Abstract
Electrophysiological studies of the human heart face the fundamental challenge that experimental data can be acquired only from patients with underlying heart disease. Regarding human atria, there exist sizable gaps in the understanding of the functional role of cellular Ca2+ dynamics, which differ crucially from that of ventricular cells, in the modulation of excitation-contraction coupling. Accordingly, the objective of this study was to develop a mathematical model of the human atrial myocyte that, in addition to the sarcolemmal (SL) ion currents, accounts for the heterogeneity of intracellular Ca2+ dynamics emerging from a structurally detailed sarcoplasmic reticulum (SR). Based on the simulation results, our model convincingly reproduces the principal characteristics of Ca2+ dynamics: 1) the biphasic increment during the upstroke of the Ca2+ transient resulting from the delay between the peripheral and central SR Ca2+ release, and 2) the relative contribution of SL Ca2+ current and SR Ca2+ release to the Ca2+ transient. In line with experimental findings, the model also replicates the strong impact of intracellular Ca2+ dynamics on the shape of the action potential. The simulation results suggest that the peripheral SR Ca2+ release sites define the interface between Ca2+ and AP, whereas the central release sites are important for the fire-diffuse-fire propagation of Ca2+ diffusion. Furthermore, our analysis predicts that the modulation of the action potential duration due to increasing heart rate is largely mediated by changes in the intracellular Na+ concentration. Finally, the results indicate that the SR Ca2+ release is a strong modulator of AP duration and, consequently, myocyte refractoriness/excitability. We conclude that the developed model is robust and reproduces many fundamental aspects of the tight coupling between SL ion currents and intracellular Ca2+ signaling. Thus, the model provides a useful framework for future studies of excitation-contraction coupling in human atrial myocytes.
Highlights
In cardiac myocytes, the process triggered by the action potential (AP) and resulting in the contraction of the myocyte is commonly referred to as excitation-contraction coupling (ECC) [1]
The transient elevation of intracellular Ca2+ concentration ([Ca2+]i) that underlies the contraction is initiated by the Ca2+ influx from the extracellular space through the L-type calcium channels (LTCCs), which causes the release of more Ca2+ from the sarcoplasmic reticulum (SR) via the SR calcium release channels, This mechanism is known as Ca2+ induced Ca2+ release (CICR) [2]
The enhanced pumping function of NKA lead to a dramatic increase in the current (INKA) (Figure 8G). This mechanism has been reported previously in human atrial fibers [42] and guinea pig ventricular myocytes [43]. To confirm that this feature of the myocyte model does not depend on the Na+ parameters of model variant, we simulated the same protocol with model variant vCa and found that fast pacing resulted in a similar increase in increases Na+/ K+-ATPase current (INKA)
Summary
The process triggered by the action potential (AP) and resulting in the contraction of the myocyte is commonly referred to as excitation-contraction coupling (ECC) [1]. Whilst the same CICR mechanism initiates the transient elevation of [Ca2+]i in both ventricular and atrial myocytes, there are substantial spatiotemporal differences in the properties of the atrial and ventricular Ca2+ transients [3,4] due to the divergent intracellular ultrastructures. Mammalian atrial myocytes lack a prominent transverse tubular system [5], which in ventricular myocytes establishes the tight coupling of the SR to sarcolemma, enabling a Ca2+ release that is virtually uniform throughout the cell [6]. The Ca2+ wave arises in the periphery (junctional-SR) and propagates to the center of the cell, activating secondary release from the corbular (nonjunctional) SR compartments [3,7,8]
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