The Mechanisms of Calcium Cycling and Action Potential Dynamics in Cardiac Alternans
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:Determine whether a primary failure of intracellular Ca2+ regulation or disturbances in Vm 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 two distinctive voltage commands in form of APs recorded during large and small alternans CaTs, were applied to voltage-clamped cells. CaT alternans were 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 while APD alternans are a secondary consequence, mediated by Ca2+-dependent AP modulation.
- Received October 13, 2014.
- Revision received December 18, 2014.
- Accepted December 22, 2014.