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This study addresses the question of the choice of treatment for the individual patient with chronic ventricular arrhythmias. Acute oral drug testing offers a pragmatic approach to the rapid selection of the drug with the best efficacy/side-effect ratio by allowing multiple comparisons within the same patient. Forty patients with chronic ventricular arrhythmias received a single oral dose of the following antiarrhythmic drugs: flecainide 200 mg, propafenone 450 mg, disopyramide 300 mg, mexiletine 400 mg, tocainide 800 mg, verapamil 160 mg, propranolol 120 mg. Criteria for efficacy were suppression of complex ventricular arrhythmias and a greater than 90% reduction in premature ventricular beats lasting for at least 2 h. An antiarrhythmic effect was achieved with each of the drugs in the following percentages of patients: flecainide 69.4%, propafenone 67.5%, disopyramide 54.8%, mexiletine 45.2%, tocainide 31.3%, verapamil 31.3%, propranolol 12.5%. In no case was worsening of arrhythmia observed. At the end of the acute testing phase, the drug that had proved most effective in each patient was administered at a full dosage for 72 h. A concordant response between the two phases was observed in 80% of patients and was as high as 89% when the analysis was limited to flecainide and propafenone. This study shows the feasibility and practical advantages for patient management of a multiple comparison of antiarrhythmic drugs by acute oral drug testing. It also provides, in a non-invasive cost-effective manner, unique insights into the complex relationship between drug characteristics, individual responses and clinical efficacy.

The antiarrhythmic efficacy of a new class I agent, penticainide, was evaluated by acute oral drug testing and compared in the same patient population with the efficacy of disopyramide, flecainide, mexiletine and propafenone. Twenty-five patients with high-grade chronic ventricular arrhythmias entered the study. During acute oral drug testing, penticainide (7 mg/kg) was effective (more than 90% reduction in ventricular premature complexes and complete abolition of class 4A and 4B arrhythmias) in 17 of 25 subjects (68%). The mean plasma level of the drug at 90 minutes was 4.4 +/- 1.9 micrograms/ml; at the same time increases in the PQ interval (from 168 +/- 27 to 189 +/- 31 ms, p less than 0.0001) and QRS duration (from 89 +/- 14 to 96 +/- 18 ms, p less than 0.001) were observed. The QTc was slightly but not significantly shortened in the overall population; however, in the subgroup with a basally prolonged QTc (n = 8), a significant reduction was observed (from 456 +/- 8 to 440 +/- 18 ms, p less than 0.02). No adverse effects were reported. The antiarrhythmic efficacy of the other drugs tested in the same population was: disopyramide, 12 of 19 (63%); flecainide, 13 of 24 (54%); propafenone, 13 of 24 (54%); and mexiletine, 7 of 20 (35%). Penticainide appears to be a well-tolerated and effective compound of potential value for treatment of ventricular arrhythmias.

The potential role of calcium entry blockers in the prevention of life-threatening arrhythmias associated with acute myocardial ischemia and reperfusion is still controversial. In 98 anesthetized cats, the effect of diltiazem was examined in two experimental models. In protocol I, ventricular tachycardia or fibrillation was consistently induced by the interaction between a 2 minute coronary artery occlusion and a 30 second left stellate ganglion stimulation. After three trials under control conditions, if the same pattern of arrhythmia was induced, the drug under study was administered and three additional trials were performed. In 16 animals the administration of saline solution did not modify the pattern of arrhythmias. In contrast, diltiazem (0.1 mg/kg body weight plus 0.2 mg/kg per h) abolished both ventricular tachycardia and fibrillation that had occurred in 64 and 36%, respectively, of the cats in the control state. In protocol II, a 20 minute coronary artery occlusion was released in three groups; one served as the control group, one received diltiazem 15 minutes before occlusion and one received diltiazem 3 minutes before reperfusion. The incidence of reperfusion ventricular fibrillation was 62% (16 of 26) in the control group. It was significantly (p less than 0.05) reduced by diltiazem administered before the occlusion to 25% (4 of 16), whereas it was not affected when diltiazem was administered just before reperfusion (7 [47%] of 15). These results indicate that diltiazem exerts a striking protective effect against the malignant arrhythmias induced by the combination of acute myocardial ischemia and sympathetic hyperactivity. Diltiazem was also effective in reducing the incidence of life-threatening reperfusion arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic hyperactivity plays a major role in the genesis of malignant arrhythmias during acute myocardial ischemia. An experimental model in which life-threatening arrhythmias are specifically and consistently induced by the interaction between acute myocardial ischemia and left stellate ganglion stimulation has been developed in alpha-chloralose anesthetized cats. In this preparation, drugs that share antiischemic, antiadrenergic, and specific electrophysiologic effects, such as verapamil, diltiazem, and amiodarone, were most effective. To evaluate the relative role of these different properties in mediating the effect of antiarrhythmic drugs, we used this same model to test nifedipine, a calcium channel blocker that is able to counteract the consequences of sympathetic stimulation on coronary circulation but has no electrophysiologic properties at concentrations relevant in the clinical setting. Nifedipine (15 micrograms/kg) prevented the occurrence of ventricular fibrillation in 10 of 13 animals (77%). Its efficacy was independent of changes in the peripheral hemodynamics. Plasma concentrations of nifedipine were within the therapeutic range in humans. To evaluate if this rather striking protective effect was specifically related to the prevention of the deleterious consequences of sympathetic stimulation, the effect of nifedipine on ventricular fibrillation threshold was studied in an additional group of 13 cats in the nonischemic state, during acute myocardial ischemia and during ischemia plus sympathetic stimulation. Nifedipine did not modify ventricular fibrillation threshold in nonischemic or in ischemic conditions. However, nifedipine specifically prevented the further reduction in ventricular fibrillation threshold occurring when sympathetic stimulation was superimposed on acute ischemia. These data suggest that the extension of ischemic damage by sympathetic stimulation is an important progenitor of arrhythmogenic action during acute ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the autonomic nervous system in modulating reperfusion arrhythmias is still unclear. Experiments with sympathetic denervation or alpha- and beta-adrenergic blocking agents have provided mixed results, while the effect of parasympathetic activation has not been investigated extensively. The effect of bilateral vagotomy and of vagal stimulation was studied, with and without attendant bradycardia, on the incidence of reperfusion arrhythmias in alpha-chloralose anesthetized cats. The left anterior descending coronary artery was occluded for 20 minutes, followed by reperfusion in 105 animals. The incidence and severity of reperfusion arrhythmias was compared in 1) neurally intact animals (heart rate 208 +/- 24 beats/min), 2) animals with acute bilateral vagotomy (heart rate 233 +/- 25 beats/min), 3) animals with vagal stimulation adjusted to maintain heart rate at 90-100 beats/min, and 4) animals with vagal stimulation + ventricular pacing to maintain heart rate at prestimulation values. All the neurally intact and vagotomized animals developed complex reperfusion arrhythmias, but these arrhythmias occurred in only 60 and 72%, respectively, of the animals with vagal stimulation and vagal stimulation + pacing (p less than 0.005 vs. neurally intact and p less than 0.02 vs. vagotomy). The incidence of ventricular fibrillation was similar in neurally intact (62%) and vagotomized (58%) animals; it was strikingly lower (7%, p less than 0.01) in animals with vagal stimulation when heart rate was allowed to decrease, and it was 48% when heart rate was kept constant during vagal stimulation. A selective protection from sustained (greater than 30 seconds duration) ventricular tachycardia was observed in animals with vagal stimulation independent of heart rate changes.(ABSTRACT TRUNCATED AT 250 WORDS)

The long-term efficacy and safety of flecainide (100 to 200 mg twice a day) were evaluated in 21 patients with high-grade, chronic ventricular arrhythmias who responded to and tolerated flecainide at a preliminary evaluation (200 mg, single oral dose). Antiarrhythmic response was evaluated at 3 days and 3, 6, 12, 18, and 24 months. The mean follow-up was 25 +/- 14 months (range 3 to 52). Four patients (19%) were excluded from efficacy analysis because of spontaneous decrease in baseline arrhythmia observed after 12 months of therapy. Effective arrhythmia suppression at both Holter monitoring and during exercise stress testing was maintained in 14 of 17 patients (82%). Mean frequency of premature ventricular contractions remained reduced by more than 95% throughout the follow-up. Five patients discontinued therapy between 3 and 18 months because of drug ineffectiveness (three patients, 18%) or side effects (two patients, 12%). In 12 patients (71%) long-term efficacy and tolerance were demonstrated. In no case was aggravation of arrhythmia or adverse cardiac effects observed. Side effects (5% to 29% of patients during follow-up) were usually minor and easily abolished by dosage reduction. In patients with chronic ventricular arrhythmias, flecainide maintained a favorable ratio between efficacy and side effects during a 2-year follow-up.

Activation of cardiac sympathetic nerves is recognized as a triggering factor for cardiac arrhythmias. However, the mechanisms involved have only been speculated. Because evidence from studies in vitro has established a relation between catecholamines, delayed afterdepolarizations (DAD), and triggered rhythms, it seemed possible that in vivo adrenergic activation also might lead to the development of DAD. Because very little evidence was available for DAD in vivo, we have evaluated whether monophasic action potential (MAP) recording with a contact electrode could be a suitable technique for the detection of DAD from the endocardium of anesthetized cats. In six animals, atrial pacing and graded aortic constriction were performed during MAP recording to assess MAP stability during hemodynamic changes, and in no cases were modifications of the baseline observed. In 11 cats, calcium gluconate (0.5 g) and G-strophanthin (100 micrograms) were administered. Action potential duration at 50% (APD50) and 90% (APD90) repolarization were reduced (from 138 +/- 16 to 122 +/- 18 msec, p less than 0.02, and from 163 +/- 23 to 149 +/- 20 msec, p less than 0.025, respectively). In eight of 11 (73%) animals, DAD were elicited with a mean amplitude of 1.2 +/- 0.4 mV. In 14 cats, the left stellate ganglion was stimulated for 45 seconds. APD50 and APD90 decreased (from 153 +/- 15 to 145 +/- 16 msec, p less than 0.005, and from 176 +/- 18 to 165 +/- 13 msec, p less than 0.001, respectively). DAD were induced in 10 of 14 animals (71%) with a mean amplitude of 1.2 +/- 0.3 mV. These results show that DAD can be induced in vivo by administration of calcium and digitalis and by activation of the cardiac sympathetic nerves. This latter finding further strengthens the existing link between adrenergic activation and ventricular arrhythmogenesis and suggests triggered activity as a likely mechanism.