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

• DOI: 10.1371/journal.pcbi.1002061
• Publication Date: 2011-05-26T17:14:18Z
• Authors: Thomas O'Hara; László Virág; András Varró; Yoram Rudy
• Keywords: Afterdepolarization; Ventricular action potential; Cardiac action potential

Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such requires extensive experimental data, but essential elements have been unavailable. Here, we develop AP using new data: Ca(2+) versus voltage dependent inactivation L-type current (I(CaL)); kinetics transient outward, rapid delayed rectifier (I(Kr)), Na(+)/Ca(2+) exchange (I(NaCa)), inward currents; recordings at all cycle lengths; rate dependence restitution duration (APD) without variety specific channel blockers. Simulated APs reproduced morphology, APD dependence, restitution. Using mRNA protein models different transmural were developed. Experiments (including peak decay) intracellular sodium ([Na(+)](i)) myocytes quantitatively by model. Early afterdepolarizations induced I(Kr) block during slow pacing, alternans appeared rates >200 bpm, as observed nonfailing ventricle. Ca(2+)/calmodulin-dependent kinase II (CaMK) modulated cycling. I(NaCa) linked alternation to alternans. CaMK suppression SERCA upregulation eliminated Steady state was caused primarily changes [Na(+)](i), via its modulation electrogenic Na(+)/K(+) ATPase current. At fast pacing rates, late Na(+) I(CaL) also contributors. shortening on reduced currents due short diastolic intervals, additional contribution from elevated incomplete deactivation.