Robert L. Rinkenberger

Clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation

We evaluated the effects of amiodarone in 45 patients with recurrent ventricular tachycardia or ventricular fibrillation. At a mean follow-up time of 12.7 +/- 8.8 months (range, three to 36), amiodarone was successful in nine of 16 patients with recurrent ventricular fibrillation and 21 of 29 with recurrent ventricular tachycardia. During amiodarone therapy, ventricular tachycardia could be induced in 18 of 19 patients in whom it had been induced before therapy, but only six of these 19 had spontaneous recurrence during follow-up. Side effects included corneal microdeposits, hyperthyroidism, blue skin, nausea, and symptomatic bradycardia. Pulmonary fibrosis occurred in three patients. Doses of up to 2000 mg a day did not produce cardiac toxicity, but neurologic side effects precluded long-term therapy at this dose. We conclude that amiodarone is effective for long-term therapy of recurrent ventricular tachyarrhythmias, that induction of arrhythmia during therapy does not always predict efficacy, and that side effects are frequent but do not usually limit therapy.

Effects of intravenous and chronic oral verapamil administration in patients with supraventricular tachyarrhythmias.

The efficacy of i.v. and oral verapamil was studied in 28 patients with supraventricular tachycardia (SVT). Verapamil (5-10 mg i.v.) terminated SVT in all six patients with atrioventricular nodal (AVN) reentrant tachycardia. In all patients verapamil prolonged antegrade but did not affect retrograde AVN conduction time. Two patients had associated sinus nodal reentrant tachycardia that persisted after the AVN tachycardia terminated. In six patients with SVT using an accessory pathway for retrograde conduction, i.v. verapamil terminated SVT in four and slowed SVT in two patients. Verapamil did not affect the electrophysiologic properties of the accessory pathway and the effect on the SVT, as with AVN reentry, was caused by changes in antegrade AVN function. Verapamil lengthened AVN antegrade conduction time in patients with accessory pathways less than it did in patients with AVN reentry. Verapamil at doses that resulted in AVN Wenckebach block had no effect on the discharge rate of the three patients with automatic atrial tachycardia. In 13 of 14 patients with atrial fibrillation or flutter, i.v. verapamil promptly decreased the ventricular rate. One patient with preexcitation had an increase in ventricular rate after verapamil. The shortest RR intervals before and after verapamil were 260 and 220 msec, respectively, and after verapamil more ventricular beats were preexcited. Oral verapamil was given to 19 of 28 patients. Ten discontinued the drug within 30 days because of side effects or ineffectiveness. Seven patients treated for a mean of 19 months have shown evidence of improvement, judged by decreased frequency and shorter duration of tachycardia when it did recur. Thus, i.v. verapamil is an effective antiarrhythmic drug for most patients with SVT, but oral verapamil is effective in only selected patients.

Effect of autonomic blockade on ventricular refractoriness and atrioventricular nodal conduction in humans. Evidence supporting a direct cholinergic action on ventricular muscle refractoriness.

In humane, the parasympathetic nervous system predominates over the sympathetic nervous system in control of heart rate, but little is known about the relative influences of cholinergic and adrenergic tone on the electrophysiological properties of the ventricle and atrioventricular (AV) node. Thirteen subjects were studied using standard electrophysiological testing techniques in the control state and after propranolol (0.15 mg/kg, iv) plus atropine (0.03 mg/kg, iv) to assess the effect of autonomic blockade on ventricular and AV nodal refractoriness and AV nodal conduction. Eight subjects received propranolol first (group A) and five were given atropine first (group B). For groups A and B, the spontaneous sinus cycle length significantly decreased from control after administration of propranolol and atropine [813 ± 107 (SD) to 613 ± 57 msec and 842 ± 188 to 637 ± 115 msec, respectively]. Ventricular effective (ERP) and functional (FRP) refractory periods insignificantly increased from control after propranolol was given (group A); however, both ventricular ERP and FRP significantly shortened to less than control values after atropine was added (238 ± 23 to 218 ± 19 msec and 261 ± 22 to 243 ± 17 msec, respectively). Similar results for ventricular refractoriness occurred after administration of atropine and propranolol in group B subjects. The shortest atrial pacing cycle length sustaining 1:1 AV nodal conduction after administration of propranolol and atropine did not significantly change from control values (386 ± 109 to 372 ± 74 msec). These data suggest that (1) resting vagal tone exerts a significant effect on human ventricular refractoriness and the effect can occur in the presence of β-adrenergic blockade, and (2) in contrast to the markedly predominant effect of the parasympathetic nervous system on sinus nodal automaticity, vagal and adrenergic tone exert a balanced effect on resting AV nodal conduction.

