Electrophysiological, Anatomical and Histological Remodeling of the Heart to AV Block Enhances Susceptibility to Arrhythmogenic Effects of QT-Prolonging Drugs

Abstract

ABSTRACT-The present study was designed to investigate what kinds of adaptation occurred in the canine chronic AV block model, which has been used to study torsade de pointes (TdP). Dogs at 7 -10 days (acute phase) and 28 -56 days (chronic phase) after AV block were assessed. Ventricular effective refractory period and monophasic action potential duration were prolonged in chronic animals compared with acute animals; moreover the electrically vulnerable period was prolonged in chronic animals. Non-specific IKr channel blocker cisapride (1 and 10 mg /kg, p.o.) was administered without anesthesia to estimate the feasibility of QT prolongation. In chronic animals, QT prolongation followed by TdP was induced in one dog by the low dose and in all by the high dose, which was not observed in acute animals. MR images indicated increases of diameter and wall thickness of both ventricles in chronic animals. The degree of hypertrophy was prominent in the right ventricular wall and septal wall. Heart weight of the chronic animals was 1.7 times greater than that of normal control subjects. Photo-and electron-micrograph analyses showed myocardial cell hypertrophy with parallel increases of collagen fiber and extracellular space in chronic animals. These electrophysiological, anatomical and histological adaptations may predispose the chronic AV block heart to drug-induced QT prolongation with enhanced risk of re-entry and early afterdepolarization, leading to the onset of TdP.Keywords: Long QT syndrome, AV block, Monophasic action potential, Holter ECG, MR image Since drug-induced prolongation of the QT interval is often associated with the onset of torsade de pointes (TdP), the interest in animal models of TdP arrhythmias has considerably increased (1, 2). The dog with chronic AV block has been used as a very suitable large-animal model for the study of TdP, both under conscious (3) and anesthetized circumstances (4 -10). Previous studies revealed that the functional adaptations predispose the canine AV block heart to acquired TdP (4, 6, 8 -10). Namely, QT interval and ventricular endocardial monophasic action potential (MAP) duration are much longer than expected from the bradycardia alone largely because of the reduction of IKs and IKr (4 -6). Moreover, early afterdepolarization and interventricular dispersion of repolarization have been suggested to play major roles in the genesis of acquired TdP (8 -10). However, it is still difficult to correlate the premature depolarization (trigger) and the dispersion of repolarization (substrate) to the occurrence of TdP.The present study was designed to investigate electrophysiological, anatomical and histological adaptation possibly related to the facilitated occurrence of TdP in the AV block heart. For this purpose, we first examined the local changes of the final repolarization phase of the action potential, since the spatial proarrhythmic substrates should locate in adjoining sites involved in the perpetuation of the arrhythmias (11). AV block was induced in dogs using a recently...

Effects of Disopyramide and Mexiletine on the Terminal Repolarization Process of the In Situ Heart Assessed Using the Halothane-Anesthetized In Vivo Canine Model.

“…Experiments are now on-going to demonstrate that hypothesis using canine complete atrioventricular conduction block models in which HR can be controlled by ventricular pacing over 40-200 beats/min. 32 On the other hand, mexiletine shortened the MAP90, but prolonged the ERP, resulting in the disappearance of TRP, which could prevent premature excitation with its associated conduction slowing. 14 These differences in the electrophysiological profiles of these drugs might explain their clinically described antiarrhythmic and proarrhythmic effects.…”

Effects of the Antitussive Drug Cloperastine on Ventricular Repolarization in Halothane-Anesthetized Guinea Pigs

“…Most of the torsadogenic drugs have been shown to inhibit a rapid component of delayed rectifier K + channels (I Kr ) encoded by the human ether-a-go-go-related gene (hERG) (1, 2). Indeed, a histamine H 1 -blocker terfenadine and a gastrokinetic drug cisapride are known as non-cardiovascular torsadogenic drugs, both of which are now clinically unavailable for patients (3,4). In 2004, clobutinol, a common over-the-counter antitussive drug, was reported to induce torsades de pointes in a young patient via inhibition of hERG K + channels (5,6), and then the drug was withdrawn from the worldwide market in 2007 after subsequent clinical investigations.…”

Analysis of Arrhythmogenic Profile in a Canine Model of Chronic Atrioventricular Block by Comparing In Vitro Effects of the Class III Antiarrhythmic Drug Nifekalant on the Ventricular Action Potential Indices Between Normal Heart and Atrioventricular Block Heart

“…Arrhythmogenic substrates in the chronic atrioventricular block dogs have been analyzed by in vitro single cell experiments and in vivo electrophysiological examinations in addition to the anatomical and histological assessments, in which downregulation of K channels and prolongation of the QT interval together with cellular hypertrophy and interstitial fibrosis were demonstrated (6,7,12). Furthermore, trigger of arrhythmias including early afterdepolarization can be spontaneously induced by QT-interval-prolonging drugs via the increase of temporal dispersion of repolarization, leading to generation of ventricular tachyarrhythmias like torsades de pointes (6,10).…”