Abstract
Potassium is the predominant intracellular cation, with its extracellular concentrations maintained between 3. 5 and 5 mM. Among the different potassium disorders, hypokalaemia is a common clinical condition that increases the risk of life-threatening ventricular arrhythmias. This review aims to consolidate pre-clinical findings on the electrophysiological mechanisms underlying hypokalaemia-induced arrhythmogenicity. Both triggers and substrates are required for the induction and maintenance of ventricular arrhythmias. Triggered activity can arise from either early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). Action potential duration (APD) prolongation can predispose to EADs, whereas intracellular Ca2+ overload can cause both EADs and DADs. Substrates on the other hand can either be static or dynamic. Static substrates include action potential triangulation, non-uniform APD prolongation, abnormal transmural repolarization gradients, reduced conduction velocity (CV), shortened effective refractory period (ERP), reduced excitation wavelength (CV × ERP) and increased critical intervals for re-excitation (APD–ERP). In contrast, dynamic substrates comprise increased amplitude of APD alternans, steeper APD restitution gradients, transient reversal of transmural repolarization gradients and impaired depolarization-repolarization coupling. The following review article will summarize the molecular mechanisms that generate these electrophysiological abnormalities and subsequent arrhythmogenesis.
Highlights
Hypokalaemia is the most common electrolyte abnormality found in hospitalized patients [1] and represents an important cause of arrhythmias and associated mortality observed in clinical practice [2]
Human cardiac models tend to have differences in repolarization reserve when compared to animal models, depending on cardiac miRNA levels for ion channel subunit production [103]
While there is a limited understanding on the implications of steep AP restitution gradients within the context of human hypokalaemia, the heterogeneity of Action potential duration (APD) restitution slopes have been proposed as a substrate for arrhythmogenesis in a wholeheart modeling study [105]
Summary
Hypokalaemia is the most common electrolyte abnormality found in hospitalized patients [1] and represents an important cause of arrhythmias and associated mortality observed in clinical practice [2]. Guinea pigs [15,16,17,18,19,20,21] and mice [22,23,24], have provided much insight into the detailed mechanisms underlying hypokalaemia-induced arrhythmogenicity In these models, arrhythmic activity has been observed during regular pacing (Figure 1A), programmed electrical stimulation that delivers S1S2 pacing (increasing premature S2 stimuli delivered following trains of regular S1 stimuli) (Figure 1B) and dynamic pacing (trains of regular S1 stimuli of decreasing basic cycle length) (Figure 1C). Whether serving as a disease model for pharmaceutical purposes or toxicology, the use of animal models as fundamental building blocks has enabled rapid advances in biomedical knowledge [27] This is no different in cardiology, with mice, rabbit and guinea pigs considered to be the most frequently used animal models in experimental cardiac electrophysiology [28]. Despite similarities in cardiac ion channel distribution, salient differences in electrophysiological results are still observed between small animal species, especially within the context of hypokalaemia
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