The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome. Tridimensional mapping of activation and recovery patterns.
We have previously developed a canine in vivo model of the long QT syndrome (LQTS) using the neurotoxin anthopleurin A (AP-A), which acts by slowing sodium channel inactivation. The recent discovery of a genetic mutation in the cardiac sodium channel in some patients with the congenital LQTS, resulting in abnormal gating behavior similar to sodium channels exposed to AP-A, provides a strong endorsement of this animal model as a valid surrogate to the clinical syndrome of LQTS. In the present study, we conducted high-resolution tridimensional isochronal mapping of both activation and repolarization patterns in puppies exposed to AP-A that developed LQTS and polymorphic ventricular tachyarrhythmias (VTs). To map repolarization, we measured activation-recovery intervals (ARIs) using multiple unipolar extracellular electrograms. We demonstrated, for the first time in vivo, the existence of spatial dispersion of repolarization in the ventricular wall and differences in regional recovery in response to cycle-length changes that were markedly exaggerated after AP-A administration. Analysis of tridimensional activation patterns showed that the initial beat of polymorphic VT consistently arose as focal activity from a subendocardial site, whereas subsequent beats were due to successive subendocardial focal activity, reentrant excitation, or a combination of both mechanisms. Reentrant excitation was due to infringement of a focal activity on the spatial dispersion of repolarization, resulting in functional conduction block and circulating wave fronts. The polymorphic QRS configuration of VT in the LQTS was due to either changing the site of origin of focal activity, resulting in varying activation patterns, or varying orientations of circulating wave fronts.
el-Sherif
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Department of Medicine, State University of New York Health Science Center, Brooklyn 11203, USA. el-sherif.nabil@brooklyn.va.gov
Caref
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EB
Yin
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Restivo
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D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins; D008133:Long QT Syndrome / Q000503:physiopathology*; D010455:Peptides / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000503:physiopathology*
D002316:Cardiotonic Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C012746:anthopleurin-A