Mechanisms of excitation-contraction coupling in an integrative model of the cardiac ventricular myocyte

It is now well established that characteristic properties of excitation-contraction (EC) coupling in cardiac myocytes, such as high gain and graded Ca²⁺ release, arise from the interactions that occur between L-type Ca²⁺ channels (LCCs) and nearby ryanodine-sensitive Ca²⁺ release channels (RyRs) in localized microdomains. Descriptions of Ca²⁺-induced Ca²⁺ release (CICR) that account for these local mechanisms are lacking from many previous models of the cardiac action potential, and those that do include local control of CICR are able to reconstruct properties of EC coupling, but require computationally demanding stochastic simulations of ∼10⁵ individual ion channels. In this study, we generalize a recently developed analytical approach for deriving simplified mechanistic models of CICR to formulate an integrative model of the canine cardiac myocyte which is computationally efficient. The resulting model faithfully reproduces experimentally measured properties of EC coupling and whole cell phenomena. The model is used to study the role of local redundancy in L-type Ca²⁺ channel gating and the role of dyad configuration on EC coupling. Simulations suggest that the characteristic steep rise in EC coupling gain observed at hyperpolarized potentials is a result of increased functional coupling between LCCs and RyRs. We also demonstrate mechanisms by which alterations in the early repolarization phase of the action potential, resulting from reduction of the transient outward potassium current, alters properties of EC coupling.