Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation

By Thomas O'Hara, László Virág, András Varró, Yoram Rudy. PLoS Comput. Biol., 2011

1,200 citations recorded by the source corpus.

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 >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.

Subfields: Cardiology and Cardiovascular Medicine, Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ba5b4b5321c1dfb3124eac6f59f1fb51d0b5f555

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Citations in the corpus

Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity (2017, methodology): “…drug trials presented in this study were performed in a population of 1,213 human ventricular control models, built using the O’Hara-Rudy dynamic (ORd) model (O’Hara et al., 2011) as baseline and the methodology described by Britton et al. (2013) and further discussed by Muszkiewicz et al. (2016).”
Machine learning in drug development: Characterizing the effect of 30 drugs on the QT interval using Gaussian process regression, sensitivity analysis, and uncertainty quantification (2019, methodology): “Finally, we have assumed a particular electrode position, a particular cellular model [45], a specific heart rate, and a specific distribution of cell types [66], all of which could influence our predictions of the QT interval.”
hERG K(+) channels: structure, function, and clinical significance. (2012, background): “O’Hara and colleagues performed a partial characterization of IKr in undiseased human ventricular myocytes including steady-state activation and rates of activation and deactivation (454).”