- Email: [email protected]
Electrophysiologic and antiarrhythmic effects of oral encainide in patients with atrioventricular nodal reentry or nodoventricular reentry
Electrophysiologic and antiarrhythmic effects oral encainide in patients with atrioventricular nodal reentry or nodoventricular reentry
of
Three patients with drug-resistant atrioventricular (AV) nodal reentrant tachycardia and two patients with reciprocating tachycardia associated with nodoventricular pathways received oral encainide after a control drug-free electrophyslologfc study. In one patient with AV nodal reentry, encainide prolonged anterograde AV nodal conductton, produced complete ventrfculoatrial (VA) block, and prevented tachycardia induction. Encainide had no effect on AV or VA conduction in the second patient with AV nodal reentry, and tachycardia with similar cycle length was still induced. The third patient was not studied whfie receiving encainide, but spontaneous AV nodal reentrant tachycard,ia occurring multiple times daily was abolished. In both patients with nodoventricular pathways, anterograde AV nodal and VA conduction were prolonged by encainide and tachycardia was no longer inducible. Two patlents with AV nodal reentry were given long-term encainide therapy and have been free of recurrent arrhythmias for 16 and 30 months. One patient with a nodoventricular pathway has been without arrhythmia recurrence after 73 months of encainide therapy; the other patient required addition of propranolol to encainide because of recurrent tachycardia. We conclude that encainide can prolong anterograde AV nodal and VA conduction and prevent induced and spontaneous tachycardia in some patients with drug-resistant and highly symptomatic AV nodal or nodoventricular reentry. (AM HEART J 1987;114:26.)
William M. Miles, M.D., Mau-Song Chang, M.D., James J. Heger, M.D., Robert L. Rinkenberger, M.D., Douglas P. Zipes, M.D., and Eric N. Prystowsky, M.D. Indianapolis, Ind.
Encainide is a benzanilide derivative that when taken orally prolongs atrioventricular (AV) nodal and His-Purkinje conduction time, refractoriness in AV nodal, atrial, and ventricular tissues,’ and conduction and refractoriness of accessory pathways in the Wolff-Parkinson-White syndrome.1-5 Encainide has been reported to suppress ventricular arrhythmias,6 supraventricular arrhythmias associated with the Wolff-Parkinson-White syndrome,1-5’7 incessant supraventricular tachycardias,7 and ectopic atria1 tachycardias7ss not controlled by conventional antiarrhythmic drug trials. We report our experience with encainide in patients with drug-refractory From the Krannert Institute of Cardiology, Indiana University School of Medicine, Administration Medical Center.
the Department and the Roudebush
of Medicine, Veterans
Supported in part by the Herman C. Krannert Fund, Indianapolis; by grants HL-06308 and HL-07182 from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda; by the Attorney General of Indiana Public Health Trust; and by the Roudebush Veterans Administration Medical Center, Indianapolis. Received
for publication
Sept.
12, 1986;
Reprint requests: William M. Miles, gy, 1001 W. Tenth St., Indianapolis,
26
accepted
M.D., Krannert IN 46202.
Jan.
5, 1987.
Institute
of Cardiolo-
highly symptomatic AV nodal reentrant tachycardia and reciprocating tachycardia associated with a nodoventricular (Mahaim) pathway. METHODS
Three patients with AV nodal reentrant tachycardia and two patients with reciprocating tachycardia associated with nodoventricular pathways underwent electrophysiologic study in the control, drug-free state (Table I). All patients except patient 3 alsounderwent electrophysiologic study 4 to 7 days after oral encainide therapy. Before the control electrophysiologic study, all cardioactive medications were discontinued for a period exceeding five times their elimination half-lives. Patients were studied in the postabsorptive nonsedated state after written and oral informed consent was obtained. Encainide was administered initially at a dose of 25 mg every 6 hours after the control electrophysiologic study was completed. The doseof encainide was increasedby increments of 40 to 100 mg daily at intervals of 48 hours until spontaneous arrhythmia disappeared,adverseside effects occurred, or a total dose of 240 mglday was achieved. Patients were evaluated by one of the investigators for evidence of recurrent arrhythmia or drug toxicity at 3-month intervals during long-term outpatient treatment.
Volume Number
114 1, Part 1
Encainide
in AV nodal
or nodoventricular
reentry
27
905522T
HRA HBE PCS
Fig. 1. Induction of AV nodal reentry with two atria1 extrastimuli in patient 1. Surface leadsI, II, III, and Vl are displayed along with high right atrial (HRA), His bundle (HBE), proximal (PCS), and distal (DCS) coronary sinusand right ventricular (RV) electrograms.After an atria1 drive train (S,) of 500 msec,two atria1 premature extrastimuli (S, and S,) are introduced. The secondatria1 extrastimulus is followed by marked AH prolongation and the initiation of a narrow QRS tachycardia with a cycle length of 230 msec. Retrograde atria1 activation is concentric. The ventricle and atrium are activated simultaneously, excluding the participation of an accessorypathway. Continuation of tachycardia after slight repositioning of the catheter to obtain a better His recording is noted in the right panel.
A
A
A
A
HRA
A
2. Ventricular pacing before and during oral encainide therapy in patient 1. The format and abbreviations are similar to those used in Fig. 1. The left panel illustrates 1:l VA conduction at a right ventricular apical pacing cycle length of 250msecat the control study. The right panel illustrates VA block during ventricular pacing at a cycle length of 500 msecduring encainide therapy. The amplitude of the atria1 deflections varied with breathing. Fig.
Electrophysiologic procedure. Details of our electrophysiologic study protocol have been reported previously.‘p2 In brief, four multipolar electrode catheters were inserted percutaneously and positioned at the high lateral right atrium, right ventricle, acrossthe tricuspid valve in the region of the His bundle, and into the coronary sinus. Standard ECG leads I, II, III, and Vl and intracardiac electrograms were displayed simultaneously on a multichannel oscilloscopeand recorded at paper speedsof 75 to 150 mm/set. Surface and intracardiac electrograms were
filtered at frequencies of 0.1 to 25 Hz and 30 to 500 Hz, respectively. Programmed electrical stimulation was performed with rectangular stimuli of 2 msec duration and currents of twice diastolic threshold. Incremental atria1 and right ventricular pacing until AV or ventriculoatrial (VA) block occurred or until limited by patient symptoms, determination of atrial and ventricular refractory periods after introduction of premature extrastimuli after eight drive train complexes at a constant cycle length, and induction of reciprocating tachycardia by programmed
July
28
Miles et al.
American
Heart
1997
Journal
824874E
A I
RV-k
L
1
ql
I A
RV I
3. Documentation of a nodoventricular pathway in patient 5. The format and abbreviations are similar to those of Pigs. 1 and 2. The left panel illustrates a stimulus to QRS interval of 180 msecwhile pacing the atrium at 600 msec.The right panel illustrates that the stimulus to QRS interval increasesto 230 msecduring atria1 pacing at a cycle length of 300 mset. The AH prolongs appropriately but the HV shortensand preexcitation with a left bundle branch block morphology appears,confirming the presence of a nodoventricular pathway. Fig.
control
HRA
I 1
I *
I
9-
HE
Fig. 4. VA conduction before and after oral encainide therapy in patient 5. The format and abbreviations
are similar to those of Figs. 1 through 3. The left panel illustrates 1:l VA conduction maintained to a ventricular pacing cycle length of 280msecat the control study. The right panel illustrates VA block in the samepatient while pacing the right ventricle at a cycle length of 590 msecduring encainide treatment.
atrial or ventricular stimulation was performed. Reciproeating tachycardia wasterminated in all patients by one or more atrial or ventricular complexes. Criteria for AV nodal reentry included a concentric retrograde atrial activation sequence(low atrial septum earliest followed by right and left atrial free wall depolar-
ization) during reciprocating tachycardia and no evidence of accessorypathway conduction in either anterograde or retrograde directions, as well as one or both of the following: (1) tachycardia reproducibly initiated after a critical AV nodal delay and (2) ventricular to high right atrial interval during tachycardia < 95 msec. Ah three
Volume Number
114 1, Part 1
Encainide
or nodoventricular
reentry
29
I. Patient characteristics
Table Patient No.
Sex/age (yr)
Duration symptoms fyr)
1
F/53
19
2
M/19
15
3
F/60
50
4
M/19
11
5
F/26
6
AVNRT
in AV nodal
= Atrioventricular
nodal reentrant
of
Tocainide, &blocker, digoxin, quinidine, d-sotalol Digoxin, P-blocker, verapamil, quinidine Digoxin, P-blocker, disopyramide, procainamide, quinidine, verapamil Digoxin, quinidine, B-blocker Digoxin, disopyramide, quinidine tachycardia;
CHF = congestive
patients with AV nodal reentry in this study had ventricular to high right atria1 intervals 5 70 msec,and two had discontinuous AV nodal conduction curves. Nodoventricular pathways demonstrated the following during incremental atrial pacing or premature atria1 stimulation: (1) a progressiveincreasein the stimulus of QRS interval, (2) an increase in the duration of the QRS complex and a left bundle branch block morphology, and (3) a decreasein the HV interval.‘O Induced tachycardias associatedwith the nodoventricular pathway in both of our patients had QRS complexes of left bundle branch block morphology identical to that seen during atria1 pacing. RESULTS
Arrhythmia
Associated diseases
Palpitation, syncope
AVNRT
None
Palpitation, syncope
AVNRT
None
Syncwe, palpitation, chest pain
AVNRT
Palpitation
RT with nodoventricular pathway RT with nodoventricular pathway
Palpitation,
heart failure;
RT = reciprocating
Hypertension, diabetes, CHF None None
tachycardia.
underwent repeat electrophysiologic studies after oral administration of encainide. In patient 1 encainide prolonged the shortest atrial pacing cycle length at which 1:l anterograde AV nodal conduction occurred, increased the atria1 and ventricular effective refractory periods, prolonged the QRS duration, and resulted in complete retrograde VA block (Figs. 1 and 2). In contrast, encainide minimally affected the electrophysiologic and ECG properties of the second patient. Plasma encainide and metabolite levels were not obtained. Patient 3 did not undergo repeat electrophysiologic study, but encainide prolonged ECG PR, QRS, and QTc interV&3.
In each patient, tachycardia had recurred despite three to six drug trials before the administration of encainide, and each patient had severe and limiting symptoms as a result of tachycardia. Only patient 3 had associated structural heart disease (Table I). The average patient age was 35.4 years (range 19 to 60) and the average duration of symptoms was 20 years. The average daily dose of encainide at repeat electrophysiologic study was 205 mg (range 150 to 240). The four patients who received long-term encainide therapy were followed up for a mean of 41.9 months (range 16 to 73). Patient
Clinical symptoms
Previous drugs tried
characteristics.
Electrophysiologic
effects
III). Two of three patients
of encainide
(Tables
II and
with AV nodal reentry
Two patients with nodoventricular pathways received encainide (Fig. 3). During oral encainide therapy, anterograde AV nodal conduction was depressed and refractoriness was prolonged. However, anterograde nodoventricular pathway conduction persisted in both patients. It was not possible to determine if retrograde conduction occurred over the nodoventricular tract, the normal VA conduction system, or both. However, encainide therapy markedly altered retrograde VA conduction in both patients, and the shortest pacing cycle length maintaining 1:l VA conduction increased from < 300 msec to 540 msec in one patient and from 270 to 600 msec in the other patient (Fig. 4). Antiarrhythmic effects of encainide. Patient 1 had
30
Miles
et al.
