Electrophysiology and antiarrhythmic efficacy of intravenous pirmenol in patients with sustained ventricular tachyarrhythmias

in-travenollps pir

We assassed the electrophysiologic effects and antiarrhythmic efficacy of intravenous pirmenol in 15 patients who had spontaneous and Induced sustained ventricular tschyarrhythmias. At a plasma concentratten of’2.29 f 0.75 pg/ml, pirmenol dacreased sinus cycle length by 11 f 13%, incraaeed ORS, QT,, and tlV intervals by 14 + 12%, 13 + 12%, and 22 + 28%, respectively, and lncreaaed atrial and ventricular effective refractory periods (ER@ by 20 + 14% and 7 + 8%, respectively. There was a greater Increase in Of& duration during ventricular tachycardia and ventricular pacing than durtng sinus rhythm (p < 0.006). By electropharniacologic testfng, pirmenol was judged effective In six patients (40%) and was proarrhythmlc in one (6%). ln the nlne oattents In whom plrmenol was judged ineffective, the cycle length of induced VT increased by 36 t 15% and the assoctated mean arterial pressure Increased by 21 + 14 mm Hg. The only side effects were mild hypotenakn and mild nausea in one patient each. Intravenous pirmenol has type IA electrophysklogic effects. It can be administered safely to petknts with sustained ventricular tachyarrhythmlas and Is as effective as approved antfarrhythmk drugs when assessed by electropharinacologic testing. (AM HEART J lg87;i 13~1390.)

L. Bing Liem, D.O., Debra A. Clay, R.N., Michael Charles D. Swerdlow, M.D. Stanford, Calif.

R. Franz, M.D., and

Pirmenol is a new antiarrhythinic drug that has class IA electrophysiologic properties in vitro.’ It has been reported to prevent ventricular tachyarrhythmias in experimental preparations2 and to reduce the frequency of premature ventricular complexes in patients.3-5 We assessed the electrophysiologic effects and antiarrhythmic efficacy of intravenous pirmenol in 15 patients with spontaneous and induced sustained ventricular tachyarrhythmias. METHODS Patients.. The study group consisted of 14 men and 1 woman, aged 42 to 76 years (mean 57 + 10 years). The clinical arrhythmia was sustainedventricular tachycardia (VT) in 12 patients and ventricular fibrillation in three patients. They had been treated with two to six (mean 3.7 + 1.1) antiarrhythmic drugs that either failed to pre-

teen patients had coronary artery diseaseand a previous myocardial infarction, one had dilated cardiomyopathy, and one had no apparent structural heart disease.The left ventricular ejection fraction determined by contrast venFrom the Cardiac Arrhythmia Study Unit, Stanford University Medical Center. Received for publication July 17, 1986; accepted Nov. 7, 1986. Reprint requesta: Charles Swerdlow, M.D., Cardiac Arrhythmia Study Unit, Cardiology Division, CVRC 289, Stanford University Medical Center, Stanford, CA 94305.

triculography (n = 13) or radionuclide angiography (n = 2) ranged from 21% to 67% (mean 37 + 12). One patient was in New York Heart Association functional classI for heart failure, 10were in classII, and four werein classIII. Patients with severeleft ventricular dysfunction (New York Heart Association classIV or ejection fraction <20 % ) or markedly prolonged infranodal conduction (HV interval >80 msec)were excluded from the study, Electrophysiologic study. We performed electrophysiologic testing after all antiarrhythmic drugs had been discontinued for 5 half-lives and patients had given written, informed consent. Multipolar electrode catheters were positioned in the high right atrium,, right ventricular apex; and His bundle recording position. Three to six surface HCG leads and intracardiac electrograms were recorded on magnetictape and on a multichannel recorder at paper speedsof 100 to 250 mm/set. A femoral arterial catheter wasused to record arterial pressure.Pacing was performed at twice diastolic threshold wkk pulstls !! msec in duration. Our protocol for initiation of VT has been described previously.6 First, rapid atrial pacing was performed until atrioventricular (AV) node Wenckebach block occurred. Programmed ventricular stimulation included up to three extrastimuli delivered from two right ventricular sites at paced cycle lengths of 600 and 400 msec. We completed stimulatibn by means of two extrastimuli from two right ventricular sitesbefore adding a thiid extrastimulus. In all patients, sustained VT (lasting longer than 30

