Functional consequences of changes in the distribution of Ca2+ extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte

Abstract

The sarcolemmal Ca²⁺ efflux pathways, Na⁺-Ca²⁺-exchanger (NCX) and Ca²⁺-ATPase (PMCA), play a crucial role in the regulation of intracellular Ca²⁺ load and Ca²⁺ transient in cardiomyocytes. The distribution of these pathways between the t-tubular and surface membrane of ventricular cardiomyocytes varies between species and is not clear in human. Moreover, several studies suggest that this distribution changes during the development and heart diseases. However, the consequences of NCX and PMCA redistribution in human ventricular cardiomyocytes have not yet been elucidated. In this study, we aimed to address this point by using a mathematical model of the human ventricular myocyte incorporating t-tubules, dyadic spaces, and subsarcolemmal spaces. Effects of various combinations of t-tubular fractions of NCX and PMCA were explored, using values between 0.2 and 1 as reported in animal experiments under normal and pathological conditions. Small variations in the action potential duration (≤ 2%), but significant changes in the peak value of cytosolic Ca²⁺ transient (up to 17%) were observed at stimulation frequencies corresponding to the human heart rate at rest and during activity. The analysis of model results revealed that the changes in Ca²⁺ transient induced by redistribution of NCX and PMCA were mainly caused by alterations in Ca²⁺ concentrations in the subsarcolemmal spaces and cytosol during the diastolic phase of the stimulation cycle. The results suggest that redistribution of both transporters between the t-tubular and surface membranes contributes to changes in contractility in human ventricular cardiomyocytes during their development and heart disease and may promote arrhythmogenesis.