Simulation of the Effects of Extracellular Calcium Changes Leads to a Novel Computational Model of Human Ventricular Action Potential With a Revised Calcium Handling

The importance of electrolyte concentrations for cardiac function is well established. Electrolyte variations can lead to arrhythmias onset, due to their important role in the action potential (AP) genesis and in maintaining cell homeostasis. However, most of the human AP computer models available in literature were developed with constant electrolyte concentrations, and fail to simulate physiological changes induced by electrolyte variations. This is especially true for Ca(2+), even in the O’Hara-Rudy model (ORd), one of the most widely used models in cardiac electrophysiology. Therefore, the present work develops a new human ventricular model (BPS2020), based on ORd, able to simulate the inverse dependence of AP duration (APD) on extracellular Ca(2+) concentration ([Ca(2+)](o)), and APD rate dependence at 4 mM extracellular K(+). The main changes needed with respect to ORd are: (i) an increased sensitivity of L-type Ca(2+) current inactivation to [Ca(2+)](o); (ii) a single compartment description of the sarcoplasmic reticulum; iii) the replacement of Ca(2+) release. BPS2020 is able to simulate the physiological APD-[Ca(2+)](o) relationship, while also retaining the well-reproduced properties of ORd (APD rate dependence, restitution, accommodation and current block effects). We also used BPS2020 to generate an experimentally-calibrated population of models to investigate: (i) the occurrence of repolarization abnormalities in response to hERG current block; (ii) the rate adaptation variability; (iii) the occurrence of alternans and delayed after-depolarizations at fast pacing. Our results indicate that we successfully developed an improved version of ORd, which can be used to investigate electrophysiological changes and pro-arrhythmic abnormalities induced by electrolyte variations and current block at multiple rates and at the population level.