The Importance of a “Just Right” Serum Potassium Level

Mehta, Ankit; Emmett, Michael

doi:10.1159/000479803

Cited by 2 publications

(5 citation statements)

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“…These K + transcripts, alone or in combination, can sense and react to changes in [K + ] o with high affinity and very rapid response times. Recognition and understanding of these properties provides the basis for understanding the direct and indirect effects of clinically-relevant hypokalemia ( Macdonald and Struthers, 2004 ; Krijthe et al, 2012 ; Mehta and Emmett, 2017 ). Specifically, validated mathematical models must be able to accurately reproduce the [K + ] o -dependent modulation of the highly non-linear I-V relationship (voltage-dependent rectification) generated by “strong inward rectifier” transcripts such as Kir2.1/2.3 ( Lu, 2004 ; Dhamoon and Jalife, 2005 ; Anumonwo and Lopatin, 2010 ; Hibino et al, 2010 ) in all myocytes from human atrium ( Figure 2 ) and ventricles ( Bouchard et al, 2004 ; Trenor et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…There is a general consensus that the [K + ] o levels in a healthy adult human are closer to 4 to 4.5 mM than the 5.4 mM value typically used in wet lab and simulation experiments (Macdonald and Struthers, 2004;Mehta and Emmett, 2017) and that quite small changes (±1 to 2 mM) can confer a proarrhythmic phenotype in mammalian atria (Zaza, 2009;Krijthe et al, 2012). The associated hypo-or hyperkalemic phenotypes are observed quite frequently in clinical settings and must be monitored and managed effectively.…”

Section: Relationship To Previous Clinical Findingsmentioning

confidence: 99%

“…In contrast, a recent detailed electrolyte analysis of plasma from healthy adult human establishes the mean of this important electrolyte parameter to be around 4.2 mM ( Collins et al, 2017 ). Analyzing both a control group ( n = 339,297) and a large and geographically varied cohort of patients ( n = 911,689) with heart failure, chronic kidney disease, and/or diabetes mellitus this study found mortality was lowest in the group with potassium levels from 4 to 5 mM ( Collins et al, 2017 ; Mehta and Emmett, 2017 ). This was in agreement with an earlier study ( Macdonald and Struthers, 2004 ) that reported lowest mortality for [K + ] o levels of 4.5 to 5.5 mM.…”

Section: Introductionmentioning

confidence: 96%

“…Examples of the translational implications of changed electrolyte levels can be found in renal physiology/pathophysiology and dialysis ( Genovesi et al, 2008 ; Krueger et al, 2011 ; Zimmerman et al, 2012 ; Vincenti et al, 2014 ), in case management of hypertension ( Wrong, 1961 ; Krogager et al, 2020 ), and in clinical cardiac arrhythmia management ( Weaver and Burchell, 1960 ; Zaza, 2009 ; Goyal et al, 2012 ). During in-hospital acute patient care, plasma levels of Mg 2+ , Ca 2+ , K + , and Na + are monitored closely, and plasma K + levels ([K + ] o ) can provide essential information for diagnoses and guidance for treatment ( Macdonald and Struthers, 2004 ; Mehta and Emmett, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…As a result, close monitoring of electrolyte levels is recommended. Hypokalemia is known to occur in 20 to 30% of hospitalized patients ( Paice et al, 1986 ; Collins et al, 2017 ), but whether or not prevention or correction of abnormal plasma potassium levels has a beneficial impact on morbidity and mortality has yet to be shown in a large-scale trial ( Mehta and Emmett, 2017 ). A computational review focusing on plasma electrolyte changes, and in particular on hemodialysis effects, was published by Passini et al (2014) .…”

Section: Introductionmentioning

confidence: 99%

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Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Relationship To Previous Clinical Findingsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia

et al. 2021

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Pro-arrhythmic effects of low plasma [K + ] in human ventricle: An illustrated review

Trénor

Cardona

Romero

et al. 2018

Trends in Cardiovascular Medicine

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Potassium levels in the plasma, [K], are regulated precisely under physiological conditions. However, increases (from approx. 4.5 to 8.0mM) can occur as a consequence of, e.g., endurance exercise, ischemic insult or kidney failure. This hyperkalemic modulation of ventricular electrophysiology has been studied extensively. Hypokalemia is also common. It can occur in response to diuretic therapy, following renal dialysis, or during recovery from endurance exercise. In the human ventricle, clinical hypokalemia (e.g., [K] levels of approx. 3.0mM) can cause marked changes in both the resting potential and the action potential waveform, and these may promote arrhythmias. Here, we provide essential background information concerning the main K-sensitive ion channel mechanisms that act in concert to produce prominent short-term ventricular electrophysiological changes, and illustrate these by implementing recent mathematical models of the human ventricular action potential. Even small changes (~1mM) in [K] result in significant alterations in two different K currents, I and HERG. These changes can markedly alter in resting membrane potential and/or action potential waveform in human ventricle. Specifically, a reduction in net outward transmembrane K currents (repolarization reserve) and an increased substrate input resistance contribute to electrophysiological instability during the plateau of the action potential and may promote pro-arrhythmic early after-depolarizations (EADs). Translational settings where these insights apply include: optimal diuretic therapy, and the interpretation of data from Phase II and III trials for anti-arrhythmic drug candidates.

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The Importance of a “Just Right” Serum Potassium Level

Cited by 2 publications

References 6 publications

Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia

Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia

Pro-arrhythmic effects of low plasma [K + ] in human ventricle: An illustrated review

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