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1.Electrophysiologic effects of pirmenol N Sinus

cycle length

Es

QTc PA AH HV ERP ERP

atrium* AV node

ERP ventricle Sinus

node

recovery

Control

Pirmenol

% change

P

14

851

k 133

757

* 114

411 k 13


15 14 15 14 14 15 14 6 15 13

120 158 439 32 90 50 237 353 251 1040

k 25 36 * 49 + 18 Y!Z36 + 11 e 21 k 71 f 27 * 185

137 166 496 37 81 61 283 354 269 996

f-t 34 37 f 45

t145565 713 + 16 + 9 ?I 122 + t20 f 0 + t 7+8 1 *

NS
13

219 f 130

236

zk 106

9

289 + 69

393 k 97

+ 18 ?I f f + k k

25 18 31 50 31 184

12 12 53 22 28 14 17

NS 0.005

10

NS

8

f 40

NS

736

+ 15


time*?

Corrected sinus node recovery

time

VT cycle lengtht

Values are reported in milliseconds. QT, = corrected QT interval; ERP = effective refractory period; AV = atrioventricular; VT = ventricular tachycardia; N = number of .patienta measurements were made. *Atrial intervals and sinus node recovery time were not measured in one patient with chronic atrial fibrillation. @inus node recovery time could not be measured in another patient who developed atria1 fibrillation after baseline atria1 measurements. $VT cycle lengths were compared only in patients in whom the Bame morphology of sustained VT was induced before and after pirmenol.

secondsor requiring termination in lesstime becauseof hemodynamic collapse) was induced twice in the control state. We measuredbaseline electrophysiologic variables after sinuscycle length and arterial pressurehad returned to baseline values, at least 10 minutes after the last episodeof VT. We then gave pirmenol intravenously and repeated electrophysiologic measurements and programmed stimulation. Programmed stimulation was continued until sustainedVT wasinduced or the protocol was completed. Electrophysiologic intervals were measured from the earliest evidence of local electrical activity in any lead. Refractory periods were determined by the extrastimulus technique after eight paced complexes at a drive cycle length of 500 msec. Sinus node recovery time was measured asthe recovery time after 30 secondsof atrial pacing at a cycle length of 500 msec. In one patient, we recorded the right ventricular monophasic action potential with a contact-electrode catheter’ during atrial pacing at a cycle length of 500msec before and after administration of intravenous pirmenol. The right ventricular strength-interval relationship at the samecycle length* wasmeasuredsimultaneously with the same electrodes that recorded the monophaaic action potential. Pirmenol admlnistration. Pirmenol was given intravenously asa loading doseof 1.1 mg/kg over 5 minutes. This was followed by an infusion at 40 &irg/min for a maximum of 40 minutes, after which the rate wasreduced to 20 tg/kg/min. We measuredelectrophysiologic variables and performed programmed stimulation 35 minutes after the loading dose was started. The plasma concentration of pirmenol was determined in 13 patients after the completion of programmed stimulation.s

in whom

Definitions. We used standard definitions for the R-R, PR, QT, PA, AH, and HV intervals; QRS duration; effective refractory period of the atrium, AV node, and right ventricle; sinus node recovery time; and corrected sinus node recovery time. We used Bazett’s formula1oto calculate the corrected QT interval (QTJ. APD, and APDN denote the duration of the monophasic action potential at 50% and 90% repolarization, respectively. Pirmenol or procainamide was judged effective at electropharmacologic testing if a maximum of 15 complexesof VT could be induced after drug administration.“*” Statistical analysis. Control and post pirmenol electrophysiologic variables were compared by means of the paired t test. Pirmenol plasma concentration in patients in whom the drug was judged effective and in those in whom it was judged ineffective were compared by the unpaired t test. Continuous variables are reported as mean + 1 SD. The APD, and APD, were compared in one patient taking measurementsfrom five consecutive action potentials

before and, after pirmenol.

RESULTS Electrophysiologic

Table I summarizes pirmenol on electrophysio-

variables.

the effect of intravenous logic variables.

Sinus cycle length decreased by an average of 11% . The maximum increase in heart rate after pirmenol was 30/minute and the maximum post pirmenol heart rate was 103/minute. Sinus node recovery time and corrected sinus node recovery time were unchanged after pirmenol. AV node function. The PR and AH intervals and AV nodal effective refractory period did not change SInus node

function.

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330 ms - S2 1.

h

A-

rlj l

I

1’

HBE

AI

“I

“I

0.5 set

1. Effect of pirmenol on atrial refractoriness. Surface ECG lead II is shown with intracardiac electrograms from the high right atrium (HRA), the right ventricular apex (RV), and the His bundle position (HBE). A, Atrial functional refractory period in the baseline state. An atrial extrastimulus f&J with a coupling interval (S,S& of 260 msec captures the atrium with an A,A, interval of 270 msec, the minimum A,Az interval attained. The atrial effective refractory period was 250 msec and the atrioventricular (AV) nodal effective refractory period was 320 msec. B, Atrial functional refractory period after pirmenol. S,Sz with a coupling interval of 330 msec captures the atrium with an A,A, of 340 msec and conducts through the AV node. This was the minimum A,A, attained. C!,Atria1 effective refractory period after pirmenol. S,S, with a coupling interval of 320 msec fails to capture the ‘atrium. The AV nodal effective refractory period cannot be determined. Fig.

In five patients, the AV nodal effective refractory period could not be measured after pir-

significantly.

menol because it was shorter than the atrial functional refractory period (Fig. 1).

The PA interval did not change, but the average HV interval increased. In two patients, the WV int.ervaI increased marlredly, from 55 to 85 msec and from 55 to 100 Atrial

and

vantrkuhr

msec, respectively;

conductian

the latter patient

time.

&o developed

left bundle branch block after pirmenol (Fig. 2). Overall, the QRS interval increased by 14 + 12% during sinus rhythm. In nine patients in whom the

same morphology of VT was induced before and after pirmenol, the Ql3S interval increased by 1’7 + 11% during sinus rhythm, 20 zt 10% during ventric-

ular pacing at a cycle length of 500 maec, and 22 f. 11% during VT. The increases during ventricular pacing and VT were significantly greater than those during sinus rhythm

(p = 0.006 arrd p = 0.002,

respectively). WIW&MU

change,

but

rmarkat+. The QT interval the average QTe increased.

did not In the

patient in whrn the moimphasic action potential was recorded, the APD, was unaltered (293 + 1.2

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2. Effect of pirmenol on His-Purkinje and intraventricular conduction. Surface leadsI, aVF, and V, are shown with intracardiac electrogramsfrom the high right atrium (HRA), the right ventricular apex (RV), and the His bundle position (HBE). A, In the baselinestate, the sinuscycle length is 660 msecand the HV interval is 55 msec.B, After pirmenol, the sinus cycle length is 530 msec,the HV interval is 100 msec,and left bundle branch block has developed. Prior to pirmenol administration, decremental atria1 pacing resulted in left bundle branch block only at cycle lengths lessthan 400 msec. Fig.

msec vs 292 & 1.6 msec, p = NS), but the APDw was significantly shorter after pirmenol(245 + 2 msec vs 214 + 2 msec, p < 0.001, Fig. 3). In this patient, the QT, did not increase after pirmenol. Atrlal and ventricular refractory periods. The atria1 refractory periods and ventricular effective increased. The increase in ventricular refractoriness is illustrated by a rightward shift in the strengthinterval curve measured in one patient (Fig. 3). Antiarrhythmic efficacy. Intravenous pirmenol was judged efktive in 6 of 15 patients (40%), including two patients in whom no VT was induced after pirmenol and three patients in whom six, seven, and nine complexes of VT were induced, respectively. In a sixth patient, a maximum of five repetitive ventricular complexes could be induced by two extrastimuli from two right ventricular sites after pirmenol administration, but three extrastimuli induced ventricular fibrillation. In this patient, the clinical morphology of sustained VT was induced by constant-rate atrial pading or by a single ventricular extrastimulus at baseline electrophysiologic testing;

