulatory ECG recording - Tutorial" to learn how to analyze TWA using the Modified Moving Average (MMA) Method. Click [[Media:Excel_Model_for_TWA_analysis.xls|here‎]] to obtain the excel file with the formulas mentioned in the video. For more details, see the following from GE Healthcare, Inc.



Interpreting Results of Modified Moving Average Method
Higher TWA values indicate greater risk along a continuum. TWA ≥20µV indicates elevated risk and is particularly useful in combination with other noninvasive markers.(1, 25, 26) TWA ≥46µV as a single cutpoint indicates significantly increased risk.(27-29)  Higher optimized values ≥65µV are associated with higher levels of risk, reported in terms of hazard ratios.(28, 30)

Prognostic Value of Modified Moving Average Method
Predictive accuracy of the MMA method for arrhythmic death and cardiovascular mortality has been demonstrated in a population referred for a clinically indicated exercise test (1, 26, 28, 31, 32) and in patients with coronary artery disease,(25, 33) recent or old myocardial infarction,(27, 34) congestive heart failure,(29) and ischemic and nonischemic cardiomyopathy.(30) The largest investigation of MMA-based TWA is the Finnish Cardiovascular Study (FINCAVAS), which enrolled generally low-risk patients who were referred for routine, symptom-limited exercise testing.(1, 26, 28, 31, 32)  The MMA technique is also compatible with ambulatory ECG monitoring,(27, 29, 30, 34) atrial pacing, ECG monitoring of immediate post-exercise recovery,(25, 26, 32, 33) and by implantable devices including ICDs.

Comparison of Spectral and Modified Moving Average Methods
TWA values reported by MMA are typically 4- to 10-fold higher than Spectral Method test results. This difference is mainly attributable to the fact that the Spectral Method reports the average TWA level across the entire JT segment for 128 beats, whereas the MMA method reports the peak TWA value for each 15 seconds at any point within the JT interval.

Spectral and MMA analyses have been found in prospective investigations to exhibit similar hazard ratios for predicting sudden cardiac death and cardiovascular mortality when tested in the same population of post-MI patients with better-preserved left ventricular ejection fraction,(25) in matched populations,(30, 35) or in overall hazard ratios.(22, 24) A high negative predictive accuracy of ≥97% is found with both methods.

Clinical Significance
One proposed application of TWA testing has been to identify patients who would not benefit from implantation of an ICD,which rescues patients from a lethal arrhythmia. The current guidelines for ICD implantation state that the main parameter to be analyzed is left ventricular ejection fraction, a measure that does not reveal direct information about the electrical substrate of the heart. Interventional trials have not demonstrated that TWA test results are sufficiently accurate for denying ICD implantation to an otherwise suitable candidate patient,(36-38) as TWA did not predict appropriate ICD discharge in the MASTER trial (37) or in the TWA substudy of SCD-HeFT trial.(38) However, it is well-recognized that ICD discharge may not be an appropriate surrogate endpoint for sudden cardiac death.

A second proposed application of TWA testing is in guiding medical therapy, since many agents that have been shown to reduce incidence of arrhythmias, sudden cardiac death, or cardiovascular mortality also diminish TWA magnitude clinically.(11) These include agents that block beta-adrenergic receptors (13, 39, 40) and angiotensin II receptors.(16, 41)  Proarrhythmic effects of cardiovascular and noncardiovascular agents are also indicated by TWA.(11)  Thus, drug-induced changes in TWA magnitude may provide an indication of therapeutic efficacy on an individual patient basis.

Frontiers of TWA testing include improvement in prediction based on quantification of TWA magnitude, risk stratification among patients with preserved ejection fraction, the patient group with the highest number of sudden cardiac deaths, and combined use with other noninvasive risk markers to optimize identification of patients whose risk for lethal arrhythmias and sudden cardiac death is elevated. The potential combination parameters include heart rate turbulence,(25, 42) heart rate recovery,(26, 43) or exercise capacity.(32, 44)

Reimbursement for T-Wave Alternans Testing
The 2006 decision summary from the U.S. Center for Medicare and Medicaid Services regarding reimbursement for T-wave alternans testing (CAG-00293N) states: “CMS has determined that there is sufficient evidence to conclude that Microvolt T-wave Alternans (MTWA) diagnostic testing is reasonable and necessary for the evaluation of patients at risk of sudden cardiac death, only when the spectral analytic method is used, and CMS is issuing the following national coverage determination (NCD) for this indication. Microvolt T-wave Alternans (MTWA) diagnostic testing is covered for the evaluation of patients at risk of sudden cardiac death, only when the spectral analytic method is used.” Potential reimbursement for the Modified Moving Average method will be under consideration shortly.

References

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