Cardiac alternans and intracellular calcium cycling

Atrial fibrillation is the most common sustained arrhythmia and its prevalence is rapidly rising with the aging of the population. Cardiac alternans, defined as cyclic beat-to-beat alternations in contraction force, action potential (AP) duration and intracellular Ca2+ release at constant stimulation rate, has been associated with the development of ventricular arrhythmias. Recent clinical data also provide strong evidence that alternans plays a central role in arrhythmogenesis in atria. The aim of this article is to review the mechanisms that are responsible for repolarization alternans and contribute to the transition from spatially concordant alternans to the more arrhythmogenic spatially discordant alternans in atria.

Cardiac alternans, defined beat-to-beat alternations in contraction, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude, is a high risk indicator for cardiac arrhythmias. We investigated mechanisms of cardiac alternans in single rabbit ventricular myocytes. CaTs were monitored simultaneously with membrane currents or APs recorded with the patch clamp technique. A strong correlation between beat-to-beat alternations of AP morphology and CaT alternans was observed. During CaT alternans application of voltage clamp protocols in form of pre-recorded APs revealed a prominent Ca 2C -dependent membrane current consisting of a large outward component coinciding with AP phases 1 and 2, followed by an inward current during AP repolarization. Approximately 85% of the initial outward current was blocked by Cl ¡ channel blocker DIDS or lowering external Cl ¡ concentration identifying it as a Ca 2C -activated Cl ¡ current (I CaCC ). The data suggest that I CaCC plays a critical role in shaping beat-to-beat alternations in AP morphology during alternans.

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