The mechanisms of calcium cycling and action potential dynamics in cardiac alternans

Abstract

Rationale: Alternans is a risk factor for cardiac arrhythmia, including atrial fibrillation. At the cellular level alternans manifests as beat-to-beat alternations in contraction, action potential duration (APD), and magnitude of the Ca2+ transient (CaT). Electromechanical and CaT alternans are highly correlated, however, it has remained controversial whether the primary cause of alternans is a disturbance of cellular Ca2+ signaling or electrical membrane properties. Objective: To determine whether a primary failure of intracellular Ca2+ regulation or disturbances in membrane potential and AP regulation are responsible for the occurrence of alternans in atrial myocytes. Methods and Results: Pacing-induced APD and CaT alternans were studied in single rabbit atrial and ventricular myocytes using combined [Ca2+]i and electrophysiological measurements. In current-clamp experiments, APD and CaT alternans strongly correlated in time and magnitude. CaT alternans was observed without alternation in L-type Ca2+ current, however, elimination of intracellular Ca2+ release abolished APD alternans, indicating that [Ca2+]i dynamics have a profound effect on the occurrence of CaT alternans. Trains of 2 distinctive voltage commands in form of APs recorded during large and small alternans CaTs were applied to voltage-clamped cells. CaT alternans was observed with and without alternation in the voltage command shape. During alternans AP-clamp large CaTs coincided with both long and short AP waveforms, indicating that CaT alternans develop irrespective of AP dynamics. Conclusions: The primary mechanism underlying alternans in atrial cells, similarly to ventricular cells, resides in a disturbance of Ca2+ signaling, whereas APD alternans are a secondary consequence, mediated by Ca2+-dependent AP modulation.