| Potential mechanisms for drug-induced prolongation of QT interval and genesis of torsades de pointes evaluated in the failing rabbit heart | |
Abstract/OtherAbstract
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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 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. Currently preclinical in vitro and in vivo methods as well as biomarkers for proarrhythmias have been imperfect in predicting drug-induced TdP in humans. 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 conscious healthy rabbits, and the algorithm for removing effect of heart rate on QT is QTc=QT/(RR)0.72. 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 known torsadogens than did normal rabbits exposed to the same drug protocol. None of the rabbits in either group developed TdP when exposed to known non-torsadogens. 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. 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. 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. Verapamil, ryanodine and H-8 significantly delayed onset of VPDs and suppressed the occurrence 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. |
Authors
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Kijtawornrat, Anusak |
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Contributors
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Publication Detail
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Publisher : Ohio State University / OhioLINK Type : text Format : - |
Date Detail
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2007 |
Subject
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Conscious, Myocardial failing heart, Prolongation, QT, QTc, Rabbit, Torsades de pointes |
Coverage
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Relation
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Source
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http://rave.ohiolink.edu/etdc/view?acc_num=osu1165467926 |
Copyright Information
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unrestricted, Copyright and permissions information available at the source archive |
Other Details
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Languages : English |
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