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 syn drome (LQTS) using the neurotoxin anthopleurin A (AP-A), which acts by slowing sodium channel inactivation. The recent discovery of a geneti c mutation in the cardiac sodium channel in some patients with the con genital 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 p resent study, we conducted high-resolution tridimensional isochronal m apping of both activation and repolarization patterns in puppies expos ed to AP-A that developed LQTS and polymorphic ventricular tachyarrhyt hmias (VTs). To map repolarization, we measured activation-recovery in tervals (ARIs) using multiple unipolar extracellular electrograms. We demonstrated, for the first time in vivo, the existence of spatial dis persion of repolarization in the ventricular wall and differences in r egional recovery in response to cycle-length changes that were markedl y exaggerated after AP-A administration. Analysis of tridimensional ac tivation patterns showed that the initial beat of polymorphic VT consi stently arose as focal activity from a subendocardial site, whereas su bsequent beats were due to successive subendocardial focal activity, r eentrant excitation, or a combination of both mechanisms. Reentrant ex citation was due to infringement of a focal activity on the spatial di spersion of repolarization, resulting in functional conduction block a nd circulating wave fronts. The polymorphic QRS configuration of VT in the LQTS was due to either changing the site of origin of focal activ ity, resulting in varying activation patterns, or varying orientations of circulating wave fronts.