Recent advances in experimental and clinical electrophysiology have provided substantial evidence for a crucial role of repolarization abnormalities in arrhythmogenic conditions precipitating ventricular tachyarrhythmias. Early afterdepolarizations, beat-to-beat variability in diastolic time, and transmural heterogeneity of repolarization contribute to an arrhythmogenic cascade of ventricular tachyarrhythmias (1). Early afterdepolarizatons may arise from Purkinje fibers, but may also originate from M cells, which are particularly prone to exhibit selective prolongation and abnormalities of refractory periods. Transmural heterogeneity of repolarization, with action potentials in M cells longer than in endo- and epicardial cells, was demonstrated to facilitate the mechanism of reentry (1-3). Jhe same transmural heterogeneity of action potential duration and morphology was recently shown to underlie T-wave alternans, an ECG phenomenon consisting of 2:1 changes in ST-T-complex duration and morphology (4,5). T-wave alternans has been attributed to beat-to-beat changes in the kinetics of repolarizing ionic currents leading to varying degree of transmural heterogeneity (6). As shown in schematic Figure 1 (based on the recent NASPE presentation by Shimizu and Antzelevitch [4]), biphasic T-wave alternans is caused by the alternating "direction" of transmural heterogeneity. Odd alternating beats (negative T-waves) are caused by M cells having a shorter action potential duration than neighboring endo-and epicardial layers. The opposite is found in normal beats (with upright positive T-waves), i.e. M cells have a longer action potential duration than endo- and epicardial cells. The same concept can be applied to beat-to-beat T-wave variability which does not have a 2:1 pattern. As per analogiam shown in lower panel of Figure 1, T-wave variability is caused by beat-to-beat changes in the magnitude of transmural heterogeneity of action potential duration and morphology. Beat-to-beat variability in T-wave morphology, which can be observed in healthy subjects (7), is partially related to the regulatory function of the autonomic nervous system, but more likely it is caused by physiologic beat-to-beat variations in the kinetics of ionic channels, leading to physiologic transmural heterogeneity of repolarization. The relationship between repolarization duration (more precisely ion channel kinetics) and cycle length (QT and RR-intervals in ECG) determines the likelihood of T-wave alternans and T-wave variability occurrence (Figure 2). With a moderate elevation of the QT-RR relationship curve, one may expect to detect increased levels of T-wave variability. Further elevation of this curve may lead to 2:1 T-wave variability, known as T-wave alternans. This concept promotes the hypothesis that T-wave variability and T wave alternans are continuous manifestations of the same electrophysiologic phenomena resulting from varying degrees of transmural heterogeneity of repolarization.
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