American
July 1997 Heart Journal
Fig. 5A. Illustration of AV nodal reentrant atrial echo in a patient with nodoventricular reentry before encainide therapy (patient 4). The format and abbreviations are similar to those of Figs. 1 through 4. Atrial pacing at drive train cycle length 500 msec (S,) is followed by a premature atrial stimulus (.‘$A,). The nodoventricular pathway doesnot conduct after A, and a normal QRS morphology results, followed by an atrial echo with a VA interval of 10 msecin the His bundle lead and 30 msecin the high right atria1 lead. This atrial echo is most consistent with AV nodal reentry. Table II. Electrophysiologic characteristics
Patient No. 1
2 3 4 5
1:1 VA retrograde conduction (msec)
Spontaneous cycle length (msec)
1:l AVN anterograde conduction (msec)
EN dose (w/day)
C
EN
C
EN
C
EN
C
EN
225 200 150 210 240
540 620 680 710
670 710 760
5 220 300 5 330 5300 300
290 320 350 420
5 250 290 320 5300 270
B 290 540 600
220 220 210 260 -
300 280 310 210
Atria1 ERP (msec)
C = Control; EN = encainide; AVN = atrioventricular node; ERP = effective refractory period; VACS = ventriculoatrial conduction system; RT = reciprocating tachycardia; B = block; NI = not inducible. All refractory periods were determined at pacing cycle length 500 rnsec. Modes of induction: A,A,A, = Two atria1 extrastimuli during atrial pacing; RA,A, = two atria1 extrastimuli during sinus rhythm; RV,V, = two ventricular extrastimuli during sinus rhythm; V,V, = one ventricular extrastimulus during ventricular pacing; VP = decremental ventricular pacing; RA, = one atria1 extrastimulus during sinus rhythm; A,A, = one atrial extrastimulus during atria1 pacing; AP = decremental atria1 pacing.
Table Ill. ECG characteristics of patients with AV nodal reentry QRS Patient No.
PR interval (met) C
EN
EN
C
EN
430 430 430
480 420 460
1
110
140
80
120
130 260
140 280
80 80
90 120
EN = encainide;
h.d
C
2 3 C * Control;
QTc
interval (msec)
QTc = QT/@R.
repeated episodes of AV nodal reentry induced with two atrial extrastimuli at control study, but during encainide therapy no reciprocating tachycardia or echo beats could be induced, this patient has had no recurrence of arrhythmia for a follow-up period of 16 months. She had mild, tolerable blurred vision while receiving encainide, 75 mg t.i.d. Patient 2 had AV nodal reentry similar in cycle length induced at control and encainide study, and the drug was d&continued. Atrioventricular nodal reentry was diagnosed at control study in patient 3, who did not
Volume Number
114 1, Part 1
Encainide
in AV nodal
or nodoventricular
reentry
31
Fig. 58. Same patient as in Fig. 5A. S, is introduced 10 msec earlier, the AH interval prolongs, nodoventricular pathway conduction occurs, and a reciprocating tachycardia with left bundle branch block morphology is induced. Nodoventricular conduction occurs despite a shorter S,S, interval, possibly becauseof delay in the AV node proximal to the takeoff of the nodoventricular pathway (gap).
-
-
AVN ERP anterograde (msec) c
EN
<260 230
<330 <310
<210
-
<270 275
320 340
VACS ERP retrograde (msec)
Ventricular ERP (msec)
C
EN
C
EN
<260 < 230 <270 300 <270
B < 330 -
230 210 240 240 240
270 < 330 240 260
RT cycle length (RT mode of induction) (msec) c
EN
250U&A,) 340 (RA,A,, A,A2A3, 360 (RA,, A,Az, AP) 310 (RA,, A,&) 330 W,V,)
RV2V,, V,V,)
NI 310 (A,A,A,, V,Vz, VP) NI NI
FollouHLp ho) 16
30 73 47
-
undergo an electrophysiologic study while receiving encainide. This patient had multiple episodes daily of reciprocating tachycardia, almost continuously for the 12 hours before institution of oral encainide, but she has had no tachycardia since encainide therapy and no clinical arrhythmia recurrence during 30 months of follow-up. Reciprocating tachycardia was induced in both patients with nodoventricular pathways at control electrophysiologic study, but neither reciprocating tachycardia nor echo beats were inducible after oral encainide therapy. Of note, each of these patients also had evidence of dual AV nodal physiology; patient 4 had AV nodal echoes with premature atrial stimuli at control study (Fig. 5), and patient 5 had
discontinuous AV nodal curves demonstrated at drug study (H,H, increased from 295 to 450 msec when A,A, decreased from 360 to 345 msec). Patient 4 has done well without recurrence of arrhythmia during 73 months of follow-up. Patient 5 had to decrease her encainide dose to 225 mg/day because of headaches; she then required the addition of propranolol, 40 mg q.i.d., because of recurrent supraventricular tachycardia. She continued to have occasional palpitations but no further sustained tachycardia could be documented. DISCUSSION
We demonstrated antiarrhythmic efficacy of encainide in two of three patients with AV nodal
32
Miles
et al.
