Abstract
Cardiovascular disease is one of the leading causes of death worldwide, in particular myocardial dysfunction, which may lead to heart failure eventually. Understanding the electro-mechanics of the heart will help in developing more effective clinical treatments. In this paper, we present a multi-scale electro-mechanics model of the left ventricle (LV). The Holzapfel-Ogden constitutive law was used to describe the passive myocardial response in tissue level, a modified Grandi-Pasqualini-Bers model was adopted to model calcium dynamics in individual myocytes, and the active tension was described using the Niederer-Hunter-Smith myofilament model. We first studied the electro-mechanics coupling in a single myocyte in the healthy and diseased left ventricle, and then the single cell model was embedded in a dynamic LV model to investigate the compensation mechanism of LV pump function due to myocardial dysfunction caused by abnormality in cellular calcium dynamics. The multi-scale LV model was solved using an in-house developed hybrid immersed boundary method with finite element extension. The predictions of the healthy LV model agreed well with the clinical measurements and other studies, and likewise, the results in the failing states were also consistent with clinical observations. In particular, we found that a low level of intracellular Ca2+ transient in myocytes can result in LV pump function failure even with increased myocardial contractility, decreased systolic blood pressure, and increased diastolic filling pressure, even though they will increase LV stroke volume. Our work suggested that treatments targeted at increased contractility and lowering the systolic blood pressure alone are not sufficient in preventing LV pump dysfunction, restoring a balanced physiological Ca2+ handling mechanism is necessary.
Highlights
Myocardial dysfunction is a considerable social and economic burden because it can lead to heart failure due to repeated stresses and injuries [1]
It will provide a platform to understand the functional and structural remodelling in failing hearts. Using this multi-scale left ventricle (LV) model, we found that (1) profiles of AP, intracellular calcium transient (CaT) and active tension are very different at cellular level from healthy to failing states; (2) a lower CaT can lead to a much less active tension generation; and (3) a lower intracellular CaT in individual myocytes can result in LV pump function failure even with increased myocardial contractility, decreased afterload, and increased diastolic filling pressure
We only studied the effects of CaT from different failing stages on myocardial active contraction that is caused by ion channel and transporter remodelling [28, 48]
Summary
A modified GPB model by Cardona et al [29] was used to simulate the Ca2+ dynamics in healthy and failing states. The reasons for choosing the GPB model were that (1) it matches experimental data well [22]; (2) it is adequate to analyse action potential with detailed Ca2+ dynamics, which plays a crucial role in excitation-contraction in myocardium [16]; (3) other studies have demonstrated that it can reproduce the electrical changes of failing myocytes caused by remodelling in ion channels and transporters [28, 29]. The intracellular sodium concentration and Ca2+ handing are closely related. The intracellular sodium concentration, especially INaL, is increased in failing myocytes, which contributes to cellular Ca2+ accumulation. The introduced INaL in the modified GBP model was modelled following the Hodgkin-Huxley formula [32], INaLjunc 1⁄4 Fjunc gNaL m3L hLðVm À EjuncÞ; ð1Þ
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