Implementation of Contraction to Electrophysiological Ventricular Myocyte Models, and Their Quantitative Characterization via Post-Extrasystolic Potentiation

Abstract

Heart failure (HF) affects over 5 million Americans and is characterized by impairment of cellular cardiac contractile function resulting in reduced ejection fraction in patients. Electrical stimulation such as cardiac resynchronization therapy (CRT) and cardiac contractility modulation (CCM) have shown some success in treating patients with HF. Computer simulations have the potential to help improve such therapy (e.g. suggest optimal lead placement) as well as provide insight into the underlying mechanisms which could be beneficial. However, these myocyte models require a quantitatively accurate excitation-contraction coupling such that the electrical and contraction predictions are correct. While currently there are close to a hundred models describing the detailed electrophysiology of cardiac cells, the majority of cell models do not include the equations to reproduce contractile force or they have been added ad hoc. Here we present a systematic methodology to couple first generation contraction models into electrophysiological models via intracellular calcium and then compare the resulting model predictions to experimental data. This is done by using a post-extrasystolic pacing protocol, which captures essential dynamics of contractile forces. We found that modeling the dynamic intracellular calcium buffers is necessary in order to reproduce the experimental data. Furthermore, we demonstrate that in models the mechanism of the post-extrasystolic potentiation is highly dependent on the calcium released from the Sarcoplasmic Reticulum. Overall this study provides new insights into both specific and general determinants of cellular contractile force and provides a framework for incorporating contraction into electrophysiological models, both of which will be necessary to develop reliable simulations to optimize electrical therapies for HF.

Simultaneous Quantification of Spatially Discordant Alternans in Voltage and Intracellular Calcium in Langendorff-Perfused Rabbit Hearts and Inconsistencies with Models of Cardiac Action Potentials and Ca Transients

“…The mechanical and electrical behaviors of the heart are strongly coupled through calcium signaling. Very few mathematical models incorporate both aspects (Ji et al, 2015 ) even though there exists a strong bi-directional coupling between them. We did not study the effect of alternans on contraction or vice versa in either experiments or simulations and we did not study the effect of temperature on calcium and voltage alternans.…”

An integrative appraisal of mechano-electric feedback mechanisms in the heart

“…(see Fig. 1) and Ji et al (2015). by ensuring calcium-dependent feedback from the myofilament model to the ionic model.…”

Myofilament protein dynamics modulate EAD formation in human hypertrophic cardiomyopathy

“…Bidirectionally coupling the models with a dynamic representation of [Ca] Troponin was important and necessary, because it has been shown to be crucial for accurately reproducing contractile experiment data in myocyte simulations (Ji et al, 2015). …”