Differential effect of intravenous procainamide on anterograde and retrograde accessory pathway refractoriness

JACC V.I . 19, Na. I January 1992:118-24

I1a

Differential Effect of Intravenous Procainamide on Anterograde and Retrograde Accessory Pathway Refractoriness JAMES W . LEITCH, MIBS,v GEORGE 1 . KLEIN, MD, FACC, RAYMOND YEE, MD, ROSS D . FELDMAN, MD, JAMES BROWN, MD London, Ontario,

Canada

Although prrcaieamide may markedly impair nr abolish anterograde conduction over an accessory atrionentrirular IAVI pathway, arthodrmnfc AV reentry may remain indueihle . This dill ewe may be related to a systemic differential effect of procalaamide on anterograde and retrograde accessory pathway refiadtmness . To examine Ibis pliamormenam. an Infusion, or proralnamidr producing Hoe ; rserenanbt blood tenets over 7S min was administered to 15 patients with the Wolff•Parkinmn-White syndrome. At each procainamde level, accessory Pathway WereMe refractory period and accessory pathway block cycle length wen determined in the anterograde and retrograde directions . At baseline, there were no significant differences helwnn anterograde ad retrograde accessory pathway effective refner, tory periods (282 ± 7 vs. 266 t 9 ms, p = 0 .08) slid block cycle lengths (28112 15 vs . 283 ± 9 ms, p = 0.66) . The concentration of proratnamfde resulting in 50% prolongation of accessory pathway refractoriness was Into in the anterograde direction than in the retrograde direction (27 .S [log concentration -4 .56 ± SE 0 .131 on.

64.61-4.19 e: 0.1 11 µntalititer, p = 0.02). Similarly. the canceatraion fprocaimdersultingI 50%ptoklngion tsemy sory pathway black cycle length in the anerograde direction (25 .1 1-4.60 t 0.131 pnol1iter) was less than the retrograde direction (52,5 1-4.28 s 0 .071 pmdNhr, p = 0.01) .

Procainamide may impair or abolish anterograde conduction over accessory atrioventricutar (AV) pathways, diminishing the ventricular response during atrial fibrillation (1-3). Despite a favorable effect on anterograde conduction, orthudromic AV reentry may still be easily inducible, suggesting that the effects of procainamide on anterograde and retrograde accessory pathway refraclollness are distinct (2-41 . Previous reports (4,5) suggest that procainamide has a systematic differential effect on the accessory pathway, prolonging anterograde accessory pathway rrfracloriness to a greater extent khan retrograde accessory pathway refracto-

assessed in the drug-free state and after five incremental intravenous doses of procainamide.

riness, To examine Ikis hypothesis . 15 patients with the

Wolff-Parkinson-White syndrome were studied . Anterograde and retrograde accessory pathway refractoriness was

From the Derndm ul or Medicine. University of western Onudu

London.Ontario. Canada. This smdywansupported byIteHear aidStroke Foumtaeon of Omario . Tacoma, Omariw Dr. kkii in a OisAoguished Research Prnfessoe atlhe Head and Stroke Foandatian of Orlariu . stenuscrip: rewired April I . 1991 ; revised manaxdpl received June 17 . 1991 . nceeytad July 12. 1991'17esenl address and address for le prinis : Dr. James IV Leitch . John Hunter Hospital . Locked Bag 1 . Neweaslk Mail Cenic . Newcastle . NSW . Auslrain 9m . e1992 by the

American College of Cardioh,gy

The probability of persistence o accessory pathway conduction

in the aneengrsde direction was lees than (n the retrograde direction by tfaptan•M eler mall (p = 0.04) . By the 3rd procainmide dose (area pracabamide level 32 .3 * 1.36 anon liter) anterograde pre-cxMtatlen was so longer present (n 6 of me 15 patients, whereas retrograde conduction over the accessory pathway did not disappear in any patient . These cantos demvastrate that proeateamide has mare manliest elects an meregade than an retrograde accessory pathway refraclorilxa . Thus, it may be more elllcactoos for arrhy1hndas dependent en intern. grade accessory pathway connection than For arrhythnws dependent on rrogade accessory pathway cnndavtba . (J Am Cog CarAW J01;10,1111-24)

Methods Study patients. Consecutive patients with a single accessory pathway undergoing clectlaphysiologic testing were

considered fur entry into the study . To ensure adequate bidirectional conduction at baseline . patients were excluded if the accessory pathway block cycle length was >450 ms in either the anterograde or the retrograde direction . Other exclusion criteria were retrograde accessory pathway conduction that was not clearly distinguishable from conduction

ever the normal ventriculeatrial conducting system, sustained atriel fibrillation during the electropttysiologic study and contraindications to procainamide administration- This study was approved by the Review Board for Human Health Sciences of the University of Western Ontario on May 17, 1990 and all patients gave written informed consent- Fifteen patients with the Wolff-Parkinson-While syndrome and a history of symptomatic techycardia were studied . There were I I men and 4 women, with a mean age of 36 -_ 4 years . Electrophysialogic study . Medications were discontinued for >-5 half-lives before the elcctruphysiologic study . Two 0115-195T92a53 .50



JACC Vat. 19. No. I 1mwc1 1992:118-2a

I-FITCI4 ET AL. DIFFERENTIr.L EFFECT OF PROCAINAMIDE

119

GM'rW ewittielftama) Figure 1 . Diagram of the procainamide infusion protocol. Proeainamode onus given as bolus iryeotions (omlkot ar rawr)in addition 16 a continuous Info . lion . The infusion rate was adjusted and further bolus dunes given every 15 min . Electrophysiulugic measurements were made during the last S min of each or the 15-min infusion periods .

9

+9

,r

W

c a

ae

n n

Infinite Pmnu srrd . ".ion

11/Ewwevtyriabprn ."unin at

quadripoli r and one tripolar catheter were introduced into the right femoral vein and positioned in the high right atrium, right ventricular apex and [its bundle recording position, respectively. An octapolar catheter was introduced into the left subclavian vein and positioned in the coronary sinus . Intracardiac electrograms were recorded simultaneously with Surface electrocardiographic leads L 11 . 111, V, and V, on a Siemer:s mingograph at a paper speed of 1110 mm/s . Programmed stimulation was performed at twice diastolic threshold with 2-ms square wave pulses . Anterograde and retrograde accessory pathway effective refractory periods were Jeasured by the erlras6alufus teeknique at a drive cycle length of 4011 ms (5YI0 ms in two patients) with 10-ms decrements in the S,S 2 coupling interval . Anterograde accessory pathway refractory period was defined as the longest A 1 A2 interval that failed to conduct over the accessory pathway . The A,A, interval was measured on tae atrial electrogtam closest to the accessory pathway as determined by mapping of retrograde atrial activation during orthadromic AV tachