Potential mechanisms for drug-induced prolongation of QT interval and genesis of torsades de pointes evaluated in the failing rabbit heart.

摘要

Torsades de pointes (TdP) is a polymorphic ventricular tachycardia characterized by a distinctive pattern of undulating QRS complexes that twist around the isoelectric line. TdP is usually self-terminating or can subsequently degenerate into ventricular fibrillation, syncope, and sudden death. TdP has been associated with QT interval prolongation of the electrocardiogram; therefore, the QT interval has come to be recognized as a surrogate marker for the risk of TdP.; International guidelines have been developed to harmonize both the preclinical and clinical studies for the evaluation of drug-induced TdP. However, currently preclinical in vitro and in vivo methods as well as biomarkers for proarrhythmias have been imperfect in predicting drug-induced TdP in humans. It is clear that relevant biomarkers together with appropriate models are needed to assess the arrhythmic risk of new chemical entities.; The goal of the present dissertation is to create rabbit with myocardial failing heart as an in vivo animal model to predict TdP in humans and to determine mechanism(s) underlying TdP in this model.; Electrocardiograms were recorded from bipolar transthoracic leads in 7 conscious healthy rabbits previously trained to rest quietly in slings. The RR and QT relationship, QT = 2.4RR0.72 (r2 = 0.79, p 0.001) was obtained by slowed the heart rate with 2.0 mg/kg zatebradine, and the algorithm for removing effect of heart rate on QT is QTc = QT/(RR)0.72. QTc lengthened significantly in all conscious rabbits given intravenous cisapride, dofetilide or haloperidol (p 0.05), and QTc did not change with DMSO (vehicle control), propranolol or enalaprilat.; The rabbit with myocardial failure was created by coronary ligation and validated with drugs known to be torsadogenic or non-torsadogenic in humans. A greater percentage of rabbits with failing hearts developed TdP following intravenous infusion of escalating doses of dofetilide (85%), clofilium (100%), or cisapride (50%) than did normal rabbits exposed to the same drug protocol (20%, 33% and 0%, respectively). None of the rabbits in either group developed TdP when exposed to escalating doses of amiodarone, verapamil, or quinidine. These results suggested that a rabbit with myocardial failure possesses specificity and sensitivity to assess drugs that tend to induce TdP when given to humans. This is may be partly due to conscious rabbits with myocardial failing hearts had a slower heart rate, prolongation of QT and QTc intervals, and increase short-term variability when compared with the normal conscious group. Furthermore, the results from isolated myocytes of myocardial failure suggested that (1) the re-entrant circuits emanating from action potential durations of different duration, (2) triggered activity in the form of EADs, and (3) increased dispersion of repolarization are responsible for genesis of the TdP in the failing rabbit heart.; It is thought that abnormal calcium cycling is the proximate cause of EADs, and it is known that calcium cycling is abnormal in heart failure. The torsadogenic-modifying effects of verapamil, ryanodine, KB-R7943, W-7, KN-93, and H-8 on ventricular premature depolarizations (VPDs) and TdP were then evaluated in the conscious failing rabbit heart. In the vehicle control hearts, VPDs and TdP were induced in all rabbits and the times to onset of VPD and TdP were 3.6 +/- 1.3 min and 10.3 +/- 1.4 min, respectively. Verapamil, ryanodine and H-8 significantly delayed onset of VPDs (p 0.05) and suppressed the occurrence of TdP (p 0.01). On the other hand, KB-R7943, W-7, and KN-93 accelerated the onset of TdP. These results demonstrated that calcium entry via ICaL channel, calcium overload by SR Ca2+ release, and blocking of PKA may play a major role in the appearance of TdP suggested by the preventive effect of verapamil, ryanodine and H-8. Also, the data indicates that blockade of sodium/calcium exchange, calmodulin, and calcium/calmodulin depe