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 Ca(2+) 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 Ca(2+) signaling or electrical membrane properties.

OBJECTIVE

To determine whether a primary failure of intracellular Ca(2+) 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 [Ca(2+)]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 Ca(2+) current, however, elimination of intracellular Ca(2+) release abolished APD alternans, indicating that [Ca(2+)]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 Ca(2+) signaling, whereas APD alternans are a secondary consequence, mediated by Ca(2+)-dependent AP modulation.