Land Sander, Park-Holohan So-Jin, Smith Nicolas P, Dos Remedios Cristobal G, Kentish Jonathan C, Niederer Steven A
Department of Biomedical Engineering, King's College London, UK.
Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, UK.
J Mol Cell Cardiol. 2017 May;106:68-83. doi: 10.1016/j.yjmcc.2017.03.008. Epub 2017 Apr 7.
Experimental data from human cardiac myocytes at body temperature is crucial for a quantitative understanding of clinically relevant cardiac function and development of whole-organ computational models. However, such experimental data is currently very limited. Specifically, important measurements to characterize changes in tension development in human cardiomyocytes that occur with perturbations in cell length are not available. To address this deficiency, in this study we present an experimental data set collected from skinned human cardiac myocytes, including the passive and viscoelastic properties of isolated myocytes, the steady-state force calcium relationship at different sarcomere lengths, and changes in tension following a rapid increase or decrease in length, and after constant velocity shortening. This data set is, to our knowledge, the first characterization of length and velocity-dependence of tension generation in human skinned cardiac myocytes at body temperature. We use this data to develop a computational model of contraction and passive viscoelasticity in human myocytes. Our model includes troponin C kinetics, tropomyosin kinetics, a three-state crossbridge model that accounts for the distortion of crossbridges, and the cellular viscoelastic response. Each component is parametrized using our experimental data collected in human cardiomyocytes at body temperature. Furthermore we are able to confirm that properties of length-dependent activation at 37°C are similar to other species, with a shift in calcium sensitivity and increase in maximum tension. We revise our model of tension generation in the skinned isolated myocyte to replicate reported tension traces generated in intact muscle during isometric tension, to provide a model of human tension generation for multi-scale simulations. This process requires changes to calcium sensitivity, cooperativity, and crossbridge transition rates. We apply this model within multi-scale simulations of biventricular cardiac function and further refine the parametrization within the whole organ context, based on obtaining a healthy ejection fraction. This process reveals that crossbridge cycling rates differ between skinned myocytes and intact myocytes.
来自人体心肌细胞在体温下的实验数据对于定量理解临床相关心脏功能以及开发全器官计算模型至关重要。然而，目前此类实验数据非常有限。具体而言，用于表征人类心肌细胞在细胞长度受扰动时张力发展变化的重要测量数据尚不可得。为解决这一不足，在本研究中，我们展示了一组从去表皮的人体心肌细胞收集的实验数据集，包括分离心肌细胞的被动和粘弹性特性、不同肌节长度下的稳态力-钙关系，以及长度快速增加或减少后和等速缩短后的张力变化。据我们所知，该数据集首次表征了体温下人体去表皮心肌细胞中张力产生的长度和速度依赖性。我们利用这些数据开发了一个人体心肌细胞收缩和被动粘弹性的计算模型。我们的模型包括肌钙蛋白C动力学、原肌球蛋白动力学、一个考虑横桥变形的三态横桥模型以及细胞粘弹性响应。每个组件都使用我们在体温下人体心肌细胞中收集的实验数据进行参数化。此外，我们能够确认37°C时长度依赖性激活的特性与其他物种相似，钙敏感性发生了变化，最大张力增加。我们修改了去表皮分离心肌细胞中张力产生的模型，以复制在等长张力期间完整肌肉中产生的报告张力轨迹，从而为多尺度模拟提供一个人体张力产生模型。这个过程需要改变钙敏感性、协同性和横桥转换速率。我们将这个模型应用于双心室心脏功能的多尺度模拟，并基于获得健康的射血分数在全器官背景下进一步优化参数化。这个过程揭示了去表皮心肌细胞和完整心肌细胞之间横桥循环速率不同。