reentry and in two patients with nodoventricular reciprocating tachycardia, all of whom had severe symptoms as a result of tachycardia that were resistant to treatment with several antiarrhythmic drugs. Long-term encainide therapy was effective in the four patients in whom tachycardia became noninducible at electrophysiologic study while they received encainide. Two patients had side effects (blurred vision and headache), one of whom required reduction of encainide dosage with subsequent recurrent supraventricular tachycardia necessitating addition of propranolol. Oral encainide therapy substantially depresses anterograde and retrograde AV nodal conduction and prolongs refractoriness.‘, l* Thus this drug should be useful to treat patients with AV nodal reciprocating tachycardia, as well as patients with nodoventricular reciprocating tachycardia, regardless of whether the mechanism of nodoventricular tachycardia is AV nodal reentry with nodoventricular bystander conduction or reciprocating tachycardia incorporating the nodoventricular pathway in the tachycardia circuit.lOv 12,l3 The antiarrhythmic efficacy of encainide in AV nodal reentry could be related to its effects on conduction and refractoriness in either the anterograde slow AV nodal pathway, the retrograde fast pathway, or both. Data from this study show that the major antiarrhythmic action is due to the drug’s electrophysiologic effects on retrograde AV nodal function, as has been demonstrated for drugs such as procainamide.14 In patient 2, minimal changes in AV or VA conduction occurred during encainide therapy and reciprocating tachycardia was still inducible, suggesting that changes in electrophysiologic parameters tend to correlate with induction of supraventricular tachycardia. The lack of electrophysiologic and ECG effects could be due to impaired O-demethylation of encainide that occurs in approximately 10% of patients,l’ although plasma encainide and metabolite levels were not available in this patient for confirmation. Encainide markedly slowed AV nodal and VA conduction in both patients with nodoventricular pathways, and it prevented tachycardia induction in these two patients at repeat electrophysiologic study. The an&rhythmic efficacy of encainide in patients with nodoventricular pathways could be due to prolongation of conduction and refractoriness in the AV node, nodoventricular pathway, or retrograde His-Purkinje system. The persistence of anterograde preexcitation and absence of atrial ethos in our two patients after encainide therapy suggest
American
July 1987 Heart Journal
that alterations of the electrophysiologic properties of the nodoventricular pathway did not account for the ant&rhythmic efficacy of encainide. As in patients with typical AV nodal reentrant tachycardia, the major antiarrhythmic effect of encainide appears to be its marked negative dromotropic action on VA conduction. Although the exact mechanism of reciprocating tachycardia in our patients with nodoventricular pathways is not known, the occurrence of an AV nodal reentrant echo in one patient and discontinuous AV nodal curves in the other suggests that AV nodal reentry could play a role. In conclusion, encainide can prevent induction of tachycardia at electrophysiologic study and spontaneous recurrences during follow-up in patients with AV nodal reentry or nodoventricular reentry refractory to other antiarrhythmic agents. Prevention of induction of tachycardia or prolongation of AV or VA conduction by oral encainide at electrophysiologic study may be useful in identifying those patients who will benefit from long-term encainide administration. We thank Sue Hennigar for preparing the manuscript.
REFERENCES
1. Jackman WM, Zipes DP, Naccarelli GV, Rinkenberger RL, Heger JJ, Prystowsky EN. Electrophysiology of oral encainide. Am J Cardiol 1982;49:1270. 2. Prystowsky EN, Klein GJ, Rinkenberger RL, Heger JJ, Naccarelli GV, Zipes DP. Clinical efficacy and electrophysiologic effects of encainide of patients with WolfF-ParkinsonWhite syndrome. Circulation 1984;69:278. 3. Kunze KP, Kuck KH, Schluter M, Kuch B, Bleifeld W. Electrophysiologic and clinical effects of intravenous and oral encainide in accessory atrioventricular pathway. Am J Cardiol 1984,54:323. 4. Abdollah H, Brugada P, Green M, Wehr M, Wellens HJJ. Clinical efficacy and electrophysiologic effects of intravenous and oral encainide in patients with accessory atrioventricular pathways and supraventricular arrhythmias. Am J Cardiol 1984;54:544. 5. Markel ML, Prystowsky EN, Heger JJ, Miles WM, Fineberg N, Zipes DP. Encainide for treatment of supraventricular tachycardias associated with the Wolff-Parkinson-White syndrome. Am J Cardiol 1986;58:41C. 6. Mason JW, Peters FA. Antiarrhythmic efficacy of encainide in patients with refractory recurrent ventricular tachycardia. Circulation 1981;63:670. 7. Brugada P, Abdollah H, Wellens HJJ. Suppression of incessant supraventricular tachycardia by intravenous and oral encainide. J Am Co11 Cardiol 1984;4:1255. 8. Kunze KP, Kuck KH, Schluter M, Bleifeld W. Effect of encainide and flecainide on chronic ectopic atria1 tachyardia. J Am Co11 Cardiol 1986;7:1121. 9. Miles WM, Yee R, Klein G, Zipes DP, Prystowsky EN. The preexcitation index: an aid in determining the mechanism of supraventricular tachycardia and localizing accessory pathways. Circulation 1986,74:493. 10. Gallagher JJ, Smith WM, Kasell JH, Benson DW, Sterba R,
Volume
114
Number
1, Part 1
Encainide
Grant AO. Role of Mahaim fibers in cardiac arrhythmias in man. Circulation 1981;64:176. 11. Duff HJ, Dawson AK, Roden DM, Oates JA, Smith RF, Woosley RL. Electrophysiologic actions of 0-demethyl encainide: an active metabolite. Circulation 1983;68:385. 12. Gallagher JJ. Variants of preexcitation: update 1984. In: Zipes DP, Jalife J, eds. Cardiac electrophysiology and arrhythmias. Orlando: Grune and Stratton, 1985: 419.
BOUND
VOLUMES
AVAILABLE
in AV nodal or nodouentricular
reentry
33
13. Bardy GH, German LD, Packer DL, Coltorti F, Gallagher JJ. Mechanism of tachycardia using a nodofascicular Mahaim fiber. Am J Cardiol 1984;54:1140. 14. Wu D, Denes P, Bauernfeind R, Kehoe R, Amat-y-Leon F, Rosen KM. Effects of procainamide on atrioventricular nodal re-entrant paroxysmal tachycardia. Circulation 1978; 57:1171.
