Role of Adrenergic Stimulation by lsoproterenol in Reversal of Effects of Encainide in

Supraventricular Tachycardia Masood Akhtar, MD, lmran Niazi, MD, Gerald V. Naccarelli, MD, Patrick Tchou, MD, Robert Rinkenberger, MD, Anne H. Dougherty, MD, and Mohammad Jazayeri, MD

Reversal of the electrophysiologic effects of oral encainide with isoproterenoi was evaluated in 16 patients with atrioventricuiar (AV) nodal reentry (group A) and in another 16 patients with Woiff- Parkinson-White syndrome (group B). Sustained AV nodal reentry was induced in ail group A cases before administration of encainide, in 2 cases after oral encainide, and in 12 patients during infusion of isoproterenoi. Among group B cases, 14 of 16 had sustained AV reentry during control, 6 of 16 after receiving encainide, and 8 of 16 with addition of isoproterenoi.

During a mean follow-up of 19 f 10 months in group A and 17 f 9 months in group B, clinical tachycardia recurred in 8 patients (4 from each group). These 8 patients were among the 20 pa- tients who demonstrated (1) isoproterenol-induced reversibility of encainide-suppressed tachycardia, or (2) acceleration of tachycardia rate slowed by encainide. No recurrences were seen among any of the 12 cases in which isoproterenol failed to re- verse the encainide-induced tachycardia suppres- sion. Patients with ciinieai recurrences were con- trolled with a variety of means, which included 8 blockers in 3 and nonpharmacologic methods in the remaining 5.

In patients with AV junctional tachycardia treat- ed with oral encainide, our findings suggest that lack of tachycardia inducibiiity with isoproterenoi predicts freedom from clinical recurrences. Fur- thermore, addition of a ,13 blocker to oral encainide may prevent clinical recurrence in some who dem- onstrate adrenergic reversal of encainide effect.

(Am J Cardiol lSB6;62:45L-49L)

From the Electrophysiology Laboratory, University of Wisconsin-Mil- waukee Clinical Campus, Sinai Samaritan Medical Center, Milwau- kee, Wisconsin, and the Division of Cardiology, University of Texas Medical School at Houston, Houston, Texas.

Address for reprints: Masood Akhtar, MD, Electrophysiology Lab- oratory, Sinai Samaritan Medical Center, Mount Sinai Campus, 950 North 12th Street, Milwaukee, Wisconsin 53201.

F or manifestation of atrioventricular (AV) junc- tional reentry, the roles of circuit and the trigger- ing factors are well accepted.le3 In the cardiac elec-

trophysiology laboratory, artificial stimulation provides the trigger to initiate the sustained tachycardias. Antiar- rhythmic drugs that are able to suppress the tachycardia induction or depress conduction along the anterograde or retrograde limb of the reentry circuit seem to be clinically beneficial.3-7 However, the role of dynamic factors, such as modulation of autonomic tone, is often implicated in clinical recurrences after electrophysiologic testing for predicting control.

Catecholamines are known to facilitate AV nodal conduction and could therefore change the drug-induced response.8,9 In a preliminary report from our laboratory, we demonstrated reversal of procainamide-induced con- trol of both AV nodal and AV reentry, using an accessory pathway of the Kent’s bundle type with isoproterenol.1° This report deals with similar data in such patients treat- ed with oral encainide.

METHODS Patients: The study consisted of 32 patients, 16 with

AV nodal reentry and the remaining 16 with Wolff- Parkinson-White (WPW) syndrome. The mean ages, male/female ratios, and underlying structural heart dis- ease are listed in Table I. All patients with AV nodal reentry had clinically manifested, sustained, narrow QRS complex tachycardia. Fifteen of the 16 patients with WPW syndrome had orthodromic supraventricular tachycardia and 1 patient had only atria1 fibrillation us- ing an accessory pathway in the anterograde direction. Three of the 16 patients had paroxysmal orthodromic tachycardia as well as atria1 fibrillation.

Invasive eiectrophysiologic evaluation: All patients in this series underwent right-sided cardiac catheteriza- tion in a postabsorptive, nonsedated state after granting informed consenr. Under fluoroscopic guidance, multipo- lar electrode catheters (6Fr) were positioned in the region of the high atrium, tricuspid valve for recording His bun- dle and right ventricular apex activity.” In the patient with WPW syndrome, a catheter was also positioned in the coronary sinus for local electrical stimulation and recording. All atria1 electrocardiograms were filtered at frequency settings of 30 to 500 Hz and were displayed on a multichannel oscilloscope along with surface electrocar- diographic leads I, II and Vt (Fig. 1). Programmed stim-

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A SYMPOSIUM: USE OF ENCAINIDE IN SUPRAVENTRICULAR TACHYCARDIAS

ulation was performed using a digital stimulator with adjustable amplitude and duration of pacing impulses. All equipment was carefully grounded.

The pacing protocol included incremental atria1 and ventricular pacing to the point of AV and ventriculoatrial (VA) block or induction of sustained tachycardia. Induc- tion of tachycardia was also attempted using single and double premature extrastimuli from atria1 as well as ven- tricular sites at 1 or more basic cycle lengths. All episodes of induced reentrant tachycardias were terminated with atria1 or ventricular pacing, or both.

Drug intervention: After controlled studies, the pa- tients were treated with oral encainide, starting at a dos- age of 25 mg 3 times daily, which was generally increased to 50 mg 3 and 4 times daily. The mean dose level for patients with AV nodal reentry was 117 f 47 mg. In patients with WPW syndrome, the mean encainide dose was 194 f 33 mg at the time of repeat study. These follow-up studies were usually performed at the peak

TABLE I Clinical Data

Group A Group B (AV Nodal Reentry) (AV Reentry)

No. of patients Age W Male/female SHD

ASHD Hypertension MVP No SHD

16 16” 54f 17 37% 17

3/13 11/5

4 0 4 0 3 5 5 11

‘Fourteen of 16 patients had overt ventricular preexcitation. Values are expressed as mean f standard deviation. ASHD = atherosclerotic heart disease; MVP = mitral valve prolapse; SHD = struc-

tural heart disease.

level of the dose after reaching a steady state (varying between 3 and 5 days at that dosage). At the time of repeat studies, the tachycardia induction was tried and AV and VA conductions were studied. After assessment of electrophysiologic characteristics in each patient while receiving encainide, isoproterenol infusion was begun. The amount of isoproterenol was titrated to achieve a minimal increase in heart rate of 15% in patients with AV nodal reentry and 20% in those with WPW syndrome. In the 2 groups, however, the average heart rate after isopro- terenol infusion increased by 26 and 21%, respectively. During isoproterenol infusion, the AV and VA conduc- tion, as well as tachycardia induction, was again exam- ined, as they were in the control state.

Statistical analysis: Student t test and Wilcoxon analysis were used for statistical purposes. Statistical sig- nificance was defined as p <0.05; values are expressed as mean f standard deviation. Patients who underwent Wil- coxon analysis and who had accessory AV conduction block were assigned values at greater than the spontane- ous sinus cycle length.

RESULTS Patients with atrioventricular nodal reentry: Table II

lists the essential mean data on the various electrophysio- logic parameters measured in this group of patients.

Sinus cycle length: The mean sinus cycle length was 761 f 155 ms for all patients during the control studies. With encainide, the sinus cycle length was essentially unchanged (787 f 102 ms, p = not significant). After isoproterenol infusion, however, the sinus cycle length shortened considerably to a mean value of 577 f 93 ms. This was significant (p <O.Ol) when compared with both the control and postencainide states.

A CONTROL

C ENCAINIDE

:

B ENChlNlDE D ENCAINIDE & ISOPROTERENOL

FIGURE 1. Adrenergic reversal of encainide-induced retrograde block: Pane/ A shows control pacing with 1:l ventriculoatrial conduction at a ventricular paced cycle length (S-S) of 340 ms. After oral encainide (panels 6 and C), ventriculoatrial block is noted at cycle length of 680 ms. Pane/D, note the return of 1:l ventriculoatrial conduction at an S-S interval of 340 ms with the administration of isoproterenol. Tracings are I, II, and Vg surface electrocardiographic leads. A, = retrograde atrial activation; RA = right atrial electrogram; V = ventricular electrogram.

