Pablo A. Chiale

Clinical efficacy of amiodarone as an antiarrhythmic agent.

Amiodarone, administered orally in doses of 200 to 600 mg/day, was remarkably effective in the treatment and prevention of a wide variety of atrial and ventricular arrhythmias. Total suppression and control was provided in 98 (92.4 percent) of 106 patients with supraventricular arrhythmias and in 119 (82 percent) of 145 patients with ventricular arrhythmias. The rates of total control of the arrhythmia were: 96.6 percent in 30 patients with recurrent atrial flutter or fibrillation, 96.6 percent in 59 patients with repetitive supraventricular tachycardia, 100 percent in 27 patients with Wolff-Parkinson-White syndrome and 77.2 percent in 44 patients with recurrent ventricular tachycardia unsuccessfully treated with other drugs. Excellent results were obtained in 6 to 8 patients with repetitive ventricular tachycardia and ventricular fibrillation related to postinfarction ventricular aneurysm and in 12 of 14 patients with ventricular extrasystoles and ventricular tachycardia related to Chagasic myocarditis. Amiodarone proved safe in patients with severe congestive heart failure and severe myocardial damage. Its clinical efficacy was related to its electrophysiologic properties and to two unique properties: its wide safety margin and its cumulative effect. The latter liberates patients from a rigid hourly schedule and provides for continuous antiarrhythmic control, days and even weeks after treatment is discontinued.

Control of Tachyarrhythmias Associated with Wolff-Parkinson-White Syndrome by Amiodarone Hydrochloride

Abstract Amiodarone hydrochloride proved to be highly effective in preventing and treating arrhythmias of the Wolff-Parkinson-White (WPW) syndrome in 11 patients with WPW conduction and recurrent tachyarrhythmias. Paroxysmal supraventricular tachycardia (six patients), atrial fibrillation (four patients) and atrial flutter (one patient) were the most significant arrhythmias. In most patients the arrhythmia was seriously disabling because of the extremely rapid ventricular rate, adverse hemodynamic consequences and frequent recurrence and long duration of the episodes. Other known antiarrhythmic agents were ineffective. In all 11 patients amiodarone, in doses of 300 to 600 mg daily, totally, easily and safety controlled the arrhythmias for periods of 2 to 8 months. The drug was fully effective after an average of 7 days of treatment. Tolerance to amiodarone was excellent. The occurrence of corneal microdeposits of the drug was the only Important undesirable effect, but subjective ocular disturbances were not noted. The microdeposits are reversible, and can be avoided by discontinuing the drug for 7 days every 1 to 2 months. Amiodarone apparently causes a significant prolongation of refractoriness in the normal (A-V node and His-Purkinje system) as well as in the anomalous pathway, thus creating favorable conditions for prevention and Interruption of any reentry mechanism requiring participation of both pathways.

Antibodies to Beta‐Adrenergic Receptors Disclosing Agonist‐Like Properties in Idiopathic Dilated Cardiomyopathy and Chagas’ Heart Disease

Antibodies to Beta‐Adrenergic Receptors. Recent studies confirm the existence of antibodies (Abs) to β adrenoceptors in patients with idiopathic dilated cardiomyopathy and Chagas’ heart disease. These Abs can be shown to exert both stimulatory and inhibitory effects, which may play a role in the development of the cardiac abnormalities known to occur in these diseases, including advanced heart failure. The hypothesis is advanced that Chagas’ heart disease and some forms of idiopathic dilated cardiomyopathy may represent, at least partially, a form of “adrenergic cardiomyopathy.”

Efficacy of Amiodarone for the Termination of Chronic Atrial Fibrillation and Maintenance of Normal Sinus Rhythm: A Prospective, Multicenter, Randomized, Controlled, Double Blind Trial

Objective: We sought to assess the efficacy and safety of amiodarone for restoration and maintenance of sinus rhythm in patients with chronic atrial fibrillation in a prospective, randomized, double blind trial. Background: Restoration and preservation of sinus rhythm is difficult in patients with chronic atrial fibrillation. The efficacy of oral amiodarone has not been conclusively established. Methods: Ninety-five patients with chronic atrial fibrillation, lasting an average of 35.6 months, were randomized to either amiodarone (600 mg/d) (47 patients) or placebo (48 patients) during four weeks. Nonresponders underwent electric cardioversion, and those who reverted continued with amiodarone (200 mg/d) or placebo. End-points were successful cardioversion and sinus rhythm maintenance. Results: Sixteen patients (34.04%) in the amiodarone group reverted within 27.28 ± 8.85 days in comparison with 0% in the placebo group (P < 0.000009). The conversion rate rose to 51.72% in patients with chronic atrial fibrillation lasting less than 12 months. Twenty-eight patients in the amiodarone group and 39 in the placebo group underwent electric cardioversion, which was successful in 19 patients (67.8%) of the amiodarone group and in 15 (38.46%) of the placebo group (P = 0.017). Altogether, conversion was obtained in 79.54% of the amiodarone group patients and in 38.46% of the placebo group patients (P < 0.0001). During follow-up, atrial fibrillation relapsed in 13 (37.14%) of 35 patients of the amiodarone group within 8.84 + 8.57 months and in 12 (80%; P = 0.009) of 15 patients of the placebo group within 2.74 ± 3.41 months. Conclusions: Oral amiodarone restored sinus rhythm in one third of patients with chronic atrial fibrillation, increased the success rate of electric cardioversion, decreased the number of relapses and delayed their occurrence.

Efficacy of amiodarone during long-term treatment of malignant ventricular arrhythmias in patients with chronic chagasic myocarditis

Oral amiodarone was administered to 24 patients with chronic chagasic myocarditis (CCM) and malignant ventricular arrhythmias. Control 24-hour Holter recordings revealed frequent ventricular premature beats (VPBs) (157 to 2572/hr; mean 714 +/- 125), multiform VPBs, and countless numbers of ventricular couplets in all patients, R-on-T phenomenon in 17 patients, and ventricular tachycardia in 21 patients. Amiodarone caused total and persistent suppression of ventricular couplets and tachycardia and greater than 93% reduction of VPB number in 22 patients, during a follow-up of 26.6 months (range 2 to 55 months). In 1 patient, ventricular couplets and tachycardia persisted despite the fact that a 98.2% reduction of VPB number was achieved. This latter patient was the only one in the whole group who experienced sudden death. The maximal antiarrhythmic effect was attained gradually after 3 to 26 weeks (mean 7.4). In four patients in whom treatment was discontinued after 3 to 12 months, the antiarrhythmic protection lasted 4 to 9 weeks. In nine patients the dose of amiodarone was 600 to 800 mg/day. In 15 patients the dose had to be increased to 800 to 1000 mg/day. Despite the presence of congestive heart failure in seven patients and intraventricular block in 17 patients, no limiting side effects were observed. Amiodarone proved to be extremely effective and safe against the most malignant ventricular arrhythmias of CCM.

Unmasking of ventricular preexcitation by vagal stimulation or isoproterenol administration.

Twenty-one patients were studied in whom ventricular preexcitation (VP) had been recorded in the past and had later disappeared, indicating antegrade block in the accessory pathway (AP), either spontaneously (10 patients) or under the effect of chronic treatment with amiodarone (11 patients). VP reappeared in nine cases during vagal stimulation, and in five cases during an i.v. isoproterenol infusion. Retrograde conduction over the AP was studied in four of the remaining seven patients and was found to be present in three and absent in one. Although these patients differ from the ordinary patient with concealed AP in that antegrade preexcitation had been demonstrated in the past, this study suggests that concealed VP may result from the following mechanisms: 1) an extremely prolonged refractory period in the AP, causing a ratedependent VP that can be identified during vagal stimulation; 2) a rate-independent depression of antegrade conduction that can be reversed by isoproterenol; 3) a depression of conduction that is apparently no longer reversible. Only in the latter case is a study of retrograde conduction needed to identify the concealed VP. These three mechanisms are likely to be a natural sequence of events leading to complete antegrade block in the AP.

Malignant Ventricular Arrhythmias in Chronic Chagasic Myocarditis

We studied 28 cases of chronic chagasic myocarditis (CCM) with frequent ventricular arrhythmias. Two‐hundred and three conventional ECGs recorded during 3 months showed ventricular extrasystoles (VE) ranging between 0.2 and 6 per ten beats in 100%; multiform VE in 97.04%; couplets in 79.31%; ventricular tachycardia (VT) in 42.85%; and R on T in 21.67%. A 24‐hour continuous recording showed that VE ranged between 3780 and 61733 (mean 16618 ± 2627); muitiform VE and couplets were present in 100% of patients, and VT was present in 78.5%. In 16 patients (group I) the frequency of VE was persistently high, without diurnal variation; 11 patients showed sustained reduction during sieeping hours and only one showed an increase during night sleep (group II). Even in group II, VE never disappeared for periods longer than 10 minutes. In five patients, four 24‐hour recordings were obtained at weekly intervals, and in five other patients a second 24‐hour recording was performed 10 to 24 months later. The remarkable frequency, persistence and low variability of ventricular arrhythmias in CCM suggest that such arrhythmias can be used as a most stable, reliable, but highly demanding model for testing the efficacy of antiarrhythmic drugs. (PACE, Vol. 5, March‐April, 1982)

Relationships Between Increased Automaticity and Depressed Conduction in the Main Intraventricular Conducting Fascicles of the Human and Canine Heart

Escapes from the injured fascicle (EIF) were investigated in 281 cases of bundle branch block (BBB), and during 35 experiments in which rate-dependent BBB was provoked in the intact canine heart. During vagal stimulation, EIF occurred in 27 of the 35 canine experiments, in seven of 24 patients with phase 4 (bradycardia-dependent) BBB, and in nine of 31 patients with fixed BBB. Changes in the degree of fascicular injury and phase 4 BBB were accompanied by correlative changes in the frequency and coupling interval of the EIF, indicating the existence of a close relationship between degree of injury, phase 4 BBB and EIF or enhanced automaticity within the affected fascicle. Therapeutic doses of isoproterenol and lidocaine were tested and were shown to have a simultaneous and sometimes concordant effect on the BBB and the EIF. Occasionally in the acute experiments on dogs, commonly in chronic patients, or at times in patients under the effects of lidocaine, a dissociation or desynchronization between the phase 4 BBB and the EIF was documented. This dissociation implies the existence of other physiologic factors, which may eventually cause the occurrence of concealed or abortive escapes. The fact that phase 3 (tachycardia dependent) and phase 4 BBB can be identified in patients or provoked experimentally in the intact canine heart, with or without EIF, provides with a model of great potential value for studying effects of antiarrhythmic drugs.

Supernormal conduction in the accessory pathway of patients with overt or concealed ventricular pre-excitation

It was recently shown that supernormal conduction in the diseased His-Purkinje system is more common than previously thought, and is always associated with prolongation of refractoriness. To assess whether supernormal conduction could also occur in the accessory pathway of patients with ventricular pre-excitation, 21 patients with manifestly prolonged refractoriness in the accessory pathway were studied. Under these conditions, programmed atrial stimulation revealed a phase of supernormal conduction in 16 (76%) of the 21. Therefore, what was believed to be a nonexistent or exceptional physiologic event was shown to be a rather common finding, at least under certain circumstances. Supernormal conduction occurred in all 7 patients with an anterograde refractory period of 480 to 980 ms, and in 5 of 10 patients with a refractory period greater than 1.0 second or with no anterograde conduction. Supernormal conduction could not be demonstrated in four patients with a refractory period less than or equal to 440 ms, but appeared in all four patients after the refractory period was prolonged by a rapid rate of stimulation or administration of ajmaline. The electrophysiologic changes underlying the occurrence of supernormal conduction in the accessory pathway are similar to those previously reported for the bundle branch system. The demonstration of supernormal conduction in the accessory pathway may uncover the presence of concealed ventricular pre-excitation. Supernormal conduction over the accessory pathway may facilitate a rapid ventricular response during atrial fibrillation, even if the refractory period is prolonged.

Effects of isoproterenol on abnormal intraventricular conduction.

An isoproterenol infusion (1.0-4.0, ug/min) was administered to 15 patients with intermittent bundle branch block (BBB) and two patients with apparently fixed BBB. Three main effects were documented: (1) In all patients with phase 3, or tachycardia-dependent, BBB, isoproterenol caused a pronounced shortening of refractoriness in the affected fascicle. (2) In patients showing phase 4, or bradycardia-dependent, BBB, isoproterenol prolonged the phase 4 block range, probably because of enhanced diastolic depolarization. In one patient (four studies) in whom phase 4 block was not present, isoproterenol caused the appearance of a phase 4 block range. (3) In the two patients with fixed BBB, isoproterenol restored conduction, probably as a result of a hyperpolarizing effect. This study shows that isoproterenol tends to restore or improve conduction related to tachycardia-dependent block, but may impair conduction related to bradycardia-dependent block.