Flunarizine allows differentiation between mechanisms of arrhythmias in the intact heart.

Abstract

The calcium antagonist flunarizine suppresses pathologic accumulation of calcium intracellularly without affecting the fast sodium or the slow calcium channel. To establish its value in differentiating between mechanisms of arrhythmias in the canine heart, the effect of flunarizine was investigated on ventricular tachycardia (VT) induced by ouabain intoxication or occurring 16-24 hours after occlusion of the left anterior descending coronary artery. Four groups of dogs were studied. Group 1 consisted of 13 animals with VT induced by ouabain intoxication (triggered-activity group). Group 2 included nine dogs in whom VT developed 16-24 hours after occlusion of the left anterior descending coronary artery (abnormal automaticity group). Group 3 included six dogs with normally conducted sinus beats, whereas group 4 consisted of six animals having a ventricular escape rhythm. With the exception of group 3, all dogs had surgically induced complete atrioventricular block. All animals were studied while conscious and without premedication. In groups 1 and 2, 2-3 mg/kg flunarizine was given intravenously after VT had persisted for at least 20 minutes. In groups 3 and 4, 2 mg/kg flunarizine was given after the rhythm was registered for 20 minutes. The cycle lengths of the different rhythms were compared before and after flunarizine. In group 1, flunarizine increased the cycle length of the VT from 300±30 to 410+50 msec (pO.001). Termination of VT was seen in 11 out of 13 animals. In group 2, flunarizine resulted in a nonsignificant shortening of the RR interval from 450±60 to 440+60 msec. Persistent termination was observed in only one of nine dogs. A significant acceleration in rate was seen in groups 3 and 4. In conclusion, flunarizine slows and terminates ventricular arrhythmias resulting from triggered activity but accelerates rhythms based on normal and abnormal automaticity. These findings suggest that flunarizine can be used to differentiate between mechanisms of arrhythmias. (Circulation 1990;81:343-349) T wo decades ago, clinically occurring cardiac arrhythmias were thought to result from either automaticity, reentry, or a combination of these mechanisms.' In vitro, other mechanisms have been described, like triggered activity induced by early and delayed afterdepolarizations (DADs) and abnormal automaticity.2 While reentry has been proven to be responsible for a number of human supraventricular and ventricular arrhythmias,34 the clinical relevance of the other mechanisms is not known.

Termination of a tachyarrhythmia by flunarizine is not a specific marker for a triggered mechanism

“…However, flunarizine is not effective in terminating induced, reentrant ventricular tachycardia in a canine myocardial infarction model (13). Additionally, flunarizine does not affect normal or abnormal automaticity, as shown in studies of sinus rhythm and early post myocardial infarct ventricular tachycardia in canine models and barium-depolarized canine Purkinje fibers (14,15).…”

“…Seven of these episodes were followed by open chest studies (see below). In all 11 episodes, flunarizine hydrochloride in hydroxypropyl-beta-cyclodextrin (Sigma-Aldrich, St Louis, MO, USA) was administered intravenously as a 2 mg/kg dose over 2 minutes (13,14,16). All dogs received intravenous hydration with normal saline to prevent or minimize a potential hypotensive effect from the flunarizine administration.…”

“…The drug was given as a bolus over a finite time in accordance with the majority of prior studies investigating the antiarrhythmic properties of flunarizine in vivo (12)(13)(14), rather than as a continuous infusion to achieve and maintain a steady state plasma concentration of the agent. Our observation that AFL becomes reinducible about 20 or more minutes after completion of the drug's infusion suggests that the effects of flunarizine are relatively short lived.…”

Afterdepolarizations Promote the Transition From Ventricular Tachycardia to Fibrillation in a Three-Dimensional Model of Cardiac Tissue.

“…22 On the other hand, in the present study we found that restraining afterdepolarizations is indispensable for both strategies, and our results suggest that only altering the restitution properties is insufficient to stabilize the SW reentry. We would like to stress that the reducing afterdepolarizations and TA (as with the use of agents such as lidocaine, 36 doxorubicin, 37 and calcium blocking agent 12 ) may be important as well for the latter strategy.…”

“…[10][11][12][13][14][15] The EADs are classified into phase-2 and phase-3 EADs. The phase-2 EADs can be induced experimentally by various conditions, even in the absence of calcium overload.…”