T-Wave Alternans as a Prognostic Marker in
Patients Referred for Exercise Testing
Quantitative Analysis & Combined Assessment with Exercise Capacity & Heart Rate Recovery

By Mikko Minkkinen
January 20112
Tampere University Press
Distributed By Coronet Books
ISBN: 9789514486449
185 pages
$89.50 Paper original

T-wave alternans (TWA) is an electrocardiogram (ECG) phenomenon illustrating inhomogeneities in cardiac electrical repolarization. It can be measured from the surface ECG as microvolt-level beat-to-beat alternation in the shape, timing, or amplitude of the ST segment or T wave. TWA has been experimentally and clinically linked to ventricular tachyarrhythmias as well as to the related pathogenesis. Moreover, positive TWA testing has been shown to predict all-cause and cardiovascular mortality as well as sudden cardiac death (SCD) in diverse patient populations. The present study was designed to solve the methodological issues related to the prognostic power of TWA analysis, with quantitative TWA analysis in particular. Furthermore, the prognostic power of TWA in combination with exercise capacity and heart rate recovery (HRR), a marker of autonomic nervous system imbalance, were studied.

This study is part of the Finnish Cardiovascular Study (FINCAVAS), which enrolled 4,178 (2,537 men) consecutive patients attending an exercise stress test at Tampere University Hospital between October 2001 and the end of 2008 (Study IV). A sub-population of 2,212 (1,400 men) were recruited by the end of 2004 (Studies I, II, and III). A continuous digital ECG signal (500 Hz) was recorded during the entire exercise test from the pre-exercise to the post-exercise phase. The Modified Moving Average (MMA) analysis, which allows TWA analysis during a normal symptom-limited exercise test, was employed. Exercise capacity was assessed in the form of metabolic equivalents (METs) in a standard manner, and HRR was determined as the maximum heart rate minus the heart rate at 1 minute after the cessation of exercise. Hazard ratios for all-cause and cardiovascular mortality as well as SCD were estimated with Cox regression analysis.

During the median follow-up of 48 months (37–59 interquartile range [IQ]), there were 126 deaths, 62 cardiovascular deaths, and 33 SCDs in the sub-population (Studies I, II, and III). The overall follow-up time for the 3,609 patients investigated in Study IV was 57 months (35–78 IQ), during which 233 patients died—96 of these deaths were further categorized as cardiovascular deaths. Elevated TWA levels measured during the exercise phase were found to be independently associated with an increased risk of all-cause and cardiovascular mortality and SCD when grouped in increments of 10µV. All-cause and cardiovascular mortality, but not SCD, were also predicted when TWA was measured during the pre- or post-exercise phase (Study I). When analyzed as a continuous variable, increased TWA voltage was a significant predictor of all-cause (Study I) and cardiovascular mortality (Studies I and IV).

Poor exercise capacity (METs <8) was a strong predictor of SCD (hazard ratio of 8.8, 95% confidence interval [CI] 2.0–38.9, p=0.004). The risk was further increased when combined with heightened TWA (? 65µV; hazard ratio 36.1, 95% CI 6.3–206.0, p<0.001 in comparison to patients with neither factor; Study II). The combination of poor HRR (? 18 beat/min) and elevated TWA (? 60µV) yielded a hazard ratio of 12.3 (95% CI 4.3–35.3, p<0.01) for cardiovascular mortality when analyzed in comparison to patients with neither factor, with a C-index of 0.713 (95% CI 0.648–0.777; Study III). When all three prognostic markers—namely exercise capacity in METs, HRR, and TWA—were combined, the prognostic capacity of exercise testing increased further. The linear model that contained all three study parameters predicted cardiovascular mortality significantly better than the model without METs (p<0.001), HRR (p=0.002), or TWA (p=0.01). The hazard ratio of cardiovascular mortality for the combination of the three parameters with the previously reported cut-off points of <8 for METs, ?18 beats/min for HRR, and ?60 µV for TWA was 5.7 (95% CI 1.8–18.2, p=0.003) when compared to all other patients included in the study. The corresponding Harrell C-index was 0.719 (95% CI 0.665–0.772; Study IV).

Measuring TWA from surface ECG is inherently challenging, and the future will show whether this non-invasive TWA assessment can be incorporated into clinical use or whether, for example, TWA analysis based on cardiac implantable electric devices will break through.

Finally, the present study produces new information concerning the predictive capacity and characteristics of TWA in patients referred for exercise testing. The evidence derived from our study, together with information uncovered by experimental and clinical studies, clearly shows that elevated levels of TWA are pathophysiologically linked with increased risk for cardiovascular mortality. The study also demonstrates that poor exercise capacity predicts SCD in a population of patients referred for exercise testing.

Moreover, it shows that the combination of exercise capacity, HRR, and TWA enhances the prognostic capacity of exercise stress testing. These three parameters that can be measured during routine exercise testing offer an avenue for improving the risk stratification for cardiovascular mortality and SCD.


Acta Universitatis Tamperensis No. 1684

Return to Coronet Books main page