A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

Abstract

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.

Influence of atrial contraction dynamics on cardiac function

“…Our previously published ventricular model [24], when driven by an atrial calcium transient, produces a TPT = 113 ms, RT 50 = 96 ms, compatible with the measurements by Brixius et al Note that due to the differences in calcium kinetics, peak tension in the atria is marginally lower than in the ventricles. We consider this difference of 15-20% to be physiologically plausible, due to lower pressures in the atria (See Figure 2C) = 0.86 µM, resulting in TPT = 82 ms, RT 50 = 75 ms.…”

“…To circumvent this uncertainty and variability surrounding the atrial calcium transient in computational models, we use experimentally measured calcium transient data from Brixius et al [6], offset by the local activation time described in the previous section. As this data has not been calibrated, we assume peak and diastolic calcium levels of 0.6 µM and 0.1 µM respectively, based on the ranges seen in computational models [42] and ventricular myocytes [24]. The resulting calcium transient based on calibrating, smoothing and extrapolating the experimental data can be seen in Figure 2A, compared to several recent computational models.…”

“…We base the atrial contraction model on our previously published ventricular model [24], which models calcium binding to troponin C, tropomyosin cooperativity, and a three-state crossbridge model There is only limited data available for contraction in human atrial myocytes. Thus, in creating a computational model of human atrial cellular contraction, we assume atrial myocytes are broadly similar to ventricular myocytes.…”

“…The goals of this paper is to provide a numerical framework with a new biophysical model of human atrial contraction, based on our previous work in ventricular mechanics [24]. We use this framework to study the influence of changes in atrial contraction on whole heart function.…”

Fully coupled fluid‐electro‐mechanical model of the human heart for supercomputers

“…Extensive review articles can be found in Göktepe et al, Clayton et al, and Finka for electrophysiology, solid mechanics, and ECC single problems, respectively. To summarize, the electrophysiology models range form the phenomenological two variable Fitzhugh‐Nagumo model to multi‐ion‐channel cell models that include ECC . For the solid mechanics portion, exponential energy functions are generally used due to the simplicity in parameter estimation .…”