Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 106, Issue -, Pages 68-83Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2017.03.008
Keywords
Cardiac muscle; Force generation; Viscoelasticity; Human cardiomyocytes; Computational modelling
Categories
Funding
- Biotechnology and Biological Sciences Research Council [BB/J017272/1]
- Engineering and Physical Sciences Research Council [EP/M012492/1]
- Department of Health via the National Institute for Health Research (NIHR)
- King's College Hospital NHS Foundation Trust
- BBSRC [BB/J017272/1] Funding Source: UKRI
- EPSRC [EP/M012492/1, EP/F043929/2] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J017272/1] Funding Source: researchfish
- British Heart Foundation [PG/11/101/29212] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/F043929/2, EP/M012492/1] Funding Source: researchfish
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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 degrees 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. (C) 2017 Elsevier Ltd. All rights reserved.
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