IKs blockade reduces dispersion of repolarization in heart failure.
BACKGROUND
The slow and rapid (I(Kr)) components of I(K) are major determinants of ventricular repolarization. Unlike I(Kr), which is homogeneously expressed across the transmural wall, I(Ks) expression is reduced in midmyocardial cells and presumably contributes significantly to transmural dispersion of repolarization. Increased dispersion of repolarization during pharmacologic blockade of I(Kr) is proarrhythmic, primarily due to relatively selective prolongation of midmyocardial cell action potential duration (APD). The mechanisms underlying proarrhythmia in heart disease associated with impaired repolarization, such as heart failure, are unknown. We hypothesize that, in contrast to I(Kr) blockade, I(Ks) blockade will have little effect on midmyocardial cells and hence decrease dispersion of repolarization in heart failure.


OBJECTIVE
The purpose of this study was to determine the effect of blockade of the slow component of the delayed rectifier current (I(Ks)) on arrhythmogenic dispersion of repolarization and proarrhythmia in heart failure.


METHODS
Optical action potentials were simultaneously recorded from 256 sites spanning the transmural wall of the arterially perfused canine wedge preparation. Hearts from dogs with heart failure induced by rapid pacing (n = 6) were compared with normals (n = 6).


RESULTS
Baseline dispersion of repolarization, as measured from the range of transmural APD during stimulation at a cycle length of 2,000 ms, was significantly higher in heart failure (75 +/- 24 ms) compared with controls (39 +/- 21 ms, P < .04). I(Ks) blockade with 30 microM chromanol decreased dispersion of repolarization by 40% (P < .02) in heart failure, reducing it to values found in normals. Decreased dispersion of repolarization was due to a larger, relatively selective, drug-induced APD prolongation of epicardial (23%) compared with midmyocardial cells (9%, P < .02). VT could not be induced in failing hearts under conditions of I(Ks) blockade, and no proarrhythmia was observed.


CONCLUSIONS
I(Ks) blockade significantly reduced heart failure-induced dispersion of repolarization to values seen in nonfailing hearts. By prolonging repolarization without increasing dispersion of repolarization, I(Ks) blockade may have antiarrhythmic effects without creating proarrhythmia.
Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109-1998, USA.
Mehdi
M
Pajouh
Lance D
LD
Wilson
Steven
S
Poelzing
Nancy J
NJ
Johnson
David S
DS
Rosenbaum
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology; D002839:Chromans / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*
D002839:Chromans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane