Abstract
Cardiomyocytes and myocardial sleeves dissociated from pulmonary veins (PVs) potentially generate ectopic automaticity in response to noradrenaline (NA), and thereby trigger atrial fibrillation. We developed a mathematical model of rat PV cardiomyocytes (PVC) based on experimental data that incorporates the microscopic framework of the local control theory of Ca2+ release from the sarcoplasmic reticulum (SR), which can generate rhythmic Ca2+ release (limit cycle revealed by the bifurcation analysis) when total Ca2+ within the cell increased. Ca2+ overload in SR increased resting Ca2+ efflux through the type II inositol 1,4,5-trisphosphate (IP3) receptors (InsP3R) as well as ryanodine receptors (RyRs), which finally triggered massive Ca2+ release through activation of RyRs via local Ca2+ accumulation in the vicinity of RyRs. The new PVC model exhibited a resting potential of −68 mV. Under NA effects, repetitive Ca2+ release from SR triggered spontaneous action potentials (APs) by evoking transient depolarizations (TDs) through Na+/Ca2+ exchanger (APTDs). Marked and variable latencies initiating APTDs could be explained by the time courses of the α1- and β1-adrenergic influence on the regulation of intracellular Ca2+ content and random occurrences of spontaneous TD activating the first APTD. Positive and negative feedback relations were clarified under APTD generation.
Highlights
Several types of atrial fibrillation may be attributed to the ectopic activity of myocardial cells in the sleeves of pulmonary vein cardiomyocytes (PVCs) under augmented sympathetic stimulation [1,2,3,4,5,6]
Different cell types might be involved in the arrhythmogenic activity in the pulmonary vein in different species [3], we focused on a particular cell type, which has been well characterized in a rat pulmonary vein [7,8]
We examined mechanisms underlying the generation of a train of spontaneous APTDs in response to NA stimulation by developing a mathematical PVC model
Summary
Several types of atrial fibrillation may be attributed to the ectopic activity of myocardial cells in the sleeves of pulmonary vein cardiomyocytes (PVCs) under augmented sympathetic stimulation [1,2,3,4,5,6]. Supporting this hypothesis, electrophysiological and histochemical experiments of rat PVCs by Okamoto et al demonstrated generations of spontaneous action potentials under the influence of noradrenaline (NA) in dissociated PVCs [7,8] as observed in the tissue preparations [9]. The AR-mediated decrease of the background IKbg was set at 20%–30% with a time constant of 120 s to obtain the experimental time course of depolarization.
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