TO SUBSCRIBERS
Bound volumes of the AMERICAN HEART JOURNAL are available to subscribers (only) for the 1987 issues from the Publisher at a cost of $45.90 ($58.90 international) for Vol. 113 (JanuaryJune) and Vol. 114 (July-December). Shipping chtirges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Company, Circulation Department, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA; phone (809) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.
of
Three patients with drug-resistant atrioventricular (AV) nodal reentrant tachycardia and two patients with reciprocating tachycardia associated with nodoventricular pathways received oral encainide after a control drug-free electrophyslologfc study. In one patient with AV nodal reentry, encainide prolonged anterograde AV nodal conductton, produced complete ventrfculoatrial (VA) block, and prevented tachycardia induction. Encainide had no effect on AV or VA conduction in the second patient with AV nodal reentry, and tachycardia with similar cycle length was still induced. The third patient was not studied whfie receiving encainide, but spontaneous AV nodal reentrant tachycard,ia occurring multiple times daily was abolished. In both patients with nodoventricular pathways, anterograde AV nodal and VA conduction were prolonged by encainide and tachycardia was no longer inducible. Two patlents with AV nodal reentry were given long-term encainide therapy and have been free of recurrent arrhythmias for 16 and 30 months. One patient with a nodoventricular pathway has been without arrhythmia recurrence after 73 months of encainide therapy; the other patient required addition of propranolol to encainide because of recurrent tachycardia. We conclude that encainide can prolong anterograde AV nodal and VA conduction and prevent induced and spontaneous tachycardia in some patients with drug-resistant and highly symptomatic AV nodal or nodoventricular reentry. (AM HEART J 1987;114:26.)
William M. Miles, M.D., Mau-Song Chang, M.D., James J. Heger, M.D., Robert L. Rinkenberger, M.D., Douglas P. Zipes, M.D., and Eric N. Prystowsky, M.D. Indianapolis, Ind.
Encainide is a benzanilide derivative that when taken orally prolongs atrioventricular (AV) nodal and His-Purkinje conduction time, refractoriness in AV nodal, atrial, and ventricular tissues,’ and conduction and refractoriness of accessory pathways in the Wolff-Parkinson-White syndrome.1-5 Encainide has been reported to suppress ventricular arrhythmias,6 supraventricular arrhythmias associated with the Wolff-Parkinson-White syndrome,1-5’7 incessant supraventricular tachycardias,7 and ectopic atria1 tachycardias7ss not controlled by conventional antiarrhythmic drug trials. We report our experience with encainide in patients with drug-refractory From the Krannert Institute of Cardiology, Indiana University School of Medicine, Administration Medical Center.
the Department and the Roudebush
of Medicine, Veterans
Supported in part by the Herman C. Krannert Fund, Indianapolis; by grants HL-06308 and HL-07182 from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda; by the Attorney General of Indiana Public Health Trust; and by the Roudebush Veterans Administration Medical Center, Indianapolis. Received
for publication
Sept.
12, 1986;
Reprint requests: William M. Miles, gy, 1001 W. Tenth St., Indianapolis,
26
accepted
M.D., Krannert IN 46202.
Jan.
5, 1987.
Institute
of Cardiolo-
highly symptomatic AV nodal reentrant tachycardia and reciprocating tachycardia associated with a nodoventricular (Mahaim) pathway. METHODS
Three patients with AV nodal reentrant tachycardia and two patients with reciprocating tachycardia associated with nodoventricular pathways underwent electrophysiologic study in the control, drug-free state (Table I). All patients except patient 3 alsounderwent electrophysiologic study 4 to 7 days after oral encainide therapy. Before the control electrophysiologic study, all cardioactive medications were discontinued for a period exceeding five times their elimination half-lives. Patients were studied in the postabsorptive nonsedated state after written and oral informed consent was obtained. Encainide was administered initially at a dose of 25 mg every 6 hours after the control electrophysiologic study was completed. The doseof encainide was increasedby increments of 40 to 100 mg daily at intervals of 48 hours until spontaneous arrhythmia disappeared,adverseside effects occurred, or a total dose of 240 mglday was achieved. Patients were evaluated by one of the investigators for evidence of recurrent arrhythmia or drug toxicity at 3-month intervals during long-term outpatient treatment.
Volume Number
114 1, Part 1
Encainide
in AV nodal
or nodoventricular
reentry
27
905522T
HRA HBE PCS
Fig. 1. Induction of AV nodal reentry with two atria1 extrastimuli in patient 1. Surface leadsI, II, III, and Vl are displayed along with high right atrial (HRA), His bundle (HBE), proximal (PCS), and distal (DCS) coronary sinusand right ventricular (RV) electrograms.After an atria1 drive train (S,) of 500 msec,two atria1 premature extrastimuli (S, and S,) are introduced. The secondatria1 extrastimulus is followed by marked AH prolongation and the initiation of a narrow QRS tachycardia with a cycle length of 230 msec. Retrograde atria1 activation is concentric. The ventricle and atrium are activated simultaneously, excluding the participation of an accessorypathway. Continuation of tachycardia after slight repositioning of the catheter to obtain a better His recording is noted in the right panel.
A
A
A
A
HRA
A
2. Ventricular pacing before and during oral encainide therapy in patient 1. The format and abbreviations are similar to those used in Fig. 1. The left panel illustrates 1:l VA conduction at a right ventricular apical pacing cycle length of 250msecat the control study. The right panel illustrates VA block during ventricular pacing at a cycle length of 500 msecduring encainide therapy. The amplitude of the atria1 deflections varied with breathing. Fig.
Electrophysiologic procedure. Details of our electrophysiologic study protocol have been reported previously.‘p2 In brief, four multipolar electrode catheters were inserted percutaneously and positioned at the high lateral right atrium, right ventricle, acrossthe tricuspid valve in the region of the His bundle, and into the coronary sinus. Standard ECG leads I, II, III, and Vl and intracardiac electrograms were displayed simultaneously on a multichannel oscilloscopeand recorded at paper speedsof 75 to 150 mm/set. Surface and intracardiac electrograms were
filtered at frequencies of 0.1 to 25 Hz and 30 to 500 Hz, respectively. Programmed electrical stimulation was performed with rectangular stimuli of 2 msec duration and currents of twice diastolic threshold. Incremental atria1 and right ventricular pacing until AV or ventriculoatrial (VA) block occurred or until limited by patient symptoms, determination of atrial and ventricular refractory periods after introduction of premature extrastimuli after eight drive train complexes at a constant cycle length, and induction of reciprocating tachycardia by programmed
July
28
Miles et al.
American
Heart
1997
Journal
824874E
A I
RV-k
L
1
ql
I A
RV I
3. Documentation of a nodoventricular pathway in patient 5. The format and abbreviations are similar to those of Pigs. 1 and 2. The left panel illustrates a stimulus to QRS interval of 180 msecwhile pacing the atrium at 600 msec.The right panel illustrates that the stimulus to QRS interval increasesto 230 msecduring atria1 pacing at a cycle length of 300 mset. The AH prolongs appropriately but the HV shortensand preexcitation with a left bundle branch block morphology appears,confirming the presence of a nodoventricular pathway. Fig.
control
HRA
I 1
I *
I
9-
HE
Fig. 4. VA conduction before and after oral encainide therapy in patient 5. The format and abbreviations
are similar to those of Figs. 1 through 3. The left panel illustrates 1:l VA conduction maintained to a ventricular pacing cycle length of 280msecat the control study. The right panel illustrates VA block in the samepatient while pacing the right ventricle at a cycle length of 590 msecduring encainide treatment.
atrial or ventricular stimulation was performed. Reciproeating tachycardia wasterminated in all patients by one or more atrial or ventricular complexes. Criteria for AV nodal reentry included a concentric retrograde atrial activation sequence(low atrial septum earliest followed by right and left atrial free wall depolar-
ization) during reciprocating tachycardia and no evidence of accessorypathway conduction in either anterograde or retrograde directions, as well as one or both of the following: (1) tachycardia reproducibly initiated after a critical AV nodal delay and (2) ventricular to high right atrial interval during tachycardia < 95 msec. Ah three
Volume Number
114 1, Part 1
Encainide
or nodoventricular
reentry
29
I. Patient characteristics
Table Patient No.
Sex/age (yr)
Duration symptoms fyr)
1
F/53
19
2
M/19
15
3
F/60
50
4
M/19
11
5
F/26
6
AVNRT
in AV nodal
= Atrioventricular
nodal reentrant
of
Tocainide, &blocker, digoxin, quinidine, d-sotalol Digoxin, P-blocker, verapamil, quinidine Digoxin, P-blocker, disopyramide, procainamide, quinidine, verapamil Digoxin, quinidine, B-blocker Digoxin, disopyramide, quinidine tachycardia;
CHF = congestive
patients with AV nodal reentry in this study had ventricular to high right atria1 intervals 5 70 msec,and two had discontinuous AV nodal conduction curves. Nodoventricular pathways demonstrated the following during incremental atrial pacing or premature atria1 stimulation: (1) a progressiveincreasein the stimulus of QRS interval, (2) an increase in the duration of the QRS complex and a left bundle branch block morphology, and (3) a decreasein the HV interval.‘O Induced tachycardias associatedwith the nodoventricular pathway in both of our patients had QRS complexes of left bundle branch block morphology identical to that seen during atria1 pacing. RESULTS
Arrhythmia
Associated diseases
Palpitation, syncope
AVNRT
None
Palpitation, syncope
AVNRT
None
Syncwe, palpitation, chest pain
AVNRT
Palpitation
RT with nodoventricular pathway RT with nodoventricular pathway
Palpitation,
heart failure;
RT = reciprocating
Hypertension, diabetes, CHF None None
tachycardia.
underwent repeat electrophysiologic studies after oral administration of encainide. In patient 1 encainide prolonged the shortest atrial pacing cycle length at which 1:l anterograde AV nodal conduction occurred, increased the atria1 and ventricular effective refractory periods, prolonged the QRS duration, and resulted in complete retrograde VA block (Figs. 1 and 2). In contrast, encainide minimally affected the electrophysiologic and ECG properties of the second patient. Plasma encainide and metabolite levels were not obtained. Patient 3 did not undergo repeat electrophysiologic study, but encainide prolonged ECG PR, QRS, and QTc interV&3.
In each patient, tachycardia had recurred despite three to six drug trials before the administration of encainide, and each patient had severe and limiting symptoms as a result of tachycardia. Only patient 3 had associated structural heart disease (Table I). The average patient age was 35.4 years (range 19 to 60) and the average duration of symptoms was 20 years. The average daily dose of encainide at repeat electrophysiologic study was 205 mg (range 150 to 240). The four patients who received long-term encainide therapy were followed up for a mean of 41.9 months (range 16 to 73). Patient
Clinical symptoms
Previous drugs tried
characteristics.
Electrophysiologic
effects
III). Two of three patients
of encainide
(Tables
II and
with AV nodal reentry
Two patients with nodoventricular pathways received encainide (Fig. 3). During oral encainide therapy, anterograde AV nodal conduction was depressed and refractoriness was prolonged. However, anterograde nodoventricular pathway conduction persisted in both patients. It was not possible to determine if retrograde conduction occurred over the nodoventricular tract, the normal VA conduction system, or both. However, encainide therapy markedly altered retrograde VA conduction in both patients, and the shortest pacing cycle length maintaining 1:l VA conduction increased from < 300 msec to 540 msec in one patient and from 270 to 600 msec in the other patient (Fig. 4). Antiarrhythmic effects of encainide. Patient 1 had
30
Miles
et al.
