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The aim of this study was to investigate the efficacy and safety of bepridil (a multichannel blocker including several potassium channels) for conversion of long-lasting atrial fibrillation (AF). Bepridil restored sinus rhythm alone or in combination with aprindine in 69% of 32 patients with persistent AF lasting ≥3 months. The time to conversion after starting bepridil was 30 ± 12 days. An increase in fibrillation cycle length with bepridil was greater in responders (31 ± 10%), but an increase in QTc did not differ between responders and nonresponders. Bepridil is effective and safe for terminating long-lasting persistent AF.

Five cases of aprindine-induced polymorphous ventricular tachycardia (torsade de pointes) are presented. In four cases, polymorphous ventricular tachycardia appeared after the oral administration of aprindine and in one patient after the intravenous administration of 400 mg of aprindine. One patient had mild hypokalemia at the time of polymorphous ventricular tachycardia so that a direct cause and effect relation between the drug and the tachycardia cannot be established. All five patients manifested Q-T prolongation and recurrent syncope due to polymorphous ventricular tachycardia. In all five, polymorphous ventricular tachycardia subsided once administration of aprindine was discontinued.

A recent study has identified functional dissociation of atrial conduction in the genesis of sinus nodal reentry. The present study attempted to identify the spread of activation within Bachmann's bundle using the extrastimulus method in 17 dogs to provide further evidence for functional dissociation within or near Bachmann's bundle as a mechanism of paroxysmal supraventricular tachycardia. Premature stimuli were introduced in the high left atrium. In nine dogs of Group 1, recordings were obtained from the left atrial portion of Bachmann's bundle, high right atrium and both appendages. In six of the nine dogs achievement of critical delay in the interatrial conduction time (30 to 90 msec) resulted in echo beats with a similar activation sequence to that of high left atrial paced beats. In three of these six dogs the interatrial conduction time was abruptly increased from 25 to 50, 50 to 90 and 15 to 50 msec, respectively (with 10 msec decrements of coupling interval) at the critical coupling intervals, accounting for the discontinuous response curves. In another eight dogs (Group 2) Bachmann's bundle conduction was further studied with two additional recording electrodes impaled along Bachmann's bundle between the high right and high left atrial electrodes. Longitudinal dissociation of Bachmann's bundle was suggested by fragmentation of electrograms with initiation of a secondary wave. Induction and site of reentry appeared to be closely related to the appearance of fragmentation of the electrograms in the area of Bachmann's bundle. It is concluded that (1) Bachmann's bundle could undergo functional dissociation as evidenced by fragmentation of electrograms and discontinuous curves, (2) Bachmann's bundle reentry should be considered one mechanism of supraventricular tachycardia, and (3) reentry within the sinus and atrioventricular nodes, intraatrial or Bachmann's bundle is indistinguishable without precise mapping of atrial activation.

Moxaprindine, a new derivative of aprindine, possesses antiarrhythmic properties and is significantly less toxic than its parent compound on hematopoietic cells in culture. Its electrophysiologic effects were studied with programmed electric stimulation of the heart in 19 patients with recurrent episodes of reentrant tachyarrhythmias (atrioventricular nodal tachycardia, 8 cases; circus movement tachycardia involving an accessory pathway, 6 cases; ventricular tachycardia, 4 cases; ventricular tachycardia and atrioventricular nodal tachycardia, 1 case). Moxaprindine was perfused intravenously at a dose of 0.15 (10 cases) or 0.2 mg/kg per min (9 cases) during 15 minutes. Moxaprindine lengthened the conduction time along the His-Purkinje system as well as the refractory periods of right atrial and ventricular muscle. Depressing effects on the atrioventricular node were also seen, especially at the larger dose. The effects of the drug on accessory pathways used in anterograde manner were measurable in three cases. Complete blockade along the bypass was seen in two and prolongation of the effective refractory period in the remaining one. After moxaprindine, five of six patients showed retrograde blockade along the accessory pathway, whereas the last subject had prolongation of the refractory period of the bypass used in a ventriculoatrial direction. Perfused intravenously during episodes of tachycardia (atrioventricular nodal tachycardia, eight cases; circus movement tachycardia using an accessory pathway, six cases; ventricular tachycardia, three cases), the drug interrupted the rhythm disorder in all 17 instances. No tachycardia could be elicited after moxaprindine in 11 of the 19 patients. Among the six in whom sustained tachycardia could still be initiated, five had received the smaller dose. It is concluded that moxaprindine is a potent antiarrhythmic agent whose long-term efficacy and toxicity in patients deserve further investigation.

