Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death

For nearly 100 years, beat to beat alternation of T wave amplitude, termed T wave alternans (TWA), has been closely linked to electrical instability in the heart. TWA is now established among the strongest markers of susceptibility to sudden cardiac death. Since computer technology allows for detection of very subtle yet clinically significant TWA during standard exercise testing, TWA has been used increasingly as a noninvasive clinical tool for identifying and treating patients at risk for sudden cardiac death. The observation of TWA hastening ventricular tachyarrhythmias in an extraordinary variety of clinical and experimental conditions suggest potential universality of TWA in the pathophysiological mechanism of sudden death. High resolution optical mapping studies have shown that TWA arises from alternans of repolarization at the level of the ventricular myocyte. Cellular alternans is likely due to the actions of one or more ionic currents and is closely related to, if not directly dependent on, the kinetics of intracellular calcium cycling. Impairment in calcium cycling at the cellular and sub-cellular levels has been implicated in the mechanism of cellulcar alternans. Importantly, spatially discordant alternans between cells is most likely a consequence of heterogeneities of electrophysiological properties between cells which span the ventricular wall, serving to amplify spatial heterogeneities of repolarization, and forming a substrate for reentrant excitation. Through this mechanism, TWA is linked directly and mechanistically to the pathogenesis of arrhythmias. Although available data would suggest that TWA is certainly closely related to a mechanism of arrhythmogenesis, and is a strong marker of clinical risk, the precise sequence of events which triggers sudden cardiac death, and the potential role of TWA in this process remains elusive.