Abstract
Although plasma electrolyte levels are quickly and precisely regulated in the mammalian cardiovascular system, even small transient changes in K+, Na+, Ca2+, and/or Mg2+ can significantly alter physiological responses in the heart, blood vessels, and intrinsic (intracardiac) autonomic nervous system. We have used mathematical models of the human atrial action potential (AP) to explore the electrophysiological mechanisms that underlie changes in resting potential (Vr) and the AP following decreases in plasma K+, [K+]o, that were selected to mimic clinical hypokalemia. Such changes may be associated with arrhythmias and are commonly encountered in patients (i) in therapy for hypertension and heart failure; (ii) undergoing renal dialysis; (iii) with any disease with acid-base imbalance; or (iv) post-operatively. Our study emphasizes clinically-relevant hypokalemic conditions, corresponding to [K+]o reductions of approximately 1.5 mM from the normal value of 4 to 4.5 mM. We show how the resulting electrophysiological responses in human atrial myocytes progress within two distinct time frames:(i) Immediately after [K+]o is reduced, the K+-sensing mechanism of the background inward rectifier current (IK1) responds. Specifically, its highly non-linear current-voltage relationship changes significantly as judged by the voltage dependence of its region of outward current. This rapidly alters, and sometimes even depolarizes, Vr and can also markedly prolong the final repolarization phase of the AP, thus modulating excitability and refractoriness.(ii) A second much slower electrophysiological response (developing 5–10 minutes after [K+]o is reduced) results from alterations in the intracellular electrolyte balance. A progressive shift in intracellular [Na+]i causes a change in the outward electrogenic current generated by the Na+/K+ pump, thereby modifying Vr and AP repolarization and changing the human atrial electrophysiological substrate.In this study, these two effects were investigated quantitatively, using seven published models of the human atrial AP. This highlighted the important role of IK1 rectification when analyzing both the mechanisms by which [K+]o regulates Vr and how the AP waveform may contribute to “trigger” mechanisms within the proarrhythmic substrate. Our simulations complement and extend previous studies aimed at understanding key factors by which decreases in [K+]o can produce effects that are known to promote atrial arrhythmias in human hearts.
Highlights
Our goal is to gain a detailed understanding of the short- and long-term effects of moderate hypokalemia on human atrial electrophysiological parameters including the resting potential (Vr), action potential (AP) waveform, refractory period dynamics and conduction velocity (CV)
A feature-by-feature comparison of these models is given in Table 1, and baseline APs and calcium transients are shown in Supplementary Figure 2
The computational work in this paper has illustrated how hypokalemia can lead to an increased deviation of Vr from the potassium reversal potential, even resulting in depolarization at lower [K+]o
Summary
Detailed knowledge of plasma electrolyte (e.g., K+, Na+, Ca2+, and Mg2+) levels, and an understanding of the consequences of even small changes in one or more of them, are needed for optimal clinical management of various chronic diseases (Franse et al, 2000; Ahmed et al, 2007; Barrett Bowling et al, 2010; El-Sherif and Turitto, 2011; Alderman et al, 2012; Wang et al, 2013; Collins et al, 2017; Krogager et al, 2020). A computational review focusing on plasma electrolyte changes, and in particular on hemodialysis effects, was published by Passini et al (2014)
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