Vilma Torres

QT prolongation and the antiarrhythmic efficacy of amiodarone

Amiodarone is an antiarrhythmic agent known to cause prolongation of action potential duration which is reflected in the electrocardiogram as a prolongation of the QT interval. Prolongation of the QT interval in patients dying suddenly was compared with that in patients who remained alive to determine whether a difference existed between these two groups. The electrocardiogram and amiodarone levels were evaluated in 33 patients who presented with cardiac arrest and symptomatic ventricular tachycardia in whom no other antiarrhythmic agent was found effective in preventing induction of ventricular tachycardia during electrophysiologic studies. There were 30 men and 3 women (mean age 52 +/- 10 years). Twenty-three are alive after a mean follow-up period of 12 +/- 7 months. Ten died: six suddenly, three of non-cardiac causes and one of congestive heart failure. Using a two-way analysis of variance, the percent change in QT, QTc, JT and JTc intervals before and after amiodarone therapy was analyzed. Marked prolongation in the QT interval was present in patients who remained alive with amiodarone therapy. A significant difference in percent QT prolongation was seen between the latter patients and those who died suddenly (p less than 0.005). No difference was observed in the percent change in QRS interval between the two groups. The levels of amiodarone (2.5 versus 3.2 micrograms/ml) and its metabolite (desethylamiodarone) were not significantly different between the living patients and those who died suddenly. These findings suggest that a prolongation of the QT interval may be a marker for the therapeutic antiarrhythmic effect of amiodarone.

Prolongation of QT interval and antiarrhythmic action of bepridil

Studies were undertaken with bepridil, a new calcium blocker that prolongs the QT interval, to determine the antiarrhythmic and possible arrhythmogenic properties of this agent. The technique of programmed electrical stimulation was employed to evaluate bepridil in 15 patients with symptomatic ventricular tachycardia (VT). Bepridil prevented VT induction in 7 of 15 patients. Bepridil prolonged the QT and refractoriness and a linear correlation could be demonstrated between the percent change in QTc and refractory period prolongation for the bepridil-protected group. Bepridil in one patient reduced by one the number of stimuli required to induce VT, but no spontaneous arrhythmias were noted. Bepridil thus possesses antiarrhythmic properties with a minimal proarrhythmic effect.

Antiarrhythmic effects of cibenzoline

Thirty-three patients with ventricular tachyarrhythmias were referred for evaluation of their arrhythmias using programmed electrical stimulation to guide antiarrhythmic therapy. Cibenzoline succinate, a new antiarrhythmic agent, was compared to procainamide in patients with ventricular tachycardia. Cibenzoline was given intravenously, initially 1.0 mg/kg, then in 1 mg/kg increments to a maximum of 3.0 mg/kg, during electrophysiologic testing. The results were compared to procainamide, which was also administered intravenously to 1000 and then to 1500 mg. Cibenzoline provided protection against ventricular tachycardia induction in 16 of 33 patients. The PR interval increased 13%, QRS duration widened 26%, and QTc interval was prolonged by 7%. There was a 9% fall in mean arterial blood pressure. Procainamide prevented ventricular tachycardia induction in 21 out of 31 patients tested. The PR interval increased 11%, QRS duration widened 27%, and QTc interval prolonged by 8%. Cibenzoline was given orally to 13 patients for chronic treatment. Chronic oral cibenzoline therapy after a mean follow-up of 8.8 months caused a reduction of ventricular ectopy from 666 to 190 beats/hr. Ventricular tachycardia events decreased per Holter monitor recording from 6 to 0.6. Cibenzoline therapy was discontinued in 5 of 13 patients due to break-through arrhythmias (nonsustained ventricular tachycardia on Holter monitor and recurrence of symptoms). Cibenzoline may be an effective antiarrhythmic agent in selected patients.

Evaluation of lorcainide in patients with symptomatic ventricular tachycardia

One hundred patients with inducible ventricular tachycardia (VT) on electrophysiologic studies underwent serial drug testing with procainamide, lidocaine and lorcainide to determine comparative efficacy. Acute intravenous administration was followed by repeat programmed electrical stimulation (PES) studies on separate days for each antiarrhythmic agent. Lorcainide prevented VT induction in 69% of the 100 patients studied, procainamide in 50% of the 75 patients studied and lidocaine in 30% of 53 patients. After PES and serial drug testing, 46 patients were started on lorcainide, 9 on procainamide and 45 on other antiarrhythmic drug regimens. Eighty percent of the patients have remained on lorcainide therapy, whereas 47% have continued on other drug therapies started over 17.5-month mean follow-up period. Despite sleep-wake disturbances and a need for sedation at night, lorcainide therapy was well tolerated in this population and remained an effective antiarrhythmic agent with prolonged administration.

