Variability in human atrial electrophysiology is large, translating into ±100% variation in ionic conductances, with reduced Na+/Ca2+ exchanger identified as a primary mechanism for diastolic Ca2+ fluctuations.
Integrating cellular-level and ion channel recordings into computational models reveals that reduced Na+/Ca2+ exchanger is a primary mechanism for diastolic Ca2+ fluctuations in human atrial myocytes.
Variability refers to differences in physiological function between individuals, which may translate into different disease susceptibility and treatment efficacy. Experiments in human cardiomyocytes face wide variability and restricted tissue access; under these conditions, computational models are a useful complementary tool. We conducted a computational and experimental investigation in cardiomyocytes isolated from samples of the right atrial appendage of patients undergoing cardiac surgery to evaluate the impact of variability in action potentials (APs) and subcellular ionic densities on Ca 2+ transient dynamics. Results showed that 1) variability in APs and ionic densities is large, even within an apparently homogenous patient cohort, and translates into ±100% variation in ionic conductances; 2) experimentally calibrated populations of models with wide variations in ionic densities yield APs overlapping with those obtained experimentally, even if AP characteristics of the original generic model differed significantly from experimental APs; 3) model calibration with AP recordings restricts the variability in ionic densities affecting upstroke and resting potential, but redundancy in repolarization currents admits substantial variability in ionic densities; and 4) model populations constrained with experimental APs and ionic densities exhibit three Ca 2+ transient phenotypes, differing in intracellular Ca 2+ handling and Na + /Ca 2+ membrane extrusion. These findings advance our understanding of the impact of variability in human atrial electrophysiology. NEW & NOTEWORTHY Variability in human atrial electrophysiology is investigated by integrating for the first time cellular-level and ion channel recordings in computational electrophysiological models. Ion channel calibration restricts current densities but not cellular phenotypic variability. Reduced Na + /Ca 2+ exchanger is identified as a primary mechanism underlying diastolic Ca 2+ fluctuations in human atrial myocytes.
Muszkiewicz et al. (Mon,) conducted a other in Patients undergoing cardiac surgery. Computational and experimental investigation of variability in action potentials and subcellular ionic densities was evaluated on Impact of variability in action potentials and subcellular ionic densities on Ca2+ transient dynamics. Variability in human atrial electrophysiology is large, translating into ±100% variation in ionic conductances, with reduced Na+/Ca2+ exchanger identified as a primary mechanism for diastolic Ca2+ fluctuations.