Arrhythmogenic Mechanisms in Hypokalaemia: Insights From Pre-clinical Models

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.

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“…Hypokalemia is associated with abnormal intracellular calcium and sodium metabolism, which can trigger arrhythmias such as ventricular tachycardia/fibrillation, atrial fibrillation, and atrial flutter [22,23]. In our study, the odds of severe tachycardia were higher in patients with hypokalemia compared to normokalemia, but not statistically significant.…”

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“…For example, APD prolongation and changes in electrophysiological characteristics caused by the downregulation of outward potassium currents, alterations of calcium channel kinetics and increases in late sodium currents create a substrate for ventricular arrhythmias in the case of heart failure ( Zhang et al, 2018 ). A study on hypokalemia showed that APD prolongation could predispose patients to early afterdepolarizations, which in turn act as triggers for ventricular arrhythmias ( Tse et al, 2021 ). APD prolongation is also the main factor responsible for the proarrhythmic influences of drugs with cardiotoxicity.…”

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“…Hypokalemia usually presents with muscle weakness and abnormalities of cardiac rhythm. The main etiologies of hypokalemia can be categorized into three groups: increased loss (renal or gastrointestinal), intracellular shift (due to medications or hormonal abnormalities), and reduced dietary K+ intake [ 3 ]. Characteristic ECG changes of hypokalemia include dynamic changes in T wave morphology (flattening and inversion of T waves) in mild hypokalemia, followed by prolonged QT interval, prominent U wave, and mild ST segment depression in severe cases.…”