Mechanism Linking T-Wave Alternans to the Genesis of Cardiac Fibrillation

TLDR

T‑wave alternans is closely linked to ventricular arrhythmia risk, yet the cellular mechanisms underlying it and its role in reentry remain unclear. In Langendorff‑perfused guinea‑pig hearts paced at fixed rates, T‑wave alternans was induced while action potentials were recorded from 128 epicardial sites, revealing that above a critical heart‑rate, discordant repolarization alternans between neighboring cells creates spatial gradients that, when pacing is slightly accelerated, trigger unidirectional block, reentry, and ventricular fibrillation. Repolarization alternans appears at a lower heart‑rate threshold than depolarization alternans, varies in magnitude across cells, and, when discordant, generates steep repolarization gradients that produce unidirectional block, reentry, and ventricular fibrillation, thereby linking ECG T‑wave alternans to sudden cardiac death.

Abstract

Background —Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear. Methods and Results —T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209±46 bpm) that was significantly lower (by 57±36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation. Conclusions —Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG. Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death.