Adaptation of the Calcium-dependent Tension Development in Ventricular Cardiomyocytes

Stephanie Appel,Tobias Gerach,Olaf Dössel,Axel Loewe

doi:10.1515/cdbme-2021-2064

Stephanie Appel, Tobias Gerach + Show 2 more

Open Access

https://doi.org/10.1515/cdbme-2021-2064

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Abstract

Abstract Today a variety of models describe the physiological behavior of the heart on a cellular level. The intracellular calcium concentration plays an important role, since it is the main driver for the active contraction of the heart. Due to different implementations of the calcium dynamics, simulating cardiac electromechanics can lead to severely different behaviors of the active tension when coupling the same tension model with different electrophysiological models. To handle these variations, we present an optimization tool that adapts the parameters of the most recent, human based tension model. The goal is to generate a physiologically valid tension development when coupled to an electrophysiological cellular model independent of the specifics of that model's calcium transient. In this work, we focus on a ventricular cell model. In order to identify the calcium-sensitive parameters, a sensitivity analysis of the tension model was carried out. In a further step, the cell model was adapted to reproduce the sarcomere length-dependent behavior of troponin C. With a maximum relative deviation of 20.3% per defined characteristic of the tension development, satisfactory results could be obtained for isometric twitch tension. Considering the length-dependent troponin handling, physiological behavior could be reproduced. In conclusion, we propose an algorithm to adapt the tension development model to any calcium transient input to achieve a physiologically valid active contraction on a cellular level. As a proof of concept, the algorithm is successfully applied to one of the most recent human ventricular cell models. This is an important step towards fully coupled electromechanical heart models, which are a valuable tool in personalized health care.

Highlights

Calcium ions act as direct activators of the contractile apparatus in the heart
Due to different implementations of calcium handling leading to different calcium transients, the resulting tension development (TD) in a given tension model can differ significantly in magnitude and dynamics depending on the electrophysiological
Features were defined, that characterized the TD with respect to its dynamics and magnitude (Figure 1): diastolic tension (DT), force of contraction (FOC), duration of tension development (DTD), time to peak tension (TPT) and relaxation time (RT)

Summary

Introduction

Calcium ions act as direct activators of the contractile apparatus in the heart. The sarcomere length-dependent concentration of calcium bound to troponin C (TnC) ["#!"]#$%& causes a conformational change of tropomyosin, which leads to a shortening of the sarcomere as described in the cross-bridge cycle. The intracellular calcium concentration ["#!"]' has a significant impact on the development of active tension and on the contraction of the heart. For this reason, the standard procedure to model electromechanical coupling is to transfer the calcium transient from the electrophysiological cellular model to the tension model. Land et al used the experimentally determined calcium transient reported by Coppini et al [3] to parametrize the model. It is one of the few models based on human experimental data, which characterizes the length and velocity dependence of TD. To overcome deficiencies of the original model with respect to tissue simulations, activation and inactivation of the sodium current %&( were adapted as suggested in [5]

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Conclusion