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Editors-In-Chief: Richard L. Verrier, PhD, FACC, FHRS, and Tuomo Nieminen, MD, PhD; Assistant Editors-in-Chief: Jose Roberto Pegler, MD, and Caio Tavares, MD.

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).

T Wave Alternans

(Reprinted with permission from John Wiley & Sons, Inc., from [1]) This patient's peak TWA level was 124 microvolts, indicating severely abnormal risk. He died 12 months later of cardiovascular causes.

Interest is focused on this phenomenon because of its utility 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. In the video, the ABAB pattern of TWA heralds the onset of ventricular fibrillation during myocardial ischemia. The arrhythmia was successfully terminated by defibrillation countershock.

{{#ev:youtube|ZSJB3sB5Oi0}}

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.

Causes

The integrated physiology and cellular basis for the T-wave alternans phenomenon has been extensively discussed. [3][4][5][6][7][8]

Clinical Utility

T-wave alternans predicts arrhythmia, sudden cardiac death, or cardiovascular or total mortality in these patient groups:

T-wave alternans is associated with ventricular arrhythmias in these patient groups:

T-wave alternans has also been observed in these conditions


Antiarrhythmic Interventions Reduce TWA Level Allowing TWA to Serve as a Therapeutic Target

Differentiating Electrical Alternans from other Disorders

The electrical form of alternans should be differentiated from mechanical alternans, which exhibits alternation of the strength of the pulse as is observed in pulsus alternans. Electrical and mechanical alternans may coexist.

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 [88] [89] 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, [90] [91] 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.

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 was commercialized by Cambridge Heart, Inc. and Cambridge Cardiac Technologies; 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.[92] 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% [93] [94] 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 a positive test result[95] and these patients should be immediately retested.

Prognostic Value of the Spectral Method

Over 8000 subjects have been enrolled in Spectral Method studies that predicted outcomes, including the ALPHA study [96] and the ABCD study.[97] An additional 3145 (28% of total) subjects were enrolled in Spectral Method studies that did not predict outcomes, including the SCD-HeFT TWA substudy,[98] the MASTER study,[99] and the CARISMA study. [100] Withdrawal of beta-blockade to allow patients to attain the 105-110 beats/min target heart rate with its resumption after the test have been implicated in failure of these studies.[101]

Modified Moving Average (MMA) Method

This approach employs the noise-rejection principle of recursive averaging.[102] It was designed to allow TWA measurement during routine, symptom limited exercise stress testing and ambulatory ECG monitoring, as it circumvents the requirement to stabilize heart rate. It uses standard electrodes at precordial sites. Chronic medications are maintained. Thus, TWA testing with the MMA method can be performed in the flow of clinical evaluation. Specifically, 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 the TWA level; this determination is updated every 10 to 15 seconds. The influence of new incoming beats is controlled by an adjustable update factor; the sensitive 1/8 update factor is recommended. Artifacts due to respiration and motion are reduced by software. High-resolution templates of superimposed beats 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

here‎

to obtain the excel file with the formulas mentioned in the video. For more details, see the following from GE Healthcare, Inc.

{{#ev:youtube|-oC3GLoFXFo}}

Interpreting Results of Modified Moving Average Method

Higher TWA values indicate greater risk for sudden cardiac death and cardiovascular and total mortality along a continuum.[103] TWA <20µV indicates no increased risk, while TWA ≥47µV and ≥60µV are associated with abnormal and severely abnormal risk, respectively.[104] Quantification allows physicians to track disease progression as well as patients' response to medications and to cardiac rehabilitation. Fewer than 3% of MMA-based TWA tests are indeterminate.

Prognostic Value of Modified Moving Average Method

The MMA method has been endorsed by the International Society for Holter and Noninvasive Electrocardiology.

Over 5000 patients have been enrolled in MMA studies. The largest investigation of TWA by any method is the Finnish Cardiovascular Study (FINCAVAS), which enrolled >3500 generally low-risk patients who were referred for routine, symptom-limited exercise testing.[105] Approximately 1500 patients were studied during ambulatory ECG monitoring.[106] All MMA-based TWA studies have predicted outcomes. A trial of MTWA-guided ICD implantation by the MMA method, REFINE-ICD (NCT00673842), is underway.[107]

Comparison of Spectral and Modified Moving Average Methods

The MTWA consensus guideline, authored by 11 international experts in both methods, compared the methods and their utility in risk assessment [108] and established that hazard ratios for sudden cardiac death and cardiovascular mortality in all prospective studies were similar. A head-to-head prospective comparison of the Spectral and MMA methods in >300 post-myocardial infarction patients revealed similar hazard ratios, kappa statistics, and areas under the receiver-operator characteristic curve.[109]

The U.S. FDA has determined that both the Spectral and MMA methods achieve 1-microvolt resolution.

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.

Clinical Significance

MTWA testing has been recommended for arrhythmia risk assessment by the American College of Cardiology, American Heart Association and European Society of Cardiology [110] and by CMS in National Coverage Analysis for Implantable Cardioverter Defibrillators (CAG-00157N).

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 parameter that does not directly reveal information about the electrical substrate of the heart.

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. Thus, drug-induced changes in TWA magnitude may provide an indication of therapeutic efficacy on an individual patient basis.

Frontiers of TWA testing include 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.

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.”

A 2015 CMS decision memo regarding the MMA method for MTWA analysis (CAG-00293R2) states: “The Centers for Medicare & Medicaid Services has decided that no National Coverage Determination (NCD) is appropriate at this time for microvolt T-wave alternans (MTWA) testing using the modified moving average (MMA) method for the evaluation of patients at risk for sudden cardiac death (SCD). National non-coverage will be removed. Medicare coverage of MTWA using the MMA method will be determined by the local contractors.”

Both methods use CPT code 93025.

References

  1. ↑ 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.
  2. ↑ Hering HE. Das Wesen des Herzalternans. Muenchener Med Wochenschr 1908; 4:1417-1421.
  3. ↑ Narayan SM. T-wave alternans and the susceptibility to ventricular arrhythmias. J Am Coll Cardiol 2006;47:269–81.
  4. ↑ Cutler MJ, Rosenbaum DS. Explaining the clinical manifestations of T-wave alternans in patients at risk for sudden cardiac death. Heart Rhythm 2009;6:S22–8.
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  9. ↑ Alexander ME, Cecchin F, Huang KP, Berul CI. Microvolt T-wave alternans with exercise in pediatrics and congenital heart disease: limitations and predictive value. Pacing Clin Electrophysiol 2006;29: 733–41.
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  73. ↑ Verrier RL, Nieminen T. T-wave alternans as a therapeutic marker for antiarrhythmic agents. J Cardiovasc Pharmacol 2010; 55(6):544-554
  74. ↑ Schomer AC, Nearing BD, Schachter SC, Verrier RL. Vagus nerve stimulation reduces cardiac electrical instability assessed by quantitative T-wave alternans analysis in patients with drug-resistant focal epilepsy. Epilepsia 2014; 55:1996–2002.
  75. ↑ Ferrero P, Castagno D, Massa R, et al. Spinal cord stimulation affects T-wave alternans in patients with ischaemic cardiomyopathy: a pilot study. Europace 2008;10:506–8.
  76. ↑ Klingenheben T, Gronefeld G, Li YG, Hohnloser SH. Effect of metoprolol and d,l-sotalol on microvolt-level T-wave alternans. Results of a prospective, double-blind, randomized study. J Am Coll Cardiol 2001; 38:2013-9.
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  81. ↑ Chan PS, Gold MR, Nallamothu BK. Do beta-blockers impact microvolt T-wave alternans testing in patients at risk for ventricular arrhythmias? A meta-analysis. J Cardiovasc Electrophysiol 2010;21:1009–14.
  82. ↑ Kavesh NG, Shorofsky SR, Sarang SE, Gold MR. The effect of procainamide on T wave alternans. J Cardiovasc Electrophysiol 1999 May; 10:649-54.
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  101. ↑ Chan PS, Gold MR, Nallamothu BK. Do beta-blockers impact microvolt T-wave alternans testing in patients at risk for ventricular arrhythmias? A meta-analysis. J Cardiovasc Electrophysiol 2010;21: 1009–14.
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  105. ↑ Nieminen T, Lehtimäki T, Viik J, Lehtinen R, Nikus K, Kööbi T, Niemelä K, Turjanmaa V, Kaiser W, Huhtala H, Verrier RL, Huikuri H, Kähönen M. T-wave alternans predicts mortality in a population undergoing a clinically indicated exercise test. Eur Heart J 2007; 28:2332-37.
  106. ↑ Verrier RL, Malik M. Quantitative T-wave alternans analysis for guiding medical therapy: An underexploited opportunity. Trends in Cardiovascular Medicine 2015. http://dx.doi.org/10.1016/j.tcm.2014.10.006
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  110. ↑ Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006;48:e247–346 (see e401, e402).

External Links

  • Cambridge Heart Manufacturer of Microvolt T-wave Alternans Systems for the Spectral Method
  • GE Healthcare Manufacturer of Marquette MMA T-wave Alternans Stress Test and Holter Systems

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