The effects of doxorubicin on ventricular tachycardia.

Abstract

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

The response to overdrive pacing of triggered atrial and ventricular arrhythmias in the canine heart.

“…In contrast, the two dogs in sinus rhythm 24 hr after infarction showed pacing-induced ventricular ectopic activity that behaved like triggered activity. These animals might have had smaller infarcts, a condition that may beaccompanied by lesser membrane depolarization and more ready induction of triggered arrhythmias.20 The ventricular beats we observed 48 hr after infarction appeared to be triggered, as previously described.20' 24 The subendocardium at this time has a higher membrane potential than at 24 hr and in this setting triggered arrhythmias are likely to appear.20…”

“…Table 3 shows the control RR values for the ventricular tachycardia and for sinus rhythm at 24, 48, and 72 hr after coronary ligation. At 24 hr. five dogs had stable ventricular tachycardia (polymorphic in three and monomorphic in two) and two were in sinus rhythm with frequent ventricular premature beats.…”

Premature escape beats. A model for triggered activity in the intact heart?

“…Based on the response of PEBs to electrical stimulation, we postulate that PEBs are based on triggered activity resulting from delayed afterdepolarizations. This hypothesis was tested in 82 experiments by 1) stimulation under control conditions and in combination with 2) subtoxic and toxic amounts of ouabain 20-50 jig/kg, 3) lidocaine 3 mg/kg, and 4) doxorubicin [16][17][18][19][20][21][22][23][24] mg/M2. The stimulation protocol, which was repeated at random five to 10 times, consisted of 10 and 50 stimuli using interstimulus intervals of 200, 400, 600, and 800 msec.…”

Premature escape beats induced by overdrive pacing in canine Purkinje fibers. Evidence for the role of normal automaticity as an underlying cellular mechanism.

“…The Purkinje fibers were impaled with 3 M KCIfilled glass microelectrodes having tip resistances of [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Mfl. Attempts were made to impale the site of earliest impulse initiation, at which the slope of phase 4 and phase 0 merged smoothly in the typical configuration of a pacemaker fiber.…”