Enhancement of myocardial vulnerability by atrial fibrillation.

Certain groups are known to have an increased risk for sudden cardiac death. Epidemiologic studies have suggested that patients with atrial fibrillation may be at higher risk. The authors hypothesize that atrial fibrillation may increase myocardial vulnerability. To test this hypothesis, 37 dogs were studied using programmed electrical stimulation techniques to determine myocardial vulnerability as assessed by the ability to provoke ventricular tachycardia. Prior to atrial fibrillation, programmed electrical stimulation did not induce ventricular tachycardia. Aconitine was then topically applied to the right atrial appendage with care taken not to make contact with the ventricle. Application of aconitine caused atrial fibrillation with an increase in ventricular rate, but did not affect arterial blood pressure. Ventricular tachycardia was induced by programmed electrical stimulation studies in 25 of 26 dogs in atrial fibrillation. The enhanced vulnerability was noted following atrial fibrillation, not after aconitine application to the great veins, which did not cause atrial fibrillation. To further exclude the possibility that aconitine application may cause changes in ventricular threshold, atrial fibrillation was induced by pacing techniques in five dogs. Prior to atrial fibrillation induction, programmed electrical stimulation did not induce ventricular tachycardia. Following atrial fibrillation, ventricular tachycardia could be repeatedly induced. Mean heart rate following atrial fibrillation increased, while pacing animals at this increment in rate did not change the noninducibility of dogs in sinus rhythm. Six patients with a history of atrial fibrillation and ventricular tachycardia were studied to determine if AF lowered myocardial threshold to VT induction. Ventricular tachycardia could only be induced by PES techniques in four of five patients when the patients’ rhythm was AF (P < 0.05). This study suggests that atrial fibrillation lowers myocardial threshold for ventricular tachycardia induction and thus enhances myocardial vulnerability. The association of AF with a higher incidence of sudden death may be due to an enhanced electrical instability.

Antiarrhythmic efficacy of ethmozine in patients with ventricular tachycardia as determined by programmed electrical stimulation.

The antiarrhythmic properties of ethmozine were studied in 27 patients with a history of a cardiac arrest or symptomatic ventricular tachycardia. Programmed electrical stimulation studies were performed in 20 men and seven women with a mean age of 62 years and a mean left ventricular ejection fraction of 43%. All patients had inducible ventricular tachycardia by programmed electrical stimulation while off all antiarrhythmic therapy. Patients were then tested on procainamide if their treatment with this drug orally had not previously failed. Procainamide, 1000 and 1500 mg, was administered intravenously, and ventricular tachycardia could be provoked in 14 of 18 patients. Ethmozine was given in an oral loading regimen starting 24 to 36 hours later. After 500 mg oral ethmozine, patients were given 15 mg/kg ethmozine every 8 hours for seven to nine doses prior to drug testing. Ethmozine did not significantly change the baseline heart rate, blood pressure, and QTc interval from the initial drug-free values. The PR and QRS intervals were significantly prolonged. Seven patients were protected on oral ethmozine; 14 patients still had ventricular tachycardia inducible at programmed electrical stimulation testing, and six patients developed ventricular tachycardia spontaneously on ethmozine and were not tested in the programmed electrical stimulation laboratory. One patient had gastrointestinal complaints and was not discharged on the drug. The five patients who tolerated the oral protocol without side effects and who were protected against programmed stimulation induction of ventricular tachycardia were discharged on oral therapy. One patient on long-term therapy appeared to develop an allergic reaction to the agent with unexplained fevers and was switched to amiodarone therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of bepridil, verapamil, and quinidine in the prevention of ventricular tachycardia induced by programmed electrical stimulation in the digitalized dog

Bepridil, a new antianginal agent, has calcium channel-blocking activity and antiarrhythmic properties. To test the efficacy of bepridil as an antidysrhythmic agent, we looked at its effect on the induction of ventricular tachycardia (VT) in dogs, utilizing programmed electrical stimulation (PES). Incremental doses of bepridil up to 20 mg/kg were given to five nondigitalized dogs and verapamil up to 20 mg, and PES was performed at each dose. Both drugs were not found to facilitate arrhythmia induction. Seventeen dogs were chronically digitalized and following digitalization, VT could be induced in all animals by PES. Six dogs were given bepridil and PES was reperformed at each dose. An average of 1.8 mg/kg was found to protect against induction of VT. Five dogs received verapamil and none was protected (all had VT induced), while five of six dogs given quinidine were protected at an average dose of 15.4 mg/kg. Bepridil produced a significant decrease in heart rate. A significant correlation was found at the effective antiarrhythmic dose of bepridil between percentage change in the effective refractory period for the first extrastimulus (ERP S2) and QTc (r = 0.96), suggesting that a parallel and homogeneous prolongation in repolarization and refractoriness is essential for the antiarrhythmic effect of bepridil. Bepridil is thus an effective antiarrhythmic agent that affords protection against induction of VT, and this action is similar to the conventional class I antiarrhythmic agent, quinidine, while lacking in another calcium channel blocker, verapamil.

