Sarcoplasmic Reticulum Calcium Content Fluctuation Is the Key to Cardiac Alternans

Abstract

The aim of this work was to investigate whether beat-to-beat alternation in the amplitude of the systolic Ca2+ transient (Ca2+ alternans) is due to changes of sarcoplasmic reticulum (SR) Ca2+ content, and if so, whether the alternans arises due to a change in the gain of the feedback controlling SR Ca2+ content. We found that, in rat ventricular myocytes, stimulating with small (20 mV) depolarizing pulses produced alternans of the amplitude of the Ca2+ transient. Confocal measurements showed that the larger transients resulted from propagation of Ca2+ waves. SR Ca2+ content (measured from caffeine-evoked membrane currents) alternated in phase with the alternans of Ca2+ transient amplitude. After a large transient, if SR Ca 2+ content was elevated by brief exposure of the cell to a Na +-free solution, then the alternans was interrupted and the next transient was also large. This shows that changes of SR Ca2+ content are sufficient to produce alternans. The dependence of Ca2+ transient amplitude on SR content was steeper under alternating than under control conditions. During alternation, the Ca2+ efflux from the cell was also a steeper function of SR Ca2+ content than under control. We attribute these steeper relationships to the fact that the larger responses in alternans depend on wave propagation and that wave propagation is a steep function of SR Ca2+ content. In conclusion, alternans of systolic Ca2+ appears to depend on alternation of SR Ca2+ content. This, in turn results from the steep dependence on SR Ca2+ content of Ca2+ release and therefore Ca2+ efflux from the cell as a consequence of wave propagation.