Cellular basis for complex T waves and arrhythmic activity following combined I(Kr) and I(Ks) block.
BACKGROUND
A growing number of cardiomyopathies have been shown to result in a reduction in both I(Kr) and I(Ks) yet little is known about the electrophysiologic and ECG characteristics of combined I(Kr) and I(Ks) block.


RESULTS
To address this gap in our knowledge, transmembrane action potentials (APs) from epicardial, M, and endocardial cells were recorded simultaneously, together with a transmural ECG from arterially perfused canine left ventricular wedge preparations exposed to combined I(Kr) (d-sotalol; 100 micromol/L) and I(Ks) (chromanol 293B; 30 to 60 micromol/L) block. Under baseline conditions, the T wave was typically upright; epicardium repolarized first, coinciding with the peak of the T wave, and the M cells repolarized last, coinciding with the end of the T wave (T(end)). Complex (inverted, biphasic, and triphasic) T waves developed following combined I(Kr) and I(Ks) block. M and epicardial APs prolonged dramatically, so that the endocardial AP was now the earliest to repolarize, coinciding with the first nadir of the complex T wave. In the case of biphasic/triphasic or inverted T waves, Tend coincided with repolarization of either M or epicardial cells, whichever was the last to repolarize. QT intervals prolonged from 286+/-13 msec up to 744+/-148 msec and transmural dispersion of repolarization (TDR) increased from 33+/-10 msec up to 244+/-71 msec. Early afterdepolarizations (EADs) developed in M and epicardial cells, evoking extrasystoles that precipitated polymorphic ventricular tachycardia. Acceleration-induced EADs and T wave alternans also were observed.


CONCLUSIONS
Combined I(Kr) and I(Ks) block gives rise to inverted, biphasic, and triphasic T wave morphologies, a dramatic increase in TDR, and a high incidence of EADs. The diversity of T wave morphologies derives from a preferential AP prolongation of different transmural layers leading to variation in the predominance of voltage gradients on either side of the M cell region. Our study provides direct evidence linking EADs that arise in ventricular epicardial and M cells to the triggered beats that precipitate polymorphic ventricular tachycardia. Our results also suggest possible guidelines for the estimation of TDR from complex T waves appearing in the precordial leads of the surface ECG.
Emori
T
T
Masonic Medical Research Laboratory, Utica, New York 13501-1787, USA.
Antzelevitch
C
C
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology; D002839:Chromans / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography; D004699:Endocardium / Q000166:cytology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D008133:Long QT Syndrome / Q000209:etiology / Q000503:physiopathology*; D009206:Myocardium / Q000166:cytology; D010496:Pericardium / Q000166:cytology; D013015:Sotalol / Q000494:pharmacology; D016171:Torsades de Pointes / Q000188:drug therapy / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D002839:Chromans; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D013015:Sotalol