we considered the induced ventricular fibrillation to be a nonspecific response to three extrastimuli. No patient in whom pirmenol was predicted ineffective responded to another antiarrhythmic drug at electropharmacologic testing. The cycle length of induced VT increased by 36 + 15% in the patients in whom the same morphology of sustained VT was induced before and after pirmenol (p < 0.001). The corresponding arterial pressures during VT increased from 55 +_ 20 mm Hg to 76 + 20 mm Hg (p = 0.002). In the control state, VT was terminated by pacing in eight of these nine patients and by direct current cardioversion in one of them; after pirmenol, VT was terminated by pacing in all patients. Adverse effects. One patient had mild hypotension and one complained of mild nausea, but both completed the pirmenol infusion. One patient developed repetitive episode of spontaneous, sustained VT during the infusion. This VT resolved 1 hour after pirmenol was discontinued. Plasma concentration. The plasma concentration

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Fig. 3. Effect of pirmenol on ventricular refractoriness (ERP) and action potential duration (APD).

The right ventricular strength-interval curve is superimposedon the right ventricular monophasic action potential recorded at the same site during atria1 pacing at a cycle length of 500 msec. For the strength-interval curve, the ventricular extrastimulus (S,) strength is plotted on the ordinate, and the longest coupling interval (V,S,) that failed to capture the ventricle is plotted on the abscissa. After pirmenol, the strength-interval curve is shifted to the right. The monophasicAPD at 90% repolarization is unchanged(293vs 292msec),but the monophasicAPD at 50% repolarization is shorter (245vs 214msec, p < 0.001). This results in an increasein ERP/APD at 50% repolarization without a change in ERP/APD

at 90 % repolarization. of pirmenol was not measured in the patient in whom pirmenol was proarrhythmic and in one patient in whom pirmenol was ineffective. The pirmenol plasma concentration in the remaining 13 patients ranged from 1.01 to 3.56 pg/ml (mean 2.29 & 0.75). The plasma concentrations were higher in patients in whom pirmenol was judged effective than in those in whom it was judged ine&ctive, but this difference did not reach statistical significance (2.53 f 0.73 &ml vs 2.06 k 0.75 pg/ml, p = 0.3). Pirmenol was judged effective in one of four patients in whom the plasma concentration was less than 2 &ml, in three of seven in whom it was between 2 and 3 &ml, and in two of two in whom it was greater than 3 &ml. DISCUSSION

This study evaluated the electrophysiologic effects and ant&rhythmic efficacy of intravenous pirmenol in patients with sustained ventricular tachyarrhythmias. EiectrophyskWgk effects. In animal studies, pirmenol slowed His-Purkinje and intraventricular conduction and prolonged ventricular repolarization, as judged by its effecta on the NV, QRS, and QTc intervals.1 These effects are similar to those caused by other type 1A antiarrhtiic drugs.

Pirmenol caused a decrease in sinus cycle length and AH interval, but these anticholinergic e&eta were smaller in magnitude than those caused by quinidine or disopyramide. l3 The effect of intravenous pirmenol on ECG intervals in patients who were treated for premature ventricular complexes has been reported3-5; the drug decreased sinus cycle length and increased the PR, QRS, and QT, intervals. In our study, the effect of pirmenol on ECG intervals was similar. We found that the principal electrophysiologic effects of intravenous pirmenol were slowing of His-Purkinje and intraventricular conduction and prolongation of atrial and vent&&r refractoriness. The greater slowing of intraventricular conduction during VT and ventricular pacing at a cycle length of 500 msec than in sinus rhythm suggests that

pirmenol has frequency-depend& effects similar block the sodium channel.“-l6 Pirmenol’s effect on atrial refractoriness may explain its reported e&acy in converting atrial fibrillation to sinus rhythm.17 Pirrnend did not alter sinus node recovery time, intra-atrial or AV nodal conduction, or AV nodal reti&ness. The effect of intzavenous pirrrrrseaol on electrophysiologic variablea in pa&&s w&h ventricular arrhythmias has been reported by two groups of

to those of other drugs that

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investigators who used infusion protocols identical to ours.‘*. lo Estes et al . ** reported that pirmenol increased atrial refractoriness, but Easley et allo reported no significant change in atrial refractoriness; our findings are in agreement with those of Estes et al. In our study, the effects of primenol on other electrophysiologic variables were similar to those reported previously.16s lg Pirmenol’s effect on the transmembrane action potential has been measured in isolated canine Purkinje fibers.’ Unlike other class IA drugs, pirmeno1 decreased APDso. Through its shortening effect on APD, and prolongation of refractoriness, pirmeno1 increased the ratio of refractoriness to APD,, a property which is believed to favor antiarrhythmic efficacy. We noted a similar effect of pirmenol on the time course of human ventricular repolarization in one patient as measured by shortening of the APD,. Pirmenol’s disparate effect on the time course of ventricular repolarization and refractoriness in this patient was demonstrated by the simultaneous rightward shift of the strength-interval curve. Although this preliminary finding is based on data from one patient, APD measurements using the contact-electrode technique are highly reproducible, with standard deviations in this patient ~2 msec. To the best of our knowledge, this is the first report in which the effect of an antiarrhythmic drug in humans has been evaluated by recording the strength-interval relation and APD simultaneously at the same site. Antiarrhythmic efficacy. We judged intravenous pirmenol effective by electropharmacologic testing in 40% of the patients in this study. Five (33 % ) of the patients in whom pirmenol was predicted effective met the previously validated criterion of 15 or fewer induced ventricular complexes69 ll; we considered pirmenol effective in one additional patient in whom we judged that ventricular fibrillation induced by three extrastimuli during pirmenol administration was not clinically relevant.12 The 33% incidence of preventing initiation of more than 15 induced complexes for pirmenol in our study can be compared to a 24% incidence for procainamide and a 35% incidence for quinidine reported by Rae et al.” in a similar patient population. Bv the use of the similar criterion of “no

Pirmenol electrophysiology

pirmenol better than VT induced in the baseline state. This is in contrast to VT induced after intravenous quinidine, which is not always better tolerated despite a longer cycle length.20 Pirmenol plasma concentrations. In dogs after coronary artery ligation,, plasma concentrations of 0.8 g/ml correlated with 80% success in converting ventricular tachyarrhythmias to sinus rhythm.2 In patients with chronic premature ventricular complexes, reported plasma concentrations of pirmenol have varied from 0.7 to 3.8 &ml; the minimal concentration that suppressed 96% of premature ventricular complexes has varied from 0.6 to 1.4 ~g/m1.3-6 In our study, pirmenol plasma concentrations exceeded 1.4 in 11 of 13 patients. Plasma concentrations were higher in patients in whom pirmenol was judged effective than in those in whom it was judged ineffective, but this difference did not reach statistical significance. Adverse effects. We,noted adverse effects in three patients: transient hypotension, mild nausea, and a marked proarrhythmic effect in one patient each. Only the patient who had exacerbation of VT required termination of the infusion. Previously reported adverse effects of intravenous pirmenol include hypotension, hypertension, sinus tachycardia, and arrhythmia exacerbation. Bitter taste and sleepiness have also been reported, but they are more common during chronic, oral administration.3-5* lo The 7 % incidence of arrhythmia exacerbation in our study is similar to the 4% incidence of proarrhythmic effects reported for pirmenol by Easley et al. and in the range reported for other antiarrhythmic drugs in patients with sustained ventricular tachyarrhythmias.21p22 Conclusions. Intravenous pirmenol can be administered safely to patients with sustained ventricular tachyarrhythmias. It has effects on standard electiophysiologic variables that are similar to other type IA ant&rhythmic drugs. Electropharmacologic testing predicts that pirmenol should be as effective as approved antiarrhythmic drugs in this patient population. REFERENCES

sustained VT,”Eiasley etal.reported thatpirmenol

prevented initiation of VT in 5-of 24 patients (24 % ) with spontaneous and inducible sustained VT. Effect of induced VT. Like other type 1A antiarrhythmic drugs, pirmenol prolonged the cycle length of induced VT. Patients tolerated VT induced after

1395

Reder RF, Danilo P Jr, Rosen MR. Rffects of pirmenol HCl on electrophysiologic properties of cardiac Purkinje fibers.

Bur 11 Phaimacol1980:~1:321. Mertz TR. Steffe TJ. Pirmenol hydrochloride (CI-9451:

Antiarrhvthmic profile in coronary artery ligated ccnscious dogs. J Cardiovasc Pharmacol 1980;2:527.- Anderson JL. Lutz JR. NaDDi JbI. Pirmenol for control of ventricular arrhythmias: Oral dose-ranging and short-term maintenance study. Am J Cardiol 1984;53:522. Hammill SC, Shand DG, Routledge PA, Hindman MC, Baker

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9.

10. 11.

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JT, Pritchett ELC. Pirmenol, a new antiarrhythmic agent: Initial study of efficacy, safety and pharmacokinetics. Circulation 1982;65:369. Reiter MJ, Hammill SC, Shand DG, Verghese C, McCarthy E, Pritchett ELC. Efficacy, safety, and pharmacokinetics of a concentration-maintaining regimen of intravenous pirmenol. Am J Cardiol 1983;52:83.Swerdlow CD. Winkle RA. Mason JW. Proenostic sianificance of the number of induced ventricular complexes during assessment of therapy for ventricular tachyarrhythmias. Circulation 1983;68:400. Franz MR. Long-term recording of monophasic action potentials from human endocardium. Am J Cardiol 1981;51:1629. Michelson EL, Spear JF, Moore NM. Strength-interval relations in a chronic canine model of myocardial infarction. Implications for the interpretation of electrophysiologic studies. Circulation 1981;63:1158. Shand DG, Verghese C, Barchowsky A, Hammill SC, Pritchett ELC. High-performance liquid chromatographic analysis of a new antiarrhythmic drug, pirmenol, in biological fluids. J Chromatogr 1981;224:343. Bazett HC. An analysis of the time-relation of electrocardiogram. Heart 1920;7:353. Rae AP, Greenspan AM, Spielman SR. Sokoloff NM, Webb CR, Kay HR, Horowitz LN. Antiarrhythmic drug efficacy for ventricular tachyarrhythmias associated with coronary artery disease as assessed by electrophysiologic studies. Am J Cardiol 1985;55:1494. Brugada P, Green M, Abdollah H, Wellens HJJ. Significance of ventricular arrhythmias initiated by programmed ventricular stimulation: The importance of the type of ventricular arrhythmia induced and the number of premature stimuli. Circulation 1984;69:87.

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13. Baukema J, Black ME, Tartaglia B. Summary for investigators. Pirmenol hydrochloride. Warner-Lambert Research Report No. RR-X 720-00757, 1983. 14. Hondeehem LM. Katzune BG. Time and voltage-denendent interaciions of antiarrhythmic drugs with cardiac sodium channels. Biochem Biophys Acta 1977;474:373. 15 Morady F, DiCarlo LA Jr, Baerman JM, Krol RB. Ratedependent effects of intravenous lidocaine, procainamide and amiodarone on intraventricular conduction. J Am Co11 Cardiol 1985;6:179. 16. Gang ES, Denton TA, Oseran DS, Mandel WJ, Peter T. Rate-deuendent effects of nrocainamide on His-Purkinie conduction in man. Am J &rdiol 1985;55:1525. 17. Toivoness LK, Nieminen MS, Manninen V, Frick MH. Intravenous pirmenol in conversion of paroxysmal atria1 fibrillation (abstr). J Am Co11 Cardiol 1986:7:93A. 18. Estes NAM; Gold RL, Haffajee CI, Ma&all M, Charos G, Cameron J. Electrophysiologic effects, efficacy, and safety of pirmenol in patients with ventricular tachycardia (abstr). Circulation 1985;72:11-657. 19. Easley AR, Mann DE, Reiter MJ, Sakun V, Sullivan SM, Magro SA, Luck JL, Wyndham CRC. Electrophysiologic evaluation of pirmenol for sustained ventricular tachycardia secondary to coronary artery disease. Am J Cardiol 1986; 5886. 20. Swerdlow CD, Yu EO, Jacobson E, Mann F, Winkle RA, Griffin JC, Ross DL, Mason JW. Safety and efficacy of intravenous quinidine. Am J Med 1983;75I36. 21. Torres V. Flowers D. Sombere JC. The arrhvthmosenicitv of antiarrhythmic agents. AM H&T J 1985;10”91090~~ ” 22. Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982;65:886.