46L THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62

Tachycardia cycle length: During the control state, tachycardia could be induced in all patients, and for the entire group the cycle length was 380 f 49 ms. During encainide administration, in the 2 patients who still had sustained AV nodal reentry, the tachycardia cycle length was longer and changed from a baseline of 300 and 400 ms to 530 and 480 ms, respectively. In another 7 cases, only a few beats (<8) of AV nodal reentry were seen, and the termination occurred in the retrograde limb of the circuit. With isoproterenol, the tachycardia accelerated in both of the above-mentioned patients (cycle length of 380 and 4 10 ms, respectively). In addition, sustained AV nodal reentrant tachycardia became inducible in another 8 patients having a mean cycle length of 357 f 42 ms. The difference between this value and that of the control state, which was 402 f 40 ms in the same 8 patients, is not statistically significant (p = not significant).

Anterograde conduction studies: The shortest cycle length of atria1 pacing producing 1: 1 AV conduction was prolonged significantly after encainide compared with the control (Table II). Anterograde conduction through the AV node was significantly enhanced after isoprotere- nol. The values after isoproterenol were statistically sig- nificant when compared with both the control and the encainide period after encainide administration.

Retrograde conduction studies: During the baseline evaluation, the shortest mean ventricular pacing cycle length for sustaining 1:l retrograde conduction was 337 f 56 ms. There was a marked increase in this value after encainide (p <O.Ol compared with control). A complete retrograde block was achieved in 2 patients. During iso- proterenol infusion, the minimal ventricular cycle length producing 1:l conduction significantly shortened to 354 f 72 ms (p <O.Ol compared with encainide, Table II). Despite the presence of encainide, VA block was reversed after isoproterenol in the 2 patients in whom this phenom- enon was seen.

Patients with Wolff-Parkinson-White syndrome: The essential electrophysiologic data on this group of patients are presented in Table III.

Sinus cycle length: As in the patients with AV nodal reentry, the sinus cycle length did not change after encai- nide administration in patients with WPW syndrome. However, it was significantly shortened after isoprotere- no1 compared with both control and encainide (Table III).

Accessory pathway conduction: In 14 of the 16 pa- tients in this group, there was overt accessory pathway conduction during the baseline study, whereas 2 patients had so-called concealed WPW syndrome without antero- grade preexcitation. After encainide administration, an accessory pathway block was seen in an additional 10 patients during sinus rhythm. Isoproterenol reversed this encainide-induced anterograde accessory pathway con- duction block in 3 of these 10 patients. In the remaining patients, the minimal pacing cycle length maintaining 1: 1 anterograde accessory pathway conduction shortened significantly after isoproterenol administration. Conduc- tion over the AV node also was facilitated after isoproter- enol. However, because of the presence of preexcitation in many of the patients, changes in AV nodal conduction, per se, could not be assessed in all cases.

Encainide produced retrograde accessory pathway block in 5 of the 16 patients, and this effect was reversed with isoproterenol in 1 of the 5. In the remaining 11 patients, encainide produced significant depression of ret- rograde accessory pathway conduction, and isoproterenol improved the encainide-induced depression of retrograde conduction so markedly that the minimal pacing cycle length maintaining 1: 1 retrograde accessory pathway conduction decreased significantly.

Tachycardia induction: A narrow complex orthodro- mic tachycardia was initiated in 14 patients during the control study and in only 6 after encainide. After isopro-

TABLE II Electrophysiologic Data on Patients with Atrioventricular Nodal Reentry

Shortest-Paced SCL CL with 1:l AVC

Shortest-Paced CL with 1:l VAC

CL Tachycardia

Control Encainide Encainide and

isoproterenol

761& 155 358 zk 57 337 f 56 380 -+ 49 787 f 102 409 zk 49* 551 f 124” 455 f 577 f 93t 313&31” 354 f 72t 353 f 42

* p <O.Ol vs control; + p <O.Ol vs encainide. Only 2 patients had tachycardia after enmmde. All values are expressed as mean f standard deviation in ms. AVC = atrioventricular conduction; CL = cycle length; SCL = wws cycle length; VAC = ventriculoatrial conduction.

