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Description
Heart failure with preserved ejection fraction (HFpEF) is growing in prevalence, often attributed to an ageing and obese population. It lacks effective treatments due to poorly understood pathophysiology and absence of translationally relevant animal models \cite{gao_animal_2024}. The aim of this work is to couple an in vitro system of strip-based engineered heart tissue (EHT) with a mathematical model of excitation-contraction coupling. This is used to gain a translational model of heart failure for investigation of potential drug targets. The mathematical model integrates the ODE-based “ORd” \cite{ohara} electrophysiology model of dimension 41 with the ODE-based “HMT” \cite{hmt} contractile force model of dimension 6. The physiological coupling of the models is through calcium binding to troponin, which initiates the muscle contraction. The model is calibrated against twitch force data from EHTs consisting of human stem cell-derived cardiomyocytes and primary fibroblasts. The model reproduces baseline twitch force and captures the sigmoidal dependence of peak force on extracellular calcium concentration (0.2–1.8 mM). Experiments with administration of the well characterized calcium channel blocker verapamil (0.1, 0.5 and 1 µM) produced a dose dependent decrease in twitch force in the EHTs, which was in close agreement with model predictions. Ongoing work couples this model to a cardiac mechanics framework, enabling simulation of in vivo cardiac function and drug effects.
Bibliography
@article{gao_animal_2024,
title = {Animal models of heart failure with preserved ejection fraction ({HFpEF}): from metabolic pathobiology to drug discovery},
volume = {45},
copyright = {2023 The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society},
issn = {1745-7254},
shorttitle = {Animal models of heart failure with preserved ejection fraction ({HFpEF})},
url = {https://www.nature.com/articles/s41401-023-01152-0},
doi = {10.1038/s41401-023-01152-0},
abstract = {Heart failure (HF) with preserved ejection fraction (HFpEF) is currently a preeminent challenge for cardiovascular medicine. It has a poor prognosis, increasing mortality, and is escalating in prevalence worldwide. Despite accounting for over 50\% of all HF patients, the mechanistic underpinnings driving HFpEF are poorly understood, thus impeding the discovery and development of mechanism-based therapies. HFpEF is a disease syndrome driven by diverse comorbidities, including hypertension, diabetes and obesity, pulmonary hypertension, aging, and atrial fibrillation. There is a lack of high-fidelity animal models that faithfully recapitulate the HFpEF phenotype, owing primarily to the disease heterogeneity, which has hampered our understanding of the complex pathophysiology of HFpEF. This review provides an updated overview of the currently available animal models of HFpEF and discusses their characteristics from the perspective of energy metabolism. Interventional strategies for efficiently utilizing energy substrates in preclinical HFpEF models are also discussed.},
language = {en},
number = {1},
urldate = {2026-03-06},
journal = {Acta Pharmacologica Sinica},
author = {Gao, Si and Liu, Xue-ping and Li, Ting-ting and Chen, Li and Feng, Yi-ping and Wang, Yu-kun and Yin, Yan-jun and Little, Peter J. and Wu, Xiao-qian and Xu, Suo-wen and Jiang, Xu-dong},
month = jan,
year = {2024},
keywords = {Biomedicine, general, Pharmacology/Toxicology, Medical Microbiology, Immunology, Internal Medicine, Vaccine},
pages = {23--35},
}
@article{hmt,
title = {Modelling the mechanical properties of cardiac muscle},
volume = {69},
issn = {0079-6107},
url = {https://www.sciencedirect.com/science/article/pii/S0079610798000133},
doi = {10.1016/S0079-6107(98)00013-3},
abstract = {A model of passive and active cardiac muscle mechanics is presented, suitable for use in continuum mechanics models of the whole heart. The model is based on an extensive review of experimental data from a variety of preparations (intact trabeculae, skinned fibres and myofibrils) and species (mainly rat and ferret) at temperatures from 20 to 27°C. Experimental tests include isometric tension development, isotonic loading, quick-release/restretch, length step and sinusoidal perturbations. We show that all of these experiments can be interpreted with a four state variable model which includes (i) the passive elasticity of myocardial tissue, (ii) the rapid binding of Ca2+ to troponin C and its slower tension-dependent release, (iii) the kinetics of tropomyosin movement and availability of crossbridge binding sites and the length dependence of this process and (iv) the kinetics of crossbridge tension development under perturbations of myofilament length.},
number = {2},
urldate = {2026-03-06},
journal = {Progress in Biophysics and Molecular Biology},
author = {Hunter, P. J. and McCulloch, A. D. and ter Keurs, H. E. D. J.},
month = mar,
year = {1998},
pages = {289--331},
}
@article{ohara,
title = {Simulation of the {Undiseased} {Human} {Cardiac} {Ventricular} {Action} {Potential}: {Model} {Formulation} and {Experimental} {Validation}},
volume = {7},
issn = {1553-7358},
shorttitle = {Simulation of the {Undiseased} {Human} {Cardiac} {Ventricular} {Action} {Potential}},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1002061},
doi = {10.1371/journal.pcbi.1002061},
abstract = {Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca2+ versus voltage dependent inactivation of L-type Ca2+ current (ICaL); kinetics for the transient outward, rapid delayed rectifier (IKr), Na+/Ca2+ exchange (INaCa), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by IKr block during slow pacing, and AP and Ca2+ alternans appeared at rates {\textgreater}200 bpm, as observed in the nonfailing human ventricle. Ca2+/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca2+ cycling. INaCa linked Ca2+ alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na+]i, via its modulation of the electrogenic Na+/K+ ATPase current. At fast pacing rates, late Na+ current and ICaL were also contributors. APD shortening during restitution was primarily dependent on reduced late Na+ and ICaL currents due to inactivation at short diastolic intervals, with additional contribution from elevated IKr due to incomplete deactivation.},
language = {en},
number = {5},
urldate = {2026-03-06},
journal = {PLOS Computational Biology},
author = {O'Hara, Thomas and Virág, László and Varró, András and Rudy, Yoram},
month = may,
year = {2011},
keywords = {Muscle cells, Heart, Drug dependence, Cardiac ventricles, Simulation and modeling, Arrhythmia, Electrophysiology, Rectifiers},
pages = {e1002061},
}
