Amplified transmural dispersion of repolarization as the basis for arrhythmogenesis in a canine ventricular-wedge model of short-QT syndrome.
BACKGROUND
The short-QT syndrome is a new clinical entity characterized by corrected QT intervals <300 ms and a high incidence of ventricular tachycardia (VT) and fibrillation (VF). Gain-of-function mutations in the gene for outward potassium currents have been shown to underlie the congenital syndrome. The present study examined the cellular basis of VT/VF in an experimental model associated with short QT intervals created with a potassium channel activator.


RESULTS
Transmembrane action potentials from epicardial and M regions, 4 transmural unipolar electrograms, and a pseudo-ECG were simultaneously recorded in canine arterially perfused left ventricular wedge preparations. At a basic cycle length of 2000 ms, pinacidil (2 to 3 mumol/L) abbreviated the QT interval from 303.7+/-5.4 to 247.3+/-6.9 ms (mean+/-SEM, P<0.0001). The maximal transmural dispersion of repolarization (TDR(max)) increased from 27.0+/-3.8 to 64.9+/-9.2 ms (P<0.01), and an S2 applied to the endocardium induced a polymorphic VT (pVT) in 9 of 12 wedge preparations (P<0.01). Addition of isoproterenol (100 nmol/L, n=5) led to greater abbreviation of the QT interval, a further increase in TDR(max) (from 55.4+/-13.7 to 69.7+/-8.3 ms), and more enduring pVT. TDR(max) was correlated significantly with the T(peak)-T(end) interval under all conditions. The effects of pinacidil were completely reversed by glybenclamide (10 micromol/L, n=4) and partially reversed by E4031 (5 micromol/L, n=5), which prevented induction of pVT in 3 of 5 preparations.


CONCLUSIONS
Our data suggest that heterogeneous abbreviation of the action potential duration among different cell types spanning the ventricular wall creates the substrate for the genesis of VT under conditions associated with short QT intervals.
Extramiana
Fabrice
F
Masonic Medical Research Laboratory, Utica, NY 13501, USA.
Antzelevitch
Charles
C
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D004285:Dogs; D004562:Electrocardiography; D006352:Heart Ventricles / Q000503:physiopathology; D008297:Male; D013577:Syndrome; D017180:Tachycardia, Ventricular / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000503:physiopathology