Both abnormal automaticity and triggered activity induced by delayed afterdepolarizations have been proposed as the primary mechanism for ventricular tachycardia (VT) occurring in dogs 24 hr after ligation of the left anterior descending coronary artery. Because of this controversy, we studied the effects of ventricular pacing and therapeutic concentrations of lidocaine and ethmozin on sustained rhythmic activity of isolated subendocardial preparations excised from the infarct, and on VT in conscious dogs. There were differences in the sustained rhythmic activity cycle length of isolated preparations and the VT cycle length that were attributable to the absence of sympathetic input in the former and its presence in the latter. In isolated tissues, pacing for 1 or 10 beats reset the sustained rhythmic activity and pacing for 1 min induced overdrive suppression. Lidocaine (5 gtg/ml) had no effect on sustained rhythmic activity but ethmozin (2 g.g/ml) suppressed it. Delayed afterdepolarizations occurred but appeared to be induced by pacing or by the hyperpolarization associated with recovery. Although delayed afterdepolarizations were infrequent at 24 hr, their frequency increased with the hyperpolarization of the membrane that occurred at 48 to 96 hr after infarction. Delayed afterdepolarizations also occurred more readily when superfusate temperature was lowered. In conscious dogs, pacing the VT for 1 or 10 beats or 1 min had no effect. Lidocaine (2 to 10 ,Lg/ml) did not affect the VT but ethmozin (2 to 5 gg/ml) increased VT cycle length significantly. Pacing for 1 min in the presence of ethmozin, but not lidocaine, converted VT to sinus rhythm. Our results suggest that although delayed afterdepolarizations occur at 24 hr after infarction in the standard Harris preparation, they are most readily seen as an accompaniment of hyperpolarization, pacing, or lowering of bath temperature. The predominant rhythm at 24 hr appears to be automatic. Circulation 71, No. 6, 1224-1236, 1985 PREVIOUS STUDIES 14have shown that the origin of the ventricular tachycardia (VT) that occurs 24 hr after ligation of the left anterior descending coronary artery in the dog is in the subendocardial zone of the infarct. These studies attributed the VT to automaticity of depressed subendocardial Purkinje fibers that survived the infarct, although the possibility of reentry was considered.2' 3 Triggered activity resulting from delayed afterdepolarizations has also been noted in the 24 hr infarct, and From the
Doxorubicin, in concentrations that have no effect on fast or slow response action potentials, has been shown to suppress ouabain-induced delayed afterdepolarizations. In this study, we used standard microelectrode techniques to determine the effects of doxorubicin on isolated canine Purkinje fibers. We studied automaticity induced at normal and low membrane potentials, conduction in normal and K'-depolarized Purkinje fibers, and triggered activity induced by ouabain and by experimental myocardial infarction. Doxorubicin, 50 ,uM, suppressed the triggered activity and the delayed afterdepolarizations that induced it, but had no effect on the other variables. We then studied the effects of intravenous doxorubicin, 16 to 64 mg/m2 body surface area, on ouabain-induced ventricular tachycardia and the ventricular tachycardia that occurs 24 hr after ligation of the left anterior descending coronary artery in the intact dog. There was no effect on the infarct-induced arrhythmia, but concentrations of doxorubicin that had no other effect on the electrocardiogram suppressed those ouabain-induced arrhythmias that appeared to have been triggered. The automatic arrhythmias induced by ouabain were not affected. Both the latter mechanisms were verified in studies of isolated Purkinje fibers that were obtained on completion of the intact animal experiments. These results indicate that agents having high selectivity for specific arrhythmogenic mechanisms can be useful adjuncts in discriminating among the mechanisms responsible for arrhythmias in intact animals. Circulation 74, No. 4, 881-889, 1986. BECAUSE the characteristic responses to programmed electrical stimulation of such disparate mechanisms as reentry, triggered activity, and automaticity at low levels of membrane potential may at times be overlapping, the use of pacing alone to discriminate among them can be misleading (see references 1 to 4 for detailed discussion). For this reason, we5 and others6 have been using electrophysiologic testing and matrixes of drugs in an attempt to identify mechanism with a greater degree of accuracy in experimental animals and in patients. Although results with this approach have been promising, its use has been limited by the fact that most drugs act via more than one mechanism, thereby rendering discrimination among mechanisms difficult. Here we report results with the anthracycline antibiotic doxorubicin, which October 1986 has been shown in isolated tissue studies to predominantly modify one mechanism, delayed afterdepolarizations and resultant triggered activity.7 Although the doxorubicin dosages used clinically for cancer chemotherapy result in significant cardiac and noncardiac toxicity,8 we will demonstrate that the selectivity of this drug for a specific arrhythmogenic mechanism in isolated tissues and intact animals is such to encourage the search for other agents having comparably high selectivity and lesser toxicity. Methods
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