Molecular Basis of Hypokalemia-Induced Ventricular Fibrillation.
BACKGROUND
Hypokalemia is known to promote ventricular arrhythmias, especially in combination with class III antiarrhythmic drugs like dofetilide. Here, we evaluated the underlying molecular mechanisms.


RESULTS
Arrhythmias were recorded in isolated rabbit and rat hearts or patch-clamped ventricular myocytes exposed to hypokalemia (1.0-3.5 mmol/L) in the absence or presence of dofetilide (1 μmol/L). Spontaneous early afterdepolarizations (EADs) and ventricular tachycardia/fibrillation occurred in 50% of hearts at 2.7 mmol/L [K] in the absence of dofetilide and 3.3 mmol/L [K] in its presence. Pretreatment with the Ca-calmodulin kinase II (CaMKII) inhibitor KN-93, but not its inactive analogue KN-92, abolished EADs and hypokalemia-induced ventricular tachycardia/fibrillation, as did the selective late Na current (INa) blocker GS-967. In intact hearts, moderate hypokalemia (2.7 mmol/L) significantly increased tissue CaMKII activity. Computer modeling revealed that EAD generation by hypokalemia (with or without dofetilide) required Na-K pump inhibition to induce intracellular Na and Ca overload with consequent CaMKII activation enhancing late INa and the L-type Ca current. K current suppression by hypokalemia and dofetilide alone in the absence of CaMKII activation were ineffective at causing EADs.


CONCLUSIONS
We conclude that Na-K pump inhibition by even moderate hypokalemia plays a critical role in promoting EAD-mediated arrhythmias by inducing a positive feedback cycle activating CaMKII and enhancing late INa. Class III antiarrhythmic drugs like dofetilide sensitize the heart to this positive feedback loop.
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Arash
A
Pezhouman
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Neha
N
Singh
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Zhen
Z
Song
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Michael
M
Nivala
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Anahita
A
Eskandari
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Hong
H
Cao
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Aneesh
A
Bapat
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Christopher Y
CY
Ko
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Thao
T
Nguyen
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Zhilin
Z
Qu
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Hrayr S
HS
Karagueuzian
UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
James N
JN
Weiss
D000200:Action Potentials; D000818:Animals; D001596:Benzylamines / Q000627:therapeutic use; D003198:Computer Simulation; D007008:Hypokalemia / Q000150:complications*; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D011725:Pyridines / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use; D014693:Ventricular Fibrillation / Q000209:etiology* / Q000517:prevention & control; D000096926:Benzenesulfonamides
D001596:Benzylamines; D010627:Phenethylamines; D011725:Pyridines; D000254:Sodium-Potassium-Exchanging ATPase; D013449:Sulfonamides; D014230:Triazoles; C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; C072105:KN 93; D000096926:Benzenesulfonamides; C063533:dofetilide
anti-arrhythmia agents; arrhythmias, cardiac; long QT syndrome; potassium; signal transduction