Hypokalemia-Induced Arrhythmias and Heart Failure: New Insights and Implications for Therapy

Abstract

Routine use of diuretics and neurohumoral activation make hypokalemia (serum K⁺ < 3. 5 mM) a prevalent electrolyte disorder among heart failure patients, contributing to the increased risk of ventricular arrhythmias and sudden cardiac death in heart failure. Recent experimental studies have suggested that hypokalemia-induced arrhythmias are initiated by the reduced activity of the Na⁺/K⁺-ATPase (NKA), subsequently leading to Ca²⁺ overload, Ca²⁺/Calmodulin-dependent kinase II (CaMKII) activation, and development of afterdepolarizations. In this article, we review the current mechanistic evidence of hypokalemia-induced triggered arrhythmias and discuss how molecular changes in heart failure might lower the threshold for these arrhythmias. Finally, we discuss how recent insights into hypokalemia-induced arrhythmias could have potential implications for future antiarrhythmic treatment strategies.

Keywords: Na+ - K+-ATPase; arrhythmia (heart rhythm disorders); calcium; heart failure; hypokalaemia.

Figure 1

Model for transformation of a Ca²⁺ wave into an afterdepolarization. (a) Ca²⁺ ions are released spontaneously from the SR, either due to Ca²⁺ overload or increased RyR conductance (reduced threshold). The Ca²⁺ ions released from RyRs have three possible routes: (I) SERCA2 pumps the Ca²⁺ ions directly back into the SR. The Ca²⁺ wave is interrupted and no afterdepolarizations occur. (II) The Ca²⁺ ions diffuse to the neighboring RyRs, which leads to release of new Ca²⁺ ions. Repetitive events where Ca²⁺ ions are released and activate the next cluster of RyRs along the SR membrane lead to a Ca²⁺ wave. (III) Ca²⁺ can be extruded across the sarcolemma through the Na⁺/Ca²⁺ exchanger (NCX). This causes an inward, depolarizing current due to the inward flux of three positively charged Na⁺ ions per one Ca²⁺ that is extruded over the cell membrane. (b) Regular APs trigger synchronous Ca²⁺ release, which leads to cardiomyocyte contraction. Ca²⁺ waves can lead to DADs between two regular APs, and trigger a spontaneous AP as shown in the figure. Ca²⁺ waves during an AP can trigger EADs.

Figure 2

Proposed model for hypokalemia-induced triggered arrhythmias. (1) Low ${\text{K}}_{\text{e}}^{+}$ reduces the activity of the NKAα2 isoform. (2) Intracellular Na⁺ accumulates and leads to reduced inward NCX current, and by this less extrusion of Ca²⁺. (3) Intracellular and SR Ca²⁺ increases as a result. (4) Ca²⁺ overload increases the activity of the Ca²⁺/calmodulin-dependent kinase (CaMKII), which leads to a vicious cycle by phosphorylation of voltage-gated Na⁺ channels and L-type Ca²⁺ channels. (5) Increased influx of Na⁺ and Ca²⁺ amplifies Ca²⁺ overload and triggers EADs. (6) Hypokalemia-induced EADs can trigger ventricular tachyarrhythmias.