Efficacy and safety of flecainide acetate for atrial tachycardia or fibrillation

Thirty-nine patients with symptomatic ectopic atrial tachycardia (9 paroxysmal, of which 5 were incessant) and atrial fibrillation (AF) (25 paroxysmal, 5 chronic) were treated with oral flecainide acetate (100 to 400 mg/day). Thirty-two patients had organic heart disease (16 coronary artery disease, 6 valvular, 10 cardiomyopathy, 7 primary electrical abnormality). Previous antiarrhythmic trials consisted of 0 to 5 drugs (mean 2.2). Of 39 patients with atrial tachycardia or AF, a complete response (no recurrent symptomatic atrial arrhythmia) was achieved in 22 (56%), a partial response (more than 95% reduction in arrhythmia occurrence) in 3 (8%) and no response in 14 (36%). Left atrial size, ejection fraction, underlying heart disease, duration of symptoms before treatment and drug levels were not useful for predicting clinical response. Therefore, during the follow-up period of 5.4 +/- 6.7 months (range 4 weeks to 2.5 years), flecainide had a complete or partial effect in 25 patients (64%). Complete or partial responses were noted in 8 of 9 patients (90%) with ectopic atrial tachycardia and 17 of 30 (57%) with AF. In 14 patients with concurrent ventricular arrhythmias, a significant reduction in episodes of nonsustained ventricular tachycardia was also achieved. Treatment was discontinued in 8 patients (20%) because of cardiac adverse reactions, including pulmonary edema and ventricular or atrial proarrhythmic response. Thus, oral flecainide acetate is effective therapy for some patients with ectopic atrial tachycardia or AF.

Electrophysiology of Oral Encainide

The electrophysiologic effects of oral encainide were assessed in 15 patients. Electrophysiologic studies were performed before and after 3 or more days of oral encainide therapy, 100 to 300 mg/day (mean 242 +/- 66). Patients received no other cardioactive drugs during this time. Encainide significantly (p less than 0.005) lengthened the following: A-H interval (74.5 +/- 21.5 to 105.5 +/- 39.1 ms, mean +/- standard deviation), the shortest atrial pacing cycle length maintaining 1:1 atrioventricular (A-V) nodal conduction (339.0 +/- 71.3 to 417.0 +/- 88.6 ms), H-V interval (47.5 +/- 7.8 to 67.1 +/- 12.9 ms), QRS interval (103.5 +/- 30.9 to 132.3 +/- 35.7 ms), right atrial (233.8 +/- 27.2 ms to 282.9 +/- 38.6 ms) and right ventricular (235.7 +/- 15.6 to 267.1 +/- 36.9 ms) effective refractory periods and Q-T interval (364.4 +/- 38.0 to 416.9 +/- 55.3 ms). The spontaneous sinus cycle length did not change significantly. In four patients who had accessory A-V muscle connections (two manifest, two concealed) encainide abolished anterograde conduction over the accessory pathway in two patients, and increased the retrograde effective refractory period and/or lengthened retrograde conduction time or blocked retrograde conduction in the accessory pathway, or all three variables, in all four patients. There was no correlation between the plasma encainide concentration obtained at the time of study and the magnitude of change in any electrophysiologic variable. It is concluded that (1) encainide depresses conduction in the A-V node, His-Purkinje system and accessory pathway, and increases refractoriness of the atrium, ventricle and accessory pathway, and (2) differences between these results and those of earlier studies using encainide in a single intravenous dose (which found no significant effects on A-V nodal conduction or atrial and ventricular refractoriness) may be explained in part by the effects of an active metabolite of encainide.

Enhanced parasympathetic tone shortens atrial refractoriness in man

The purpose of this study was to determine the effects of enhanced vagal tone on human right atrial refractoriness in 12 patients. A specially built neck collar connected to a vacuum source was placed around the patients neck and enhanced vagal tone was produced during neck suction using intracollar negative pressures of 50 to 60 mm Hg. Refractory periods were determined with a catheter electrode positioned in the high right atrium near the sinus node. Induced neck suction increased the spontaneous sinus cycle length from 837 +/- 96 to 1.136 +/- 273 ms (p less than 0.001) and shortened the atrial effective refractory period from 241 +/- 24 to 230 +/- 20 ms (p less than 0.01) and the atrial functional refractory period from 272 +/- 32 to 262 +/- 29 ms (p less than 0.01). In 2 of 2 patients, collar-induced decreases in atrial refractoriness and increases in spontaneous cycle length were prevented after atropine (0.03 mg/kg) was given intravenously. It is concluded that enhanced vagal tone mediated through muscarinic receptors shortens atrial refractory periods in man.

