A Novel Computational Model of the Human Ventricular Action Potential and Ca Transient

By Eleonora Grandi, Francesco Silvio Pasqualini, Donald M. Bers. Journal of Molecular and Cellular Cardiology, 2009

459 citations recorded by the source corpus.

We have developed a detailed mathematical model for Ca handling and ionic currents in the human ventricular myocyte. Our aims were to: 1) simulate basic excitation-contraction coupling phenomena; 2) use realistic repolarizing K current densities; 3) reach steady-state. The model relies on the framework of the rabbit myocyte model previously developed by our group, with subsarcolemmal and junctional compartments where ion channels sense higher [Ca] vs. bulk cytosol. Ion channels and transporters have been modeled on the basis of the most recent experimental data from human ventricular myocytes. Rapidly and slowly inactivating components of Ito have been formulated to differentiate between endocardial and epicardial myocytes. Transmural gradients of Ca handling proteins and Na pump were also simulated. The model has been validated against a wide set of experimental data including action potential duration (APD) adaptation and restitution, frequency-dependent increase in Ca transient peak and [Na]i. Interestingly, Na accumulation at fast heart rate is a major determinant of APD shortening, via outward shifts in Na pump and Na-Ca exchange currents. We investigated the effects of blocking K currents on APD and repolarization reserve: IKs block does not affect the former and slightly reduces the latter; IK1 blockade modestly increases APD and more strongly reduces repolarization reserve; IKr blockers significantly prolong APD, an effect exacerbated as pacing frequency is decreased, in good agreement with experimental results in human myocytes. We conclude that this model provides a useful framework to explore excitation-contraction coupling mechanisms and repolarization abnormalities at the single myocyte level.

Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7a5e79e0ef7f8188c914a7103c646c3079dbd914

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Citations in the corpus

Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation (2011, methodology): “Though the GB model[10] demonstrated the Na/INaK/APD rate dependence mechanism, it did not show the additional effects of late INa and ICaL.”
hERG K(+) channels: structure, function, and clinical significance. (2012, background): “1 channel block (approximated by reducing IKr conductance) in models of human ventricular cells have recapitulated some of the pro-arrhythmogenic biomarkers that are associated with druginduced prolongation of the QT interval (219, 286, 454, 621).”
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, background): “The authors showed that, even with a different cellular model [24], blocking solely IKr increases the action potential duration, while also blocking INa or ICaL decreases the action potential duration.”