The acute electrophysiologic effects of intravenous aprindine were evaluated in 48 patients to assess the effect on conduction times and refractoriness in patients with severe cardiac disease and arrhythmias. The patients had not responded to conventional antiarrhythmic medications or had been unable to tolerate effective doses of conventional medications because of side effects. Eleven patients had an abnormal H-V interval, 9 had prolonged QRS duration and 22 had evidence of severe left ventricular dysfunction. Aprindine prolonged conduction transiently in the atria, the atrioventricular (A-V) node, the His-Purkinje system and the ventricles. The refractory times of the atria, the A-V node and the ventricles increased insignificantly, both functionally and statistically. Atrioventricular block did not develop in any patient, and side effects were minor. Thus, aprindine can be safely administered intravenously (10 to 15 mg/min) to severely ill patients with arrhythmias that are refractory to other medications even in the presence of underlying conduction system and myocardial disease.

The present status, clinical experience, side effects, clinical pharmacology and electrophysiologic actions of seven new antiarrhythmic agents are reviewed. The drugs selected for comment are amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide and verapamil. Each drug has been shown to have clinical efficacy in suppressing cardiac arrhythmias.

Ten patients with recurrent or continuous Supraventricular tachycardia difficult to control with conventional antiarrhythmic agents were treated with aprindine, a new antiarrhythmic drug. Nine patients had Wolff-Parkinson-White syndrome. An electrophysiologic study was performed before and during oral administration of aprindine. At the time of the first study, circus movement Supraventricular tachycardia was initiated in Patients 1 to 8. During administration of aprindine, circus movement Supraventricular tachycardia could no longer be initiated in Patients 1 to 4 but was initiated with difficulty in Patients 5 and 6 and with greater ease in Patients 7 and 8. In Patient 9, aprindine therapy slowed the ventricular response during atrial flutter from 1:1 conduction over the accessory pathway to 2:1 conduction over the normal pathway; in Patient 10, it slowed the ventricular rate during atrial fibrillation from 140–180 to 80–100 beats/min. Patients 1 to 6, 9 and 10 had an excellent clinical response, but treatment with aprindine was discontinued in Patients 7 and 8. Electrophysiologic evaluation revealed that aprindine produced complete block or increased refractoriness of the accessory pathway in an antegrade direction in all patients and in a retrograde direction in all but two (Patients 7 and 8) tested. Aprindine also slowed conduction in the accessory pathway and, when Supraventricular tachycardia could still be initiated, it occurred at a slower rate. Neurologic side effects occurred primarily during the initial administration and dose adjustment of aprindine.

During clinical treatment of arrhythmia in patients with chronic heart failure, cardiac function sometimes worsens due to the use of class I antiarrhythmic drugs. Morganroth and Horowitz 1 reviewed the risk of chronic heart failure induced by antiarrhythmic drugs. The class I drugs are classified as local anesthetics because of their sodium channel-inhibiting property. Suppression of the fast sodium current causes a decrease in intracellular calcium concentration and, therefore, a decrease in contractile force of muscles. 2–4 Dennis and Vaughan Williams 5 discussed the role of a reduction in the slow inward current in the negative inotropic effect of antiarrhythmic drugs. Recently, Honerjaeger et al 6 compared several class I antiarrhythmic drugs and tetrodotoxin. They concluded that class I antiarrhythmic drugs have negative inotropic effects due to the sum of sodium channel block and variable additional inotropic properties. They 6 examined calcium channel inhibition as a major additional mechanism underlying the negative inotropic effects, and suggested that several effects result from the sodium, potassium-adenosine triphosphatase inhibition. Concerning the inotropic properties of class I antiarrhythmic drugs, we now report that eibenzoline and aprindine (but not quinidine or disopyramide) transiently increase force by enhancing the effects of intrinsic adrenergic nerves in ventricular muscle at concentrations comparable to those used clinically.

