Abstract
AimsHuman atrial electrophysiology exhibits high inter-subject variability in both sinus rhythm (SR) and chronic atrial fibrillation (cAF) patients. Variability is however rarely investigated in experimental and theoretical electrophysiological studies, thus hampering the understanding of its underlying causes but also its implications in explaining differences in the response to disease and treatment. In our study, we aim at investigating the ability of populations of human atrial cell models to capture the inter-subject variability in action potential (AP) recorded in 363 patients both under SR and cAF conditions.Methods and ResultsHuman AP recordings in atrial trabeculae (n = 469) from SR and cAF patients were used to calibrate populations of computational SR and cAF atrial AP models. Three populations of over 2000 sampled models were generated, based on three different human atrial AP models. Experimental calibration selected populations of AP models yielding AP with morphology and duration in range with experimental recordings. Populations using the three original models can mimic variability in experimental AP in both SR and cAF, with median conductance values in SR for most ionic currents deviating less than 30% from their original peak values. All cAF populations show similar variations in GK1, GKur and Gto, consistent with AF-related remodeling as reported in experiments. In all SR and cAF model populations, inter-subject variability in IK1 and INaK underlies variability in APD90, variability in IKur, ICaL and INaK modulates variability in APD50 and combined variability in Ito and IKur determines variability in APD20. The large variability in human atrial AP triangulation is mostly determined by IK1 and either INaK or INaCa depending on the model.ConclusionExperimentally-calibrated human atrial AP models populations mimic AP variability in SR and cAF patient recordings, and identify potential ionic determinants of inter-subject variability in human atrial AP duration and morphology in SR versus cAF.
Highlights
Atrial arrhythmias constitute a huge burden to health-care systems in the developed countries, both because of their high rate of incidence and because they usually lead to other deadly cardiovascular diseases such as stroke [1]
Ionic Determinants of Inter-subject AP duration (APD) Variability Figure 2 shows the wide range of action potential (AP) morphologies for human atrial cell models in sinus rhythm (SR) and chronic atrial fibrillation (cAF) obtained in simulations using the initial unrestricted population, and the most restricted range of variability obtained with the experimentally-calibrated populations
The population based on the Maleckar model provides the best agreement in the ranges and degrees of variability of APD90 and APD50 in cAF, but the agreement for APD values is worse in SR (Figure S1 and 3)
Summary
Atrial arrhythmias constitute a huge burden to health-care systems in the developed countries, both because of their high rate of incidence and because they usually lead to other deadly cardiovascular diseases such as stroke [1]. A large body of research has aimed at characterizing human atrial membrane kinetics and their implication in cellular and tissue electrophysiology, in an attempt to improve our understanding of the initiation and maintenance of atrial arrhythmias [2]. Characterizing and understanding inter-subject variability in atrial cellular electrophysiology is important to determine the physiological range of action potential (AP) properties, and differences under disease conditions and in the response to treatment between patients. Recent studies highlight its temporally-dynamic nature and a variety of causes, pointing towards genetic differences (including sex [3]) and factors such as age, circadian rhythms [4] and long term drug effects [5]
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