American
July 1997 Heart Journal
Fig. 5A. Illustration of AV nodal reentrant atrial echo in a patient with nodoventricular reentry before encainide therapy (patient 4). The format and abbreviations are similar to those of Figs. 1 through 4. Atrial pacing at drive train cycle length 500 msec (S,) is followed by a premature atrial stimulus (.‘$A,). The nodoventricular pathway doesnot conduct after A, and a normal QRS morphology results, followed by an atrial echo with a VA interval of 10 msecin the His bundle lead and 30 msecin the high right atria1 lead. This atrial echo is most consistent with AV nodal reentry. Table II. Electrophysiologic characteristics
Patient No. 1
2 3 4 5
1:1 VA retrograde conduction (msec)
Spontaneous cycle length (msec)
1:l AVN anterograde conduction (msec)
EN dose (w/day)
C
EN
C
EN
C
EN
C
EN
225 200 150 210 240
540 620 680 710
670 710 760
5 220 300 5 330 5300 300
290 320 350 420
5 250 290 320 5300 270
B 290 540 600
220 220 210 260 -
300 280 310 210
Atria1 ERP (msec)
C = Control; EN = encainide; AVN = atrioventricular node; ERP = effective refractory period; VACS = ventriculoatrial conduction system; RT = reciprocating tachycardia; B = block; NI = not inducible. All refractory periods were determined at pacing cycle length 500 rnsec. Modes of induction: A,A,A, = Two atria1 extrastimuli during atrial pacing; RA,A, = two atria1 extrastimuli during sinus rhythm; RV,V, = two ventricular extrastimuli during sinus rhythm; V,V, = one ventricular extrastimulus during ventricular pacing; VP = decremental ventricular pacing; RA, = one atria1 extrastimulus during sinus rhythm; A,A, = one atrial extrastimulus during atria1 pacing; AP = decremental atria1 pacing.
Table Ill. ECG characteristics of patients with AV nodal reentry QRS Patient No.
PR interval (met) C
EN
EN
C
EN
430 430 430
480 420 460
1
110
140
80
120
130 260
140 280
80 80
90 120
EN = encainide;
h.d
C
2 3 C * Control;
QTc
interval (msec)
QTc = QT/@R.
repeated episodes of AV nodal reentry induced with two atrial extrastimuli at control study, but during encainide therapy no reciprocating tachycardia or echo beats could be induced, this patient has had no recurrence of arrhythmia for a follow-up period of 16 months. She had mild, tolerable blurred vision while receiving encainide, 75 mg t.i.d. Patient 2 had AV nodal reentry similar in cycle length induced at control and encainide study, and the drug was d&continued. Atrioventricular nodal reentry was diagnosed at control study in patient 3, who did not
Volume Number
114 1, Part 1
Encainide
in AV nodal
or nodoventricular
reentry
31
Fig. 58. Same patient as in Fig. 5A. S, is introduced 10 msec earlier, the AH interval prolongs, nodoventricular pathway conduction occurs, and a reciprocating tachycardia with left bundle branch block morphology is induced. Nodoventricular conduction occurs despite a shorter S,S, interval, possibly becauseof delay in the AV node proximal to the takeoff of the nodoventricular pathway (gap).
-
-
AVN ERP anterograde (msec) c
EN
<260 230
<330 <310
<210
-
<270 275
320 340
VACS ERP retrograde (msec)
Ventricular ERP (msec)
C
EN
C
EN
<260 < 230 <270 300 <270
B < 330 -
230 210 240 240 240
270 < 330 240 260
RT cycle length (RT mode of induction) (msec) c
EN
250U&A,) 340 (RA,A,, A,A2A3, 360 (RA,, A,Az, AP) 310 (RA,, A,&) 330 W,V,)
RV2V,, V,V,)
NI 310 (A,A,A,, V,Vz, VP) NI NI
FollouHLp ho) 16
30 73 47
-
undergo an electrophysiologic study while receiving encainide. This patient had multiple episodes daily of reciprocating tachycardia, almost continuously for the 12 hours before institution of oral encainide, but she has had no tachycardia since encainide therapy and no clinical arrhythmia recurrence during 30 months of follow-up. Reciprocating tachycardia was induced in both patients with nodoventricular pathways at control electrophysiologic study, but neither reciprocating tachycardia nor echo beats were inducible after oral encainide therapy. Of note, each of these patients also had evidence of dual AV nodal physiology; patient 4 had AV nodal echoes with premature atrial stimuli at control study (Fig. 5), and patient 5 had
discontinuous AV nodal curves demonstrated at drug study (H,H, increased from 295 to 450 msec when A,A, decreased from 360 to 345 msec). Patient 4 has done well without recurrence of arrhythmia during 73 months of follow-up. Patient 5 had to decrease her encainide dose to 225 mg/day because of headaches; she then required the addition of propranolol, 40 mg q.i.d., because of recurrent supraventricular tachycardia. She continued to have occasional palpitations but no further sustained tachycardia could be documented. DISCUSSION
We demonstrated antiarrhythmic efficacy of encainide in two of three patients with AV nodal
32
Miles
et al.
