Multiphysics model of a rat ventricular myocyte: A voltage-clamp study

Background: The objective of this study is to develop a comprehensive model of the electromechanical behavior of the rat ventricular myocyte to investigate the various factors influencing its contractile response. Methods. Here, we couple a model of C a §ssup§2 + §esup§dynamics described in our previous work, with a well-known model of contractile mechanics developed by Rice, Wang, Bers and de Tombe to develop a composite multiphysics model of excitation-contraction coupling. This comprehensive cell model is studied under voltage clamp (VC) conditions, since it allows to focus our study on the elaborate C a §ssup§2 + §esup§signaling system that controls the contractile mechanism. Results: We examine the role of various factors influencing cellular contractile response. In particular, direct factors such as the amount of activator C a §ssup§2 + §esup§available to trigger contraction and the type of mechanical load applied (resulting in isosarcometric, isometric or unloaded contraction) are investigated. We also study the impact of temperature (22 to 38°C) on myofilament contractile response. The critical role of myofilament C a §ssup§2 + §esup§sensitivity in modulating developed force is likewise studied, as is the indirect coupling of intracellular contractile mechanism with the plasma membrane via the N a §ssup§ + §esup§/C a §ssup§2 + §esup§exchanger (NCX). Finally, we demonstrate a key linear relationship between the rate of contraction and relaxation, which is shown here to be intrinsically coupled over the full range of physiological perturbations. Conclusions: Extensive testing of the composite model elucidates the importance of various direct and indirect modulatory influences on cellular twitch response with wide agreement with measured data on all accounts. Thus, the model provides mechanistic insights into whole-cell responses to a wide variety of testing approaches used in studies of cardiac myofilament contractility that have appeared in the literature over the past several decades.