A computational model of pig ventricular cardiomyocyte electrophysiology and calcium handling: Translation from pig to human electrophysiology

Author summary The pig is an animal commonly used experimentally to study diseases of the heart, as well as investigate therapies to treat them, such as drugs. However, although similar, pigs differ from humans in certain aspects which may mean experimental results do not always directly translate between species. We propose a mathematical model of porcine electrophysiology which can serve as a tool to understand differences between the species and translate responses. Using new measurements along with values from literature, we built a computer model of porcine cardiac myocyte which replicated voltage and calcium behaviour over a range of pacing frequencies. The pig cell had a two-stage calcium release, unlike humans with a single stage. We predict that pigs and humans differ in the type of potassium current block that makes them most susceptible to cardiac arrhythmia. The model we developed can elucidate important differences between human and pig arrhythmia response. The pig is commonly used as an experimental model of human heart disease, including for the study of mechanisms of arrhythmia. However, there exist differences between human and porcine cellular electrophysiology: The pig action potential (AP) has a deeper phase-1 notch, a longer duration at 50% repolarization, and higher plateau potentials than human. Ionic differences underlying the AP include larger rapid delayed-rectifier and smaller inward-rectifier K+-currents (I-Kr and I-K1 respectively) in humans. AP steady-state rate-dependence and restitution is steeper in pigs. Porcine Ca2+ transients can have two components, unlike human. Although a reliable computational model for human ventricular myocytes exists, one for pigs is lacking. This hampers translation from results obtained in pigs to human myocardium. Here, we developed a computational model of the pig ventricular cardiomyocyte AP using experimental datasets of the relevant ionic currents, Ca2+-handling, AP shape, AP duration restitution, and inducibility of triggered activity and alternans. To properly capture porcine Ca2+ transients, we introduced a two-step process with a faster release in the t-tubular region, followed by a slower diffusion-induced release from a non t-tubular subcellular region. The pig model behavior was compared with that of a human ventricular cardiomyocyte (O'Hara-Rudy) model. The pig, but not the human model, developed early afterdepolarizations (EADs) under block of I-K1, while I-Kr block led to EADs in the human but not in the pig model. At fast rates (pacing cycle length = 400 ms), the human cell model was more susceptible to spontaneous Ca2+ release-mediated delayed afterdepolarizations (DADs) and triggered activity than pig. Fast pacing led to alternans in human but not pig. Developing species-specific models incorporating electrophysiology and Ca(2+-)handling provides a tool to aid translating antiarrhythmic and arrhythmogenic assessment from the bench to the clinic.

Automated summary

The research team developed a mathematical model of porcine electrophysiology to understand differences between pigs and humans and translate responses. The computer model of porcine cardiac myocyte, built using experimental data, replicated voltage and calcium behavior, highlighting significant differences in arrhythmia response between the two species.