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

FRONTIERS IN PHYSIOLOGY(2022)

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摘要
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.
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关键词
stretch activation, Monte Carlo method, finite element method, heartbeat, excitation contraction coupling, spontaneous oscillation, cross-bridge cycle
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