A model for the human fetal ventricular myocyte electrophysiology.

Abstract

Fetal cardiac arrhythmias can lead to stillbirth, but direct studies on the human fetal heart are challenging. To address this, we developed a computational model of human fetal ventricular myocyte (hfVM) electrophysiology, focusing on early gestation (10 weeks). This model incorporates major ionic currents, including fetal-specific T-type calcium and funny currents, and is calibrated using mRNA expression data and experimental measurements. The hfVM model replicates key electrophysiological features, such as a shorter action potential duration and a more positive resting membrane potential compared to adult cells. Global sensitivity analysis reveals that the resting membrane potential is primarily influenced by the funny current and IK1, while action potential repolarisation depends mainly on IKr. Additionally, the sarcoplasmic reticulum contributes to calcium release, but less so than in adults; instead, the T-type calcium current and the sodium-calcium exchanger are more prominent in initiating calcium transients. This is the first human fetal ventricular myocyte model available for studying fetal cardiac physiology, pathology, and potential pharmacological interventions. It provides novel insights into the dominant ion channels governing fetal electrophysiology and calcium dynamics, offering a foundation for understanding arrhythmias and guiding therapeutic strategies.