A novel computational model of the rat ventricular myocyte suggests that cardiac alternans produced by rapid pacing requires a synergy of voltage- and calcium-dependent mechanisms.
A novel computational model demonstrates that cardiac alternans arises from the synergistic interaction of voltage- and calcium-dependent mechanisms during rapid pacing.
Cardiac alternans is characterized by alternating weak and strong beats of the heart. This signaling at the cellular level may appear as alternating long and short action potentials (APs) that occur in synchrony with alternating large and small calcium transients, respectively. Previous studies have suggested that alternans manifests itself through either a voltage dependent mechanism based upon action potential restitution or as a calcium dependent mechanism based on refractoriness of calcium release. We use a novel model of cardiac excitation-contraction (EC) coupling in the rat ventricular myocyte that includes 20,000 calcium release units (CRU) each with 49 ryanodine receptors (RyR2s) and 7 L-type calcium channels that are all stochastically gated. The model suggests that at the cellular level in the case of alternans produced by rapid pacing, the mechanism requires a synergy of voltage- and calcium-dependent mechanisms. The rapid pacing reduces AP duration and magnitude reducing the number of L-type calcium channels activating individual CRUs during each AP and thus increases the population of CRUs that can be recruited stochastically. Elevated myoplasmic and sarcoplasmic reticulum (SR) calcium, Ca2+myo and Ca2+SR respectively, increases ryanodine receptor open probability (Po) according to our model used in this simulation and this increased the probability of activating additional CRUs. A CRU that opens in one beat is less likely to open the subsequent beat due to refractoriness caused by incomplete refilling of the junctional sarcoplasmic reticulum (jSR). Furthermore, the model includes estimates of changes in Na+ fluxes and Na+i and thus provides insight into how changes in electrical activity, Na+i and sodium-calcium exchanger activity can modulate alternans. The model thus tracks critical elements that can account for rate-dependent changes in Na+i and Ca2+myo and how they contribute to the generation of Ca2+ signaling alternans in the heart.
Hoang-Trong et al. (Mon,) conducted a other in Cardiac alternans. Rapid pacing (computational model) was evaluated on Mechanism of cardiac alternans. A novel computational model of the rat ventricular myocyte suggests that cardiac alternans produced by rapid pacing requires a synergy of voltage- and calcium-dependent mechanisms.