reentry and in two patients with nodoventricular reciprocating tachycardia, all of whom had severe symptoms as a result of tachycardia that were resistant to treatment with several antiarrhythmic drugs. Long-term encainide therapy was effective in the four patients in whom tachycardia became noninducible at electrophysiologic study while they received encainide. Two patients had side effects (blurred vision and headache), one of whom required reduction of encainide dosage with subsequent recurrent supraventricular tachycardia necessitating addition of propranolol. Oral encainide therapy substantially depresses anterograde and retrograde AV nodal conduction and prolongs refractoriness.‘, l* Thus this drug should be useful to treat patients with AV nodal reciprocating tachycardia, as well as patients with nodoventricular reciprocating tachycardia, regardless of whether the mechanism of nodoventricular tachycardia is AV nodal reentry with nodoventricular bystander conduction or reciprocating tachycardia incorporating the nodoventricular pathway in the tachycardia circuit.lOv 12,l3 The antiarrhythmic efficacy of encainide in AV nodal reentry could be related to its effects on conduction and refractoriness in either the anterograde slow AV nodal pathway, the retrograde fast pathway, or both. Data from this study show that the major antiarrhythmic action is due to the drug’s electrophysiologic effects on retrograde AV nodal function, as has been demonstrated for drugs such as procainamide.14 In patient 2, minimal changes in AV or VA conduction occurred during encainide therapy and reciprocating tachycardia was still inducible, suggesting that changes in electrophysiologic parameters tend to correlate with induction of supraventricular tachycardia. The lack of electrophysiologic and ECG effects could be due to impaired O-demethylation of encainide that occurs in approximately 10% of patients,l’ although plasma encainide and metabolite levels were not available in this patient for confirmation. Encainide markedly slowed AV nodal and VA conduction in both patients with nodoventricular pathways, and it prevented tachycardia induction in these two patients at repeat electrophysiologic study. The an&rhythmic efficacy of encainide in patients with nodoventricular pathways could be due to prolongation of conduction and refractoriness in the AV node, nodoventricular pathway, or retrograde His-Purkinje system. The persistence of anterograde preexcitation and absence of atrial ethos in our two patients after encainide therapy suggest
American
July 1987 Heart Journal
that alterations of the electrophysiologic properties of the nodoventricular pathway did not account for the ant&rhythmic efficacy of encainide. As in patients with typical AV nodal reentrant tachycardia, the major antiarrhythmic effect of encainide appears to be its marked negative dromotropic action on VA conduction. Although the exact mechanism of reciprocating tachycardia in our patients with nodoventricular pathways is not known, the occurrence of an AV nodal reentrant echo in one patient and discontinuous AV nodal curves in the other suggests that AV nodal reentry could play a role. In conclusion, encainide can prevent induction of tachycardia at electrophysiologic study and spontaneous recurrences during follow-up in patients with AV nodal reentry or nodoventricular reentry refractory to other antiarrhythmic agents. Prevention of induction of tachycardia or prolongation of AV or VA conduction by oral encainide at electrophysiologic study may be useful in identifying those patients who will benefit from long-term encainide administration. We thank Sue Hennigar for preparing the manuscript.
REFERENCES
1. Jackman WM, Zipes DP, Naccarelli GV, Rinkenberger RL, Heger JJ, Prystowsky EN. Electrophysiology of oral encainide. Am J Cardiol 1982;49:1270. 2. Prystowsky EN, Klein GJ, Rinkenberger RL, Heger JJ, Naccarelli GV, Zipes DP. Clinical efficacy and electrophysiologic effects of encainide of patients with WolfF-ParkinsonWhite syndrome. Circulation 1984;69:278. 3. Kunze KP, Kuck KH, Schluter M, Kuch B, Bleifeld W. Electrophysiologic and clinical effects of intravenous and oral encainide in accessory atrioventricular pathway. Am J Cardiol 1984,54:323. 4. Abdollah H, Brugada P, Green M, Wehr M, Wellens HJJ. Clinical efficacy and electrophysiologic effects of intravenous and oral encainide in patients with accessory atrioventricular pathways and supraventricular arrhythmias. Am J Cardiol 1984;54:544. 5. Markel ML, Prystowsky EN, Heger JJ, Miles WM, Fineberg N, Zipes DP. Encainide for treatment of supraventricular tachycardias associated with the Wolff-Parkinson-White syndrome. Am J Cardiol 1986;58:41C. 6. Mason JW, Peters FA. Antiarrhythmic efficacy of encainide in patients with refractory recurrent ventricular tachycardia. Circulation 1981;63:670. 7. Brugada P, Abdollah H, Wellens HJJ. Suppression of incessant supraventricular tachycardia by intravenous and oral encainide. J Am Co11 Cardiol 1984;4:1255. 8. Kunze KP, Kuck KH, Schluter M, Bleifeld W. Effect of encainide and flecainide on chronic ectopic atria1 tachyardia. J Am Co11 Cardiol 1986;7:1121. 9. Miles WM, Yee R, Klein G, Zipes DP, Prystowsky EN. The preexcitation index: an aid in determining the mechanism of supraventricular tachycardia and localizing accessory pathways. Circulation 1986,74:493. 10. Gallagher JJ, Smith WM, Kasell JH, Benson DW, Sterba R,
Volume
114
Number
1, Part 1
Encainide
Grant AO. Role of Mahaim fibers in cardiac arrhythmias in man. Circulation 1981;64:176. 11. Duff HJ, Dawson AK, Roden DM, Oates JA, Smith RF, Woosley RL. Electrophysiologic actions of 0-demethyl encainide: an active metabolite. Circulation 1983;68:385. 12. Gallagher JJ. Variants of preexcitation: update 1984. In: Zipes DP, Jalife J, eds. Cardiac electrophysiology and arrhythmias. Orlando: Grune and Stratton, 1985: 419.
BOUND
VOLUMES
AVAILABLE
in AV nodal or nodouentricular
reentry
33
13. Bardy GH, German LD, Packer DL, Coltorti F, Gallagher JJ. Mechanism of tachycardia using a nodofascicular Mahaim fiber. Am J Cardiol 1984;54:1140. 14. Wu D, Denes P, Bauernfeind R, Kehoe R, Amat-y-Leon F, Rosen KM. Effects of procainamide on atrioventricular nodal re-entrant paroxysmal tachycardia. Circulation 1978; 57:1171.
TO SUBSCRIBERS
Bound volumes of the AMERICAN HEART JOURNAL are available to subscribers (only) for the 1987 issues from the Publisher at a cost of $45.90 ($58.90 international) for Vol. 113 (JanuaryJune) and Vol. 114 (July-December). Shipping chtirges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Company, Circulation Department, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA; phone (809) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.