TABLE Ill Electrophysiologic Data on Patients with Wolff-Parkinson-White Syndrome

Control Encainide Encainide and

isoproterenol

SCL

813 f 133 823 f 122 648f97’t

Shortest-Paced Shortest-Paced CLwithl:lAVC=AP CL with 1:l VAC

316 f 126 295 f 66 647 f * 565 f * 461i*t 427 f * t

CL Tachycardia

335f44 437 f 101 325 f 29

* p <O.Ol vs control; t <O.Ol vs encainide. All Values are expressed as mean f standard deviation in ms. AP = Xcessory pathway; AVC = atrioventncular conductton: CL = cycle length; SCL = sinus cycle length; VAC = wntrlculoatrk cond”dlon.

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A SYMPOSIUM: USE OF ENCAINIDE IN SUPRAVENTRICULAR TACHYCARDIAS

terenol administration, tachycardia could be induced in 2 additional patients. There was a significant acceleration of tachycardia rate after isoproterenol in patients when the tachycardia could be induced both before and during isoproterenol infusion (Table III).

Follow-up: During the mean follow-up of 19 f 10 months in patients with AV nodal reentrant tachycardia and 17 f 9 months in those with WPW syndrome, 8 patients had recurrences (4 in each group). In 12 of the patients in this series, tachycardia could no longer be induced after encainide administration (despite isopro- terenol), and none of these patients experienced clinical recurrences. The clinical recurrences were observed pri- marily in patients in whom the tachycardias were still inducible, either after isoproterenol administration or iso- proterenol accelerated the rate of the tachycardia slowed by encainide. In 3 of these patients, the addition of p blockers completely eliminated the recurrent clinical epi- sodes. Two of the 3 had AV nodal reentry, and the re- maining patient had orthodromic tachycardia. The other 5 patients were treated nonpharmacologically.

more pronounced reversal of encainide’s effect on the AV node by isoproterenol may be related to a variety of factors, including: (1) inherently increased sensitivity to adrenergic stimulation of the AV node as compared with the accessory pathway; (2) geometric factors (the latter implies that several areas of tissue mismatch seen in ac- cessory pathway reentry, i.e., atria1 accessory pathway or ventricular accessory pathway junction, may be poten- tially more vulnerable to drug-induced depression of con- duction and thus more difficult to reverse)12J3; and (3) the fact that on the average, patients with WPW syn- drome received higher doses of encainide, which may also translate into less likelihood of drug reversal with compa- rable doses of isoproterenol. These explanations, how- ever, are purely hypothetical and certainly cannot be proved from the studies presented here. Also, the exact site of encainide action within or around the AV node or the accessory pathway and subsequent isoproterenol re- versal cannot be located from data presented here.

DISCUSSION Results of this study indicate that oral encainide in the

doses used is effective in controlling symptomatic tachy- cardia, both in patients with AV nodal reentry and in those with orthodromic tachycardia in association with WPW syndrome. In this group, the electrophysiologic testing demonstrated that a lack of induction of tachycar- dia after encainide therapy, despite administration of iso- proterenol, predicted freedom from clinical recurrence. On the other hand, all of the patients who had clinical recurrence had isoproterenol-induced reversal of encai- nide’s effect on the tachycardia circuits. It would appear, therefore, that continued inducibility of sustained tachy- cardia and reversibility of drug effect with isoproterenol may identify some of the patients who are prone to future recurrence, despite apparent control with encainide. It should be pointed out, however, that not all patients whose tachycardias were inducible after encainide neces- sarily experienced clinical episodes. This may be related, in part, to the previously proposed2 effect of encainide on triggering mechanisms, such as atria1 or ventricular pre- mature complexes, or both.

Mechanism of action: If one considers that encainide is primarily a sodium-channel blocking antiarrhythmic drug, its depressant effect on the accessory pathway is more readily explainable.14 The depressant effect ob- served on AV nodal conduction may or may not be an intranodal phenomenon, but may in fact be related to the drug effect on AV nodal boundaries and transitional areas. Depression or failure of conduction produced by encainide in tissues activated by sodium (Na+) current may be reversible by isoproterenol by 1 or more of the following mechanisms: (1) participation of more Na+ channels or more Na+ current with isoproterenol, (2) improvement of tissue excitability depressed by encai- nide, and (3) increase in the size of excitatory stimulus for cell-to-cell impulse propagation by virtue of facilitation and conduction around the site of encainide-induced de- pression of conduction. Some or all of these, or some additional mechanisms, may be involved in isoproterenol- induced reversal effect.15 For example, isoproterenol may have caused a facilitation in AV nodal conduction, which may not have been a primary location of encainide’s action.

