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Physiol."],"abstract":"<jats:p>Although plasma electrolyte levels are quickly and precisely regulated in the mammalian cardiovascular system, even small transient changes in K<jats:sup>+<\/jats:sup>, Na<jats:sup>+<\/jats:sup>, Ca<jats:sup>2+<\/jats:sup>, and\/or Mg<jats:sup>2+<\/jats:sup> 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 (V<jats:sub>r<\/jats:sub>) and the AP following decreases in plasma K<jats:sup>+<\/jats:sup>, [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub>, 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<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub> 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:<\/jats:p><jats:p>(i) Immediately after [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub> is reduced, the K<jats:sup>+<\/jats:sup>-sensing mechanism of the background inward rectifier current (I<jats:sub>K1<\/jats:sub>) 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, V<jats:sub>r<\/jats:sub> and can also markedly prolong the final repolarization phase of the AP, thus modulating excitability and refractoriness.<\/jats:p><jats:p>(ii) A second much slower electrophysiological response (developing 5\u201310 minutes after [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub> is reduced) results from alterations in the intracellular electrolyte balance. A progressive shift in intracellular [Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub> causes a change in the outward electrogenic current generated by the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup> pump, thereby modifying V<jats:sub>r<\/jats:sub> and AP repolarization and changing the human atrial electrophysiological substrate.<\/jats:p><jats:p>In this study, these two effects were investigated quantitatively, using seven published models of the human atrial AP. This highlighted the important role of I<jats:sub>K1<\/jats:sub> rectification when analyzing both the mechanisms by which [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub> regulates V<jats:sub>r<\/jats:sub> and how the AP waveform may contribute to \u201ctrigger\u201d mechanisms within the proarrhythmic substrate. Our simulations complement and extend previous studies aimed at understanding key factors by which decreases in [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub> can produce effects that are known to promote atrial arrhythmias in human hearts.<\/jats:p>","DOI":"10.3389\/fphys.2021.651162","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T13:51:46Z","timestamp":1622037106000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia"],"prefix":"10.3389","volume":"12","author":[{"given":"Michael","family":"Clerx","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary R.","family":"Mirams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert J.","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjiv M.","family":"Narayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne R.","family":"Giles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1093\/eurheartj\/ehm091","article-title":"A propensity matched study of the association of low serum potassium levels and mortality in chronic heart failure.","volume":"28","author":"Ahmed","year":"2007","journal-title":"Eur. 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