Mexiletine therapy in 15 patients with drug-resistant ventricular tachycardia

Mexiletine therapy was administered to 15 patients with chronic and recurrent episodes of ventricular tachycardia or ventricular fibrillation. All patients were intolerant of or had arrhythmias resistant to conventional antiarrhythmic agents. At maximal dosages of mexiletine 2 patients had more than 90 percent reduction in frequency of premature ventricular complexes, whereas 11 patients had less than 50 percent reduction, as measured on 24 hour electrocardiographic recordings. Mexiletine was unsuccessful in preventing or abolishing ventricular tachycardia in 11 patients. Adverse side effects occurred in nine patients (60 percent) and were severe enough to necessitate discontinuation of therapy in six patients (40 percent). Side effects appeared to be dosage-related. Pharmacokinetic analysis indicated a mean elimination half-life of 12.6 +/- 1.6 hours following oral administration of mexiletine. In the patients studied, mexiletine exhibited limited antiarrhythmic efficacy and was associated with frequent adverse side effects.

Electrophysiologic effects of milrinone in patients with congestive heart failure

The electrophysiologic effects of milrinone, a new inotropic agent, have not been characterized in humans. Accordingly, 10 patients with class III or IV congestive heart failure underwent hemodynamic and electrophysiologic testing before and during an infusion of milrinone (0.5 micrograms/kg/min). Cardiac index increased from a mean of 1.65 +/- 0.51 to 2.19 +/- 0.68 liters/min/m2 (p less than 0.03) and pulmonary artery capillary pressure decreased from 30 +/- 9 to 22 +/- 9 mm Hg (p less than 0.01), without a significant change in systemic arterial pressure. Holter monitoring was performed for 48 hours at baseline and during infusion of milrinone. Frequency of ventricular premature complexes and ventricular couplets did not change significantly. Frequency of ventricular tachycardia (VT) increased significantly, although no patients would be classified as having a proarrhythmic effect based on a clinical model. PR, QRS, QTc, heart rate, AH, HV, atrial, atrioventricular and ventricular effective and functional refractory periods were not affected. Milrinone decreased 1:1 atrioventricular maximal conduction from 399 +/- 133 to 374 +/- 111 ms (p less than 0.01); ventriculoatrial conduction was not significantly affected. During programmed right ventricular stimulation, 5 patients had inducible VT at baseline (3 sustained, 2 non-sustained), whereas after drug administration, none had it (p less than 0.05). Thus, intravenous milrinone is an effective inotropic drug that also enhances atrioventricular conduction and may decrease the incidence of inducible VT in patients with congestive heart failure.

Clinical efficacy and electrophysiologic effects of encainide in patients with Wolff-Parkinson-White syndrome.

We performed electrophysiologic studies in 19 patients with accessory pathways before and during encainide therapy with a mean daily dose of 197 mg. Fourteen patients had manifest accessory atrioventricular connections, and five patients had concealed accessory atrioventricular connections. The patients had recurrent atrioventricular reentrant tachycardia for a mean of 15.8 years and had received a mean of 3.6 drug trials without successful suppression of recurrent arrhythmias. Encainide caused complete antegrade conduction block in the accessory pathway in eight of 14 patients with manifest accessory atrioventricular connections. The shortest atrial pacing cycle length maintaining 1:1 conduction over the accessory pathway at control study w3as 328 +/- 66 msec in patients in whom antegrade conduction block occurred, and it was 247 +/- 21 msec (p less than .01) in patients in whom conduction remained during encainide therapy. Retrograde conduction over accessory atrioventricular connections could be evaluated in 14 patients, and complete block occurred in seven patients during encainide therapy. There was no correlation between control retrograde effective refractory period or conduction of the accessory pathway and subsequent development of conduction block with encainide therapy. It should be noted that five patients who developed drug-related retrograde block over the accessory pathway had initial retrograde effective refractory periods for the accessory pathway less than 270 msec. Nineteen patients had atrioventricular reentrant tachycardia initiated at control electrophysiologic study. Encainide prevented induction of tachycardia in 10 patients, and in the other nine patients, cycle length of tachycardia increased during drug treatment from 313.9 +/- 53.1 to 418.3 +/- 80.9 msec (p less than .001), primarily due to an increase in ventriculoatrial conduction time from 162.2 +/- 43.8 to 238.3 +/- 87.9 msec (p less than .01). Fifteen patients continued encainide treatment for a mean of 18 months (range 7 to 38), and all but one patient remain asymptomatic. Encainide is well tolerated and prevents recurrence of reentrant tachycardia in patients with Wolff-Parkinson-White syndrome very effectively.

Amiodarone: pharmacology and antiarrhythmic and adverse effects.

Amiodarone is a benzofuran derivative that has been effective for the treatment of both supraventricular and ventricular tachyarrhythmias. It has a large volume of distribution, moderate bioavailability and a long half‐life. Its pharmacokinetics are not well understood and its tissue distribution is not typical of a 2‐compartment model. Due to ocular, dermatologic, gastrointestinal, neurologic, cardiovascular, thyroid and pulmonary toxicity, amiodarone should be reserved for use in patients with refractory and/or life‐threatening arrhythmias.