Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes

Abstract

Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes. OBJECTIVE: To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes. METHODS AND RESULTS: Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K + ] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca 2+ overload and increased generation of both spontaneous Ca 2+ waves and delayed afterdepolarizations. However, similar Ca 2+-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na +-K + ATPase and Na +-Ca 2+ exchanger proteins within these structures, as reduction in Na + pump activity locally inhibited Ca 2+ extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca 2+ overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca 2+ quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na + current, as they were rapidly blocked by tetrodotoxin. Na + current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K + current (I Kur); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes. CONCLUSIONS: Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology. VISUAL OVERVIEW: An online visual overview is available for this article.

A carvedilol analogue, VK‐II‐86, prevents hypokalaemia‐induced ventricular arrhythmia through novel multi‐channel effects

“…We found a significant depolarization of the RMP in the ventricular AP for both murine and canine ventricular tissues and cells. This contrasts with previous studies reporting that hypokalaemia results in hyperpolarization of RMP (Aronsen et al, 2015; Bouchard et al, 2004; Tazmini et al, 2020). These studies all investigated the effects of acute hypokalaemia on RMP, but there are no published studies of the effects of chronic hypokalaemia on RMP.…”

“…In the present study, 1 μM VK‐II‐86 in both murine and canine models slightly hyperpolarized the resting membrane potential in low [K + ]. This could also be beneficial in reducing intracellular Ca 2+ loading, because a hyperpolarized RMP favours the forward mode of NCX (Tazmini et al, 2020), and would therefore enable more Ca 2+ extrusion from the cell.…”

“…It is therefore encouraging that VK‐II‐86 prevented the increase in I Ca and I Na_L in ventricular myocytes but did not significantly reduce these currents in cells held in normal [K + ], which could be harmful due to negative inotropy and QT alteration. Further investigation into the interaction of VK‐II‐86 with Na + channels is warranted as a recent publication found that hypokalaemia‐induced AF in atrial cells lacking T‐tubules is predominantly due to reactivation of non‐equilibrium I Na , rather than intracellular Ca 2+ loading (Tazmini et al, 2020).…”

“…However, the role of intracellular Ca 2+ loading in the pathogenesis of hypokalaemia‐induced arrhythmia (Tazmini et al, 2020) has been highlighted in recent studies. Hypokalaemia has been shown to inhibit Na/K ATPase (Aronsen et al, 2015).…”

Re-print: Ranolazine may be the Best and Safest Pharmacologic Therapy for Congestive Heart Failure, and Safe, Effective for Ventricular and Atrial Arrhythmias

“…EAD/DAD is causes of triggered ventricular ectopy [38][39] and can be induced by late INa that RAN inhibits. DAD are due to spontaneous release of Ca++ from the sarcoplasmic reticulum, and EAD are directly due to Ca++ entry through the Ca++ window current, except in Purkinje fibers where EAD are due to late INa window current (35,39) Some clinical scenarios of EAD/DAD-mediated ventricular arrhythmias include CHF [40], catechol aminergic polymorphic VT(41) hypokalemia [42] left ventricular hypertrophy (LVH) [43] long QT syndrome [44] and cocaine use [45] Our patients met criteria for VP [46][47] This is the second study reporting effects of RAN on PVCs in humans, but the first focusing exclusively on triggered ventricular ectopy.…”