Date Published: May 1, 2018
Publisher: American Physiological Society
Author(s): Anna Muszkiewicz, Xing Liu, Alfonso Bueno-Orovio, Brodie A. J. Lawson, Kevin Burrage, Barbara Casadei, Blanca Rodriguez.
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 Ca2+ 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 Ca2+ transient phenotypes, differing in intracellular Ca2+ handling and Na+/Ca2+ membrane extrusion. These findings advance our understanding of the impact of variability in human atrial electrophysiology.
Investigations of cardiomyocyte electrical properties in animal models can be controlled to limit variability; in contrast, heterogeneity in the human population and representativeness of the myocytes obtained from cardiac biopsies are key challenges in our understanding of human cardiac physiology. Ion current density can also vary in response to intracellular and external stimuli. In particular, ionic current properties are modulated by signaling molecules such as nitric oxide (13, 14, 36), hormones (1, 2, 47), nutrients (57), the circadian rhythm (19), and temperature (10, 11). Therefore, when investigating cardiac physiology, we are facing a moving target that is modulated by a host of internal and external factors.
In this report, we describe a combined experimental and computational investigation to deepen our quantitative understanding of cellular and ionic variability in human right atrial myocytes. We developed experimentally calibrated populations of in silico models based on an ex vivo data set of AP and current density recordings obtained in right atrial myocytes from patients undergoing coronary revascularization or aortic valve replacement. Our main findings are as follows: 1) variability in human atrial APs and ionic currents is wide, with large differences observed a) within and between experimental data sets from different patient cohorts (8, 39, 49, 50) and b) between APs/ionic densities in experimental recordings versus generic in silico models; 2) ex vivo cell-to-cell variability in peak current densities from human atrial cardiomyocytes is substantial and can translate to a ±100% variation in maximal conductances in populations of in silico models of human electrophysiology; 3) populations of models with a substantial variability in maximal conductances can yield AP characteristics overlapping with ex vivo data set even if outputs of in silico generic models are far away from experiment; 4) calibration with AP data constrains currents affecting upstroke and resting potential, but current redundancy in repolarization allows wide ranges of variability in currents impacting APD; 5) additional calibration with ionic currents active during repolarization constrains current density but not cellular phenotypic variability in AP; and 6) experimentally calibrated populations of atrial electrophysiological models exhibit three Ca2+ transient phenotypes, mainly determined by NCX and RyR/SERCA magnitudes rather than ICaL. The appearance of Ca2+ fluctuations in diastole can be caused by low INCX, in addition to the previously reported effect of elevated sarcoplasmic release (33).
B. Casadei and X. Liu are supported by the British Heart Foundation (BHF; https://www.bhf.org.uk/) through a program grant to B. Casadei (Grant RG/11/15/29375) and the CATCH ME project of the European Union’s Horizon 2020 research and innovation program (Grant 633196). B. Rodriguez is supported by a Wellcome Trust (https://wellcome.ac.uk/) Senior Research Fellowship (100246/Z/12/Z) in Basic Biomedical Science. A. Bueno-Orovio is funded by a BHF Intermediate Basic Science Research Fellowship (FS/17/22/32644). B. Rodriguez and A. Bueno-Orovio also acknowledge additional support from an Impact for Infrastructure Award (NC/P001076/1) of the National Centre for the Replacement, Refinement & Reduction of Animals in Research (https://www.nc3rs.org.uk/). A. Muszkiewicz holds the Engineering and Physical Sciences Research Council (EPSRC) Doctoral Prize and has been funded by an EPSRC scholarship from the Systems Biology Doctoral Training Centre of the University of Oxford. B. A. J. Lawson and K. Burrage are funded by the Australian Research Council (www.arc.gov.au/) through its Centre of Excellence for Mathematical and Statistical Frontiers (CE140100049).
No conflicts of interest, financial or otherwise, are declared by the authors.
A.M., X.L., A.B.-O., K.B., B.C., and B.R. conceived and designed research; A.M., X.L., and B.A.L. performed experiments; A.M., X.L., and B.A.L. analyzed data; A.M., X.L., A.B.-O., K.B., B.C., and B.R. interpreted results of experiments; A.M. prepared figures; A.M., X.L., A.B.-O., B.A.L., K.B., B.C., and B.R. drafted manuscript; A.M., X.L., A.B.-O., B.A.L., K.B., B.C., and B.R. edited and revised manuscript; A.M., X.L., A.B.-O., B.A.L., K.B., B.C., and B.R. approved final version of manuscript.