Use of the rabbit with a failing heart to test for torsadogenicity

Torsades de pointes is a potentially lethal arrhythmia that occurs infrequently but may be drug-induced particularly in patients with pathological substrates. However drugs are usually evaluated for torsadogenicity in normal subjects, thus potentially limiting the sensitivity of studies to predict liability in man. Heart failure is a pathological substrate permissive to drug-induced torsades cle pointes. Failing hearts may be produced with a high yield in rabbits with ligation of coronary arteries. Failing myocardium may be documented by reduced left ventricular ejection fraction and elevation of NTproBNP. QTc in failing hearts prolonged only slightly more in failing hearts than in normals in response to torsadogens, but incidence of torsades cle pointes increased dramatically. Abnormal calcium cycling resulting in early afterdepolarizations appeared to develop more in hypertrophic myocardial cells located in the border between normal myocardium and infarct. In failing hearts, torsades cle pointes appeared to develop more prevalently without greater lengthening of QT than in hearts from normal rabbits. Thus this model appears to be a facile and useful preparation for identifying torsadogenic potential of test articles, and it probably possesses anatomical and physiological substrates that mimic closely the torsadogenic substrates in the many millions of persons possessing failing hearts. (C) 2008 Elsevier Inc. All rights reserved.