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

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 Ke+ 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.