Site of drug action: Encainide produced depression of both AV nodal and accessory pathway conduction in the anterograde as well as the retrograde direction. In pa- tients with AV nodal reentry, however, the depression of retrograde conduction appeared more pronounced. This could be directly documented by ventricular pacing and indirectly deduced from the fact that almost all nonsus- tained episodes of tachycardia after encainide adminis- tration terminated in the retrograde limb of the AV nodal reentry circuit.

Even though no final explanation can be offered for our findings, the mechanisms outlined could have played a role in adrenergic reversal seen during this and our previous study in a similar patient population.

Clinical implications: The data presented imply that drug-induced depression and block with class IC agents, such as encainide, can be reversed by isoproterenol in the laboratory. We have previously shown that the beneficial effect of a class IA agent (intravenous procainamide) is also reversible with isoproterenol.1° Therefore, it is con- ceivable that similar responses may be seen with other antiarrhythmic drugs and, indeed, have been shown to occur with amiodarone as well.

Isoproterenol was able to reverse the encainide effect in the AV node as well as in the accessory pathway and in both anterograde and retrograde directions. However, depression of conduction along the accessory pathway was less readily reversed, particularly when either a com- plete anterograde or retrograde block was observed. The

Reversibility of drug effect with isoproterenol may also translate into clinical recurrence in some cases. In this regard, it seems important to demonstrate lack of adrenergic reversal of drug effect, since such a response predicts good clinical control in junctional reentrant tachycardias treated with encainide. Furthermore, some

48L THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62

of the patients experiencing clinical recurrences could have control of arrhythmia with the addition of p blockers to the antiarrhythmic regimen.

Limitations of the study: Because isoproterenol is not a natural hormone, one could argue that administration of epinephrine or norepinephrine would have been prefer- able for inducing physiologic adrenergic stimulation. The difficulty of responding to such a critique is somewhat mitigated by noting that in a nonsedated postabsorptive state, epinephrine and norepinephrine can produce signif- icant hypertension, and using them can be risky in pa- tients with cardiovascular disease. Perhaps because of these concerns, isoproterenol has more often been used for adrenergic stimulation in clinical electrophysiologic studies. Also, the dose of isoproterenol was arbitrarily determined to achieve a certain heart rate. This again may be difficult to correlate with an ambulatory state and corresponding physiologic levels of endogenous catechol- amines. Nevertheless, it is pertinent to point out that appropriate or physiologic doses of epinephrine, norepi- nephrine or isoproterenol, for a given level of physiologic activity, have not been determined for correlation with findings during electrophysiologic studies.

Although the findings of this study strongly suggest that there is a relation between isoproterenol-induced reversal of encainide’s effect and future clinical recur- rences, the 2 may not be entirely linked. For example, it is possible that the success of encainide therapy, or lack thereof, may be related to reduction or elimination of triggering currents such as atria1 or ventricular prema- ture beats. This possibility cannot be eliminated in pa- tients who had adrenergic reversal of the encainide effect and yet had no clinical recurrences. However, lack of reversibility of encainide’s effect on tachycardia induc- tion and subsequent freedom of tachycardia recurrences indicate a relation. It would be unreasonable to assume that the effect of encainide on a triggering event was much different in patients with or without demonstrable adrenergic reversal in the laboratory. In the absence of any additional data on these patients, it appears reason- able to assume that adrenergic reversal of encainide’s effect may translate into clinical recurrences, at least in some cases. At the very least, lack of isoproterenol-in- duced reversal of encainide’s effect would indicate a low probability of future tachycardia events.

CONCLUSIONS The findings in this study indicate the following: (1)

Oral encainide is an effective agent for junctional reen-

trant tachycardias. (2) Encainide’s efficacy in both AV nodal reentry and AV reentry is primarily due to its effect on depression of conduction along the retrograde limb of the circuit. (3) Encainide-induced depression or failure of conduction can be reversed both in the AV node or in the accessory pathway of the Kent’s bundle type, or in both, although the latter tissue seems less vulnerable to such a reversal. (4) Lack of reversibility of encainide’s effect with adrenergic stimulation identifies patients with better control of their tachycardia. (5) In some patients with clinical recurrences, /3 blockers may control such events.

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