A thermodynamically consistent monte carlo cross-bridge model with a trapping mechanism reveals the role of stretch activation in heart pumping

Kazunori Yoneda; Ryo Kanada; Jun-Ichi Okada; Masahiro Watanabe; Seiryo Sugiura; Toshiaki Hisada; Takumi Washio

doi:10.3389/fphys.2022.855303

A thermodynamically consistent monte carlo cross-bridge model with a trapping mechanism reveals the role of stretch activation in heart pumping

Front Physiol. 2022 Sep 8:13:855303. doi: 10.3389/fphys.2022.855303. eCollection 2022.

Authors

Kazunori Yoneda¹, Ryo Kanada², Jun-Ichi Okada^{3

4}, Masahiro Watanabe¹, Seiryo Sugiura³, Toshiaki Hisada³, Takumi Washio^{3

4}

Affiliations

¹ Section Solutions Division, Healthcare Solutions Development Unit, Fujitsu Japan Limited, Shiodome City Center, Tokyo, Japan.
² RIKEN Center for Computational Science HPC- and AI-driven Drug Development Platform Division, AI-driven Drug Discovery Collaborative Unit, Kobe, Japan.
³ UT-Heart Inc., Kashiwanoha Campus Satellite, Kashiwa, Japan.
⁴ Graduate School of Frontier Sciences, University of Tokyo, Kashiwanoha Campus Satellite, Kashiwa, Japan.

Abstract

Changes in intracellular calcium concentrations regulate heart beats. However, the decline in the left ventricular pressure during early diastole is much sharper than that of the Ca²⁺ transient, resulting in a rapid supply of blood to the left ventricle during the diastole. At the tissue level, cardiac muscles have a distinct characteristic, known as stretch activation, similar to the function of insect flight muscles. Stretch activation, which is a delayed increase in force following a rapid muscle length increase, has been thought to be related to autonomous control in these muscles. In this numerical simulation study, we introduced a molecular mechanism of stretch activation and investigated the role of this mechanism in the pumping function of the heart, using the previously developed coupling multiple-step active stiffness integration scheme for a Monte Carlo (MC) cross-bridge model and a bi-ventricular finite element model. In the MC cross-bridge model, we introduced a mechanism for trapping the myosin molecule in its post-power stroke state. We then determined the rate constants of transitions for trapping and escaping in a thermodynamically consistent manner. Based on our numerical analysis, we draw the following conclusions regarding the stretch activation mechanism: (i) the delayed force becomes larger than the original isometric force because the population of trapped myosin molecules and their average force increase after stretching; (ii) the delayed force has a duration of more than a few seconds owing to a fairly small rate constant of escape from the trapped state. For the role of stretch activation in heart pumping, we draw the following conclusions: (iii) for the regions in which the contraction force decreases earlier than the neighboring region in the end-systole phase, the trapped myosin molecules prevent further lengthening of the myocytes, which then prevents further shortening of neighboring myocytes; (iv) as a result, the contraction forces are sustained longer, resulting in a larger blood ejection, and their degeneration is synchronized.

Keywords: Monte Carlo method; cross-bridge cycle; excitation contraction coupling; finite element method; heartbeat; spontaneous oscillation; stretch activation.