T wave alternans for risk stratification during exercise stress testing
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

# Overview
Across the past decade, a sizeable body of evidence has been amassed indicating that measurement of T wave alternans (TWA), a beat-to-beat fluctuation in the morphology of the T wave, during exercise is useful in assessing risk for life-threatening arrhythmias.
TWA is a marker of repolarization instability and an indicator of a vulnerable myocardial substrate.  This electrocardiographic phenomenon parallels the beat-to-beat oscillation of action potential duration (APD) at the level of cardiac myocytes. The cellular mechanism has been linked primarily to an aberration in intracellular calcium, which results in fluctuation of calcium transients from one beat to the next. This oscillation in APD can be solely a temporal event (concordant alternans) or both a temporal and spatial occurrence (discordant alternans). Discordant alternans has the potential to create steep repolarization gradients leading to transient unidirectional block, a pre-requisite for reentrant arrhythmias  
Until recently, TWA analysis has largely involved frequency-domain based spectral analysis.  The spectral method (SM) requires provocative testing to raise and plateau the heart rate. The level of TWA detected is in the range of a few microvolts and thus cannot be observed by visual inspection. SM is the first and most widely studied commercially available algorithm (Cambridge Heart, Inc.). It employs a fast Fourier transformation of the electrocardiogram (ECG) across 128 consecutive beats into the frequency domain and employs specialized electrodes to minimize noise. The power of the spectrum at 0.5 cycle per beat (occurring on every other beat) between the JT segment is defined as the alternans power. An alternans level (Valt) >1.9 V, greater than 3 times the standard deviation of noise (k score), and sustained for at least one minute at stable heart rates 105 bpm without significant noise or premature beats. Tests that do not strictly meet the positive or negative test definitions are referred to as indeterminate  and occur in 20 to 40% of all cases. Most recent studies using SM have grouped positive and indeterminate tests together as abnormal or non-negative, since the risk of death or sustained ventricular arrhythmias in patients with indeterminate tests due to patient factors is as high as that of patients with positive tests. 
A recently developed, FDA cleared commercial method (GE Healthcare, Inc.) is time domain modified moving average (MMA) developed at Beth Israel Deaconess Medical Center (Nearing and Verrier 2002). This technique was developed to circumvent the stationarity requirements of SM, which mandates stabilization of heart rate for several minutes given the fast Fourier transform. The requirement for specialized electrodes is also eliminated through the use of advanced noise reduction algorithms. The MMA method separates odd and even beats into separate bins and creates median templates for both the odd and even complexes every 15 seconds.  These templates are then superimposed and the entire JT segment is analyzed for alternation. The peak difference between the odd and even median complexes at any point within the JT segment is defined as the TWA value. These templates of superimposed complexes may be examined visually to verify TWA presence and magnitude. Noise measurements are in part derived from mismatch of the median templates outside of the JT segment. The moving average allows control of the influence of new incoming complexes on the median templates with an adjustable update factor.  A lower update factor provides greater sensitivity in detecting transient surges in TWA.
Results from SM and MMA are highly comparable, although the TWA values reported with the MMA algorithm are consistently larger by a factor of 4 to 10. This difference is mainly attributable to the fact that SM reports the average TWA level across the entire JT segment for 128 beats that is above the noise level, while MMA method reports the peak TWA level at any point within the JT segment for each 15-second beat stream, with the noise level reported separately.
The majority of clinical studies focusing on TWA as a risk stratification tool have enrolled CAD patients with EF 40% and employed the SM.  In 2005, Gehi and colleagues  conducted a meta-analysis of 19 prospective studies of exercise-based TWA testing with SM that enrolled a total of 2608 patients. The majority of these patients had CAD, and half had depressed EF, but only a small percentage had a history of ventricular arrhythmias. Positive TWA test results conveyed an average 3.77-fold risk of future ventricular tachyarrhythmic events when compared to patients with negative TWA test results. The negative predictive value (NPV) of TWA was 97.2%. However, its positive predictive value (PPV) was quite poor, generally <30% for all subgroups.
By virtue of its excellent NPV, TWA testing has been presented as a means of identifying those patients who are least likely to experience a future ventricular tachyarrhythmic event and thus least likely to benefit from ICD implantation.
Only one large prospective observational trial has investigated TWA in a broader population. The incidence of SCD in this subgroup of patients, however, is relatively low; rendering it even more difficult to identify those most likely to benefit from ICD implantation even though the absolute number of SCD events is higher in this population than in those with depressed EF.   Nieminen and coworkers (2007) provided evidence that TWA is also suitable as a screening tool in the general population of patients with preserved ejection fraction and can be performed during routine exercise stress testing. They applied the MMA method in 1037 consecutive patients referred for exercise testing and reported that TWA 65V recorded in the precordial leads predicted all-cause death (RR= 3.3), cardiovascular mortality (RR=6.0), and sudden cardiac death (RR=7.4) across the 44 7 month follow-up. The analysis window was restricted to heart rates 125 beats/min in order to minimize the effects of noise.
Most recently, the REFINE study  enrolled 322 post-MI patients with ejection fraction 50% and measured TWA at 10 to 14 weeks. Spectral analysis was performed during the specialized exercise protocol, and MMA was employed during post-exercise recovery. Exner and colleagues (2007) determined that the predictivity of the spectral and MMA methods for TWA analysis is similar, with hazard ratios in the range of 2.75-2.94 for cardiac death or arrest during 47 months following the index event. Combining the TWA test results with heart rate turbulence, a noninvasive marker of autonomic tone, accurately predicted risk of cardiac death or arrest with a hazard ratio of 5.2 and identified the majority of patients destined to suffer serious events.
Collectively, sound scientific and clinical evidence support the utility of TWA testing for sudden death risk stratification during exercise. With the advent of time-domain based TWA analysis, this measurement can be performed seamlessly during the course of routine clinical exercise stress testing as well as ambulatory ECG monitoring. While TWA testing has been focused largely on guiding ICD implantation for primary prevention, there may be a greater role for TWA analysis in screening the broader, low-risk population and for evaluating the effectiveness of medical therapy.
Since sudden cardiac death results from diverse pathologic mechanisms, involving derangements in myocardial substrate and altered autonomic function, it is unlikely that any single parameter will adequately represent the complex factors that lead to lethal ventricular arrhythmias. Therefore, it will be valuable to examine whether combinations of several risk stratification parameters may be more effective than any individual parameter as observed in the REFINE study.