Vaughan Williams 1 first at tempted to categorize known antidysrhythmic agents according to their individual electrophysiologic and pharmacologic actions. Hoffman and Bigger 2 summarized the possible membrane effects of antiarrhythmic agents and classified these compounds into several groups. Group 1, the quinidine-like agents, includes quinidine, propranolol and procainamide. To the original list can be added antihistamines, a new ester of ajmaline (MCAA), aprindine, disopyramide phosphate and potassium. These agents are classified together because they appear to decrease automaticity and responsiveness and prolong the refractory period. Drugs in group 2 include diphenylhydantoin, lidocaine and, under certain conditions, the catecholamines. Lidocaine and diphenylhydantoin decrease automaticity and increase responsiveness and the refractory period. However, drugs in group 2 are heterogeneous with respect to membrane action, and several investigators 3-25 have observed sharp differences in their action, particularly when the drug concentration and potassium concentration have a wide range. Vaughan Williams 26 believed that bretylium tosylate, a beta adrenergic blocking agent with potent antiarrhythmic action, could not be included in group I or 2 and possi

Aprindine was administered both intravenously and orally to 25 patients with ventricular tachycardia refractory to conventional antiarrhythmic agents to test the hypothesis that the response to intravenous aprindine predicts the response to oral aprindine. Ten patients had incessant ventricular tachycardia and 15 had paroxysmal sustained inducible ventricular tachycardia. Eleven patients (43 percent) had conversion to sinus rhythm with intravenous aprindine (nine with incessant and two with paroxysmal sustained ventricular tachycardia). Thirteen patients (all with paroxysmal sustained ventricular tachycardia) manifested slowing of the tachycardia without conversion, whereas in one patient with incessant ventricular tachycardia, the tachycardia became less frequent and nonsustained after intravenous aprindine. All 11 patients who had conversion to sinus rhythm with intravenous aprindine remained free of ventricular tachycardia during oral treatment with aprindine (at 2 weeks) and for a follow-up period of 2 to 38 months (mean 16 ± 13). Of the 14 patients who did not have conversion to sinus rhythm with intravenous aprindine, 12 had spontaneous or inducible ventricular tachycardia, or both, at evaluation 1 to 2 weeks after initiation of oral aprindine. In conclusion, administration of intravenous aprindine to patients with ventricular tachycardia is helpful in predicting the subsequent response to oral aprindine. In addition, the pattern of ventricular tachycardia predicted the response to aprindine; patients with incessant ventricular tachycardia tended to respond, and those with paroxysmal sustained ventricular tachycardia tended not to respond.

Cardiac arrhythmia causing sudden cardiac death is a serious worldwide public health problem. Antiarrhythmic agents have been available for therapy, but the conventional agents cause a high degree of intolerable side effects. The recent development of many new experimental antiarrhythmic agents has increased our capacity to effectively treat cardiac arrhythmias. Using a multifaceted approach of programmed electrical stimulation studies, drug level determinations, exercise testing and 24-hour ambulatory Holter monitoring, it can reasonably be decided which patient needs therapy and if therapy is going to be effective. Both aspects of the sudden death equation, ectopy frequency (triggering mechanism) and the ability to propagate sustained ventricular tachycardia (substrate), may be examined. Careful follow-up is needed to determine continued drug efficacy and the presence of side effects that may compromise patient compliance with therapy. If side effects intervene that may cause continued therapy to be intolerable, changing the antiarrhythmic agent, as opposed to decreasing the dosage to an ineffective range, may be appropriate. A comprehensive approach to arrhythmia management may begin to reduce the high incidence of sudden death due to fatal arrhythmias.

Twenty-three patients with recurrent ventricular tachycardia or ventricular fibrillation, or both, were treated with aprindine, a new antiarrhythmic agent. It was found that: (1) no patient had a recurrence of ventricular fibrillation after aprindine therapy was begun, except as a terminal event subsequent to the development of acute myocardial infarction and cardiogenic shock or refractory congestive heart failure; (2) 6 patients experienced ventricular tachycardia after the loading dose, but with continued aprindine therapy the ventricular tachycardia was suppressed in 3 of these 6 patients, and a fourth patient was asymptomatic during brief paroxysms of ventricular tachycardia; (3) in 2 patients, aprindine was ineffective and was discontinued; (4) electrical cardioversion was not required in any patient receiving aprindine; (5) premature ventricular extrasystoles were decreased in 18 of the 23 patients treated with apprindine; (6) aprindine was discontinued in 1 patient because of intolerable side effects, although ventricular arrhythmias were suppressed in this patient; and (7) 5 patients died from acute myocardial infarction or severe heart failure while receiving aprindine.

The repetitive ventricular response, defined as the production of two or more ventricular premature complexes in response to a single ventricular pacing stimulus, is common in patients with serious ventricular arrhythmias. Twenty-seven patients with refractory ventricular tachycardia were studied to determine whether acute suppression of the repetitive ventricular response by aprindine predicts long-term effectiveness of this agent. Twenty-three of the 27 patients had the repetitive ventricular response before intravenous administration of aprindine, whereas only 6 had the response after aprindine. All patients were maintained on a regimen of oral aprindine and evaluated repeatedly for a mean of 12 months. Twenty of the 21 patients who had no repetitive ventricular response after intravenous aprindine manifested clinical improvement compared with only 1 of the 6 in whom the repetitive response was present after aprindine (P less than 0.0005). Aprindine is a useful agent in refractory ventricular tachycardia, and the absence of the repetitive ventricular response after its intravenous administration predicts long-term clinical responsiveness to the oral form.

The influence of the excitability threshold on the ventricular fibrillation threshold was studied in dogs during myocardial ischemia and potassium and aprindine infusion. Interventions that influenced excitability threshold were associated with similar changes in ventricular fibrillation threshold although the percent change in both values differed. Although it is possible that the interventions studied caused parallel but independent changes in excitability threshold and ventricular fibrillation threshold, it is likely that the excitability threshold influences the ventricular fibrillation threshold. An increase in excitability threshold could result in an increase in ventricular fibrillation threshold in spite of an increase in the actual tendency of the heart to fibrillate spontaneously. Such discordance between the “electrical stability of the heart” and the ventricular fibrillation threshold was found during myocardial ischemia.

The present status, clinical experience, side effects, clinical pharmacology and electrophysiologic actions of seven new antiarrhythmic agents are reviewed. The drugs selected for comment are amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide and verapamil. Each drug has been shown to have clinical efficacy in suppressing cardiac arrhythmias.

The effects of various drugs on delayed activation of the ischemic myocardium and the incidence of ventricular arrhythmias were studied in 34 open-chest anesthetized dogs. The left anterior descending coronary artery was occluded for 6 minutes before and 42 minutes after administration of aprindine (2.85 mg/kg body weight), quinidine (8 mg/kg) and verapamil (0.2 mg/kg) and during infusion of isoproterenol (0.2 microng/min). The time intervals from the onset of the QRS complex to the major deflection of the bipolar electrograms recorded within the normal and ischemic zones were measured at cycle lengths of 500, 400 and 300 msec and were correlated with the development of ventricular arrhythmias. At a cycle length of 500 msec, aprindine increased by 19.5 msec the delay in activation time produced by coronary ligation alone (P less than 0.05), whereas verapamil reduced by 10 msec the extent of ischemia-induced conduction delay (P less than 0.05). The delay in activation time in the ischemic zone was not significantly altered by quinidine or isoproterenol. The incidence of ventricular arrhythmias was increased by aprindine (from 1 in 11 to 8 in 11 dogs), decresed by verapamil (from 3 in 7 to 0 in 7 dogs) and was not changes by quinidine or isoproterenol. Thus, delayed activation of the ischemic myocardium appears to play an important role in the genesis of early arrhythmias due to myocardial ischemia, and drugs that significantly depress conduction in the ischemic myocardium may predispose to the development of ventricular arrhythmia whereas those that improve conduction may be protective. Contrary to their effects on slow channel-dependent conduction, verapamil improved and isoproterenol worsened conduction during ischaemia.