EDITORIAL COMMENT
Microvolt T-Wave Alternans for Arrhythmia Risk Stratification in Left Ventricular DysfunctionWhich Patients Benefit?*
Thomas Klingenheben, MD*
Cardiology Practice Bonn, Bonn, Germany; and the J. W. Goethe University, Frankfurt, Germany.
* Reprint requests and correspondence: Dr. Thomas Klingenheben, Assistant Professor of Medicine, Praxis für Kardiologie, Im Mühlenbach 2 B, D-53127 Bonn, Germany. (Email: klingenheben{at}bonn-kardiologie.de).
Patients with left ventricular (LV) dysfunction are at high risk of malignant ventricular tachyarrhythmias and may thus benefit from prophylactic placement of an implantable cardioverter-defibrillator (ICD). Several randomized trials have shown that in patients with severely depressed LV function and heart failure, primary preventive ICD therapy is effective in the setting of both ischemic (1,2) and nonischemic heart disease (2,3). However, the number of patients to be treated with an ICD to save 1 life is relatively high, indicating a low therapeutic efficacy if patient selection is based solely on LV function, which calls for further refinement of arrhythmia risk stratification in these patient populations.
Microvolt-level T-wave alternans (MTWA) has recently undergone extensive study in patients with congestive heart failure or LV dysfunction (4–10) and has been shown to be predictive of ventricular arrhythmic events in various patient populations (11). In particular, many studies have focused on patients without a prior history of ventricular tachyarrhythmic events, such as patients fulfilling clinical criteria of the population included in the MADIT (Multicenter Automatic Defibrillator Implantation Trial)-II trial (7–10). In such "MADIT-II–type" patients, a non-negative (i.e., positive or "indeterminate") test is associated with a high risk of arrhythmic mortality (9). For example, one recent study demonstrated that ICD therapy was associated with a mortality benefit only in MTWA–non-negative, but not in MTWA-negative, patients (10). Accordingly, a negative MTWA test can identify patients who may not benefit from prophylactic ICD insertion (7,8). Similar findings were reported for patients with left ventricular dysfunction from any cause who had no history of ventricular tachyarrhythmias. In a study by Bloomfield et al. (6), 549 patients with LV dysfunction underwent MTWA assessment with total mortality and nonfatal sustained ventricular arrhythmias being the primary end point. Left ventricular ejection fraction (LVEF) averaged 25 ± 6%, and one-half of the patients had ischemic cardiomyopathy. Over a follow-up period of 20 ± 6 months, a primary end point event occurred in 15% of patients with an abnormal (i.e., positive or "indeterminate") MTWA test. The negative predictive value of MTWA at 2 years was 97.5%. The authors concluded that, in this population, MTWA can identify a low-risk group unlikely to benefit from prophylactic ICD therapy (6).
The study by Cantillon et al. (12) in this issue of the Journal adds to the understanding of arrhythmia risk assessment in patients with LV dysfunction. From a population of patients referred for evaluation of syncope, nonsustained ventricular tachycardia (NSVT), or both, the authors identified patients with LV dysfunction (defined as LVEF  35%), of whom 76% had ischemic heart disease. Mean LVEF averaged 26 ± 7%, and 84% of patients had New York Heart Association functional class II or III heart failure. Patients underwent electrophysiologic testing (EPS), and MTWA assessment was performed during the same procedure, i.e., with the use of atrial pacing in order to increase heart rate. Patients were followed for 38 ± 11 months. Sixty-nine percent of patients tested MTWA–non-negative. On multivariate analysis, MTWA was a significant predictor of the primary end point, with a hazard ratio of 2.37, whereas EPS was a less effective predictor of arrhythmia-free survival and all-cause mortality. The MTWA-negative patients had improved 2-year arrhythmia-free survival compared with MTWA–non-negative patients (81% vs. 66%; p < 0.0001) (12). In patients with ischemic heart disease, the arrhythmia-free survival in MTWA negative patients was 79% and thus much lower than in previously published studies in patients with ischemic cardiomyopathy (6–8). Because all patients underwent EPS, the investigators also had the opportunity to elucidate its role in relation to MTWA testing. They did not find a significant agreement between the 2 methods: The proportion of patients with concordant and discordant results between EPS and MTWA was comparable. Also, if patients with ischemic and nonischemic LV dysfunction were analyzed separately, there was no strong agreement between MTWA and EPS in either group. However, combining the 2 tests added to the overall negative predictive value, which was 85% over 2 years if patients tested negative during both EPS and MTWA assessment (12).
At first glance, the results of this study are in contrast to earlier studies of MTWA in patients with congestive heart failure or LV dysfunction, particularly with respect to the negative predictive value of MTWA (4–8). The present study included patients referred for evaluation of syncope and/or NSVT, thus representing a higher-risk population in whom a higher ventricular tachyarrhythmic event rate can be assumed. In particular, 16% of the patients had suffered syncope before inclusion (12), which in the setting of LV dysfunction may be due to sustained ventricular tachyarrhythmias. The present study population therefore differs from a "pure" primary prevention cohort.
The mode of MTWA testing represents a potential limitation of the present study: MTWA was assessed invasively using atrial pacing, whereas in the earlier studies MTWA was assessed noninvasively using exercise-induced heart rate increase. Results of a recent study suggested that the predictive accuracy of invasive MTWA assessment may be inferior to the noninvasive approach although their negative predictive value seem to be similar (13).
Furthermore, the comparison of MTWA and EPS in the present study is hampered by the inhomogeneity of the patient population. It is known that EPS yields different predictive efficacy in ischemic and nonischemic heart disease. In the recently presented ABCD (Alternans Before Cardioverter-Defibrillator) trial (14), MTWA and EPS were studied in patients with ischemic cardiomyopathy, LVEF 40%, NSVT, and no prior ventricular tachyarrhythmic events. In that study, both tests were equivalent in predicting appropriate ICD shocks or arrhythmic death, and their negative predictive values were 95%, rising to 98% if both tests were combined (14).
Which patients may benefit from MTWA-guided antiarrhythmic therapy? In summary, the study of Cantillon et al. (12) extends our knowledge about the use of MTWA in patients with LV dysfunction and additional risk profiles (NSVT or syncope). In that population, MTWA alone may not be sufficiently effective to select patients to benefit (or not) from prophylactic ICD therapy. Putting the currently available studies of MTWA in LV dysfunction in perspective, it can be concluded that the predictive efficacy of the test is largely dependent on the patient population studied. Because the pretest probability of a ventricular tachyarrhythmic event differs according to the underlying pathology of LV dysfunction and to the presence or absence of additional clinical risk features, recommendations on the use of MTWA should be based on interventional trials in well defined patient populations. Such studies are currently underway (15–17) and may help to define the role of MTWA in a strategy of cost-effective primary preventive ICD therapy.
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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