Antiarrhythmic drug efficacy at electrophysiology testing: Predictive effectiveness of procainamide and flecainide

In an effort to assess the ability of procainamide to predict effectiveness of antiarrhythmic agents at programmed electrical stimulation (PES) testing, we compared the result of procainamide at PES testing with that of all of the other agents studied. One hundred fifty-three patients underwent PES studies because of either sustained or nonsustained ventricular tachycardia (VT). Procainamide prevented VT induction in 79 of 153 patients. Seventy-four of the remaining 153 were inducible for VT on procainamide, with 55 of these being protected by another antiarrhythmic agent (p less than 0.001). If procainamide failed to prevent VT induction, other conventional and experimental agents were equally as likely to be effective in preventing VT induction. Analysis of flecainide acetate as a predictor of efficacy was also evaluated. Fifty-five patients received flecainide and 29 of these were protected at PES testing; 26 of these patients were also protected with another agent. When VT was inducible in patients who received flecainide, 15 of these 26 patients were protected by another agent, either conventional or experimental (p less than 0.01). Thus, if procainamide or flecainide prevented VT induction they accurately predicted effectiveness of other drugs; however, when they did not prevent VT induction, they served as a poor predictor of the possible effectiveness of other drugs. Serial drug testing at PES studies with multiple conventional and experimental drugs increases the likelihood of finding an effective antiarrhythmic agent.

Intravenous quinidine by intermittent bolus for electrophysiologic studies in patients with ventricular tachycardia

The safety and efficacy of intravenous quinidine gluconate, using intermittent boluses of 80 mg/cc every 5 minutes to a total dose of 800 mg, was evaluated in 61 patients referred for electrophysiologic studies (EPS). Patients were referred because of out-of-hospital cardiac arrest (12), symptomatic ventricular tachycardia (VT) (24), asymptomatic VT (18), syncope of unknown origin (6), and supraventricular arrhythmias (1). Clinical heart failure was present in 74% of patients, with a mean ejection fraction of 45 +/- 3 for all patients. Quinidine prevented VT induction in 78% of patients at a mean dose of 9.6 mg/kg and facilitated VT induction in 7% of patients. Quinidine failed to decrease mean arterial pressure in 14 patients, and in the remaining 47 patients arterial pressure decreased by 16%. Six patients had hemodynamically significant hypotension. Two patients had hypotension severe enough to require saline administration, while four had hypotension not needing fluid replacement. Sixteen percent of patients experienced other side effects. Quinidine can be administered safely by intermittent infusion and is effective in preventing programmed stimulation induction of VT. Carefully monitored, intravenous intermittent bolus administration of quinidine should be utilized more frequently in EPS, since significant adverse side effects are infrequent.

Prophylactic tocainide or lidocaine in acute myocardial infarction

Twenty-nine patients with acute myocardial infarction (AMI) were studied in a randomized double-blind trial of intravenous lidocaine and tocainide, followed by either oral tocainide or placebo without regard to previous therapy, for the prophylaxis of arrhythmias associated with acute infarction. No patient had symptomatic ventricular tachycardia or fibrillation, although 1 patient taking lidocaine was withdrawn from therapy because of breakthrough arrhythmias. One patient in each group died from mechanical complications of AMI. Tocainide was administered to 16 patients and lidocaine to 13. Seven of the 13 patients receiving lidocaine had ventricular tachycardia or accelerated idioventricular rhythm, compared with 2 of 16 receiving tocainide (p less than 0.05). Adverse effects were noted in 11 of the 13 patients receiving lidocaine and 6 of the 16 patients receiving tocainide. The infusions used provided therapeutic levels of lidocaine or tocainide and the transition to oral tocainide was accomplished safely with maintenance of therapeutic antiarrhythmic levels. Thus, tocainide appears to be at least as efficacious and may be safer than lidocaine for the prophylaxis of ventricular arrhythmias associated with AMI. The transition to oral tocainide is well tolerated and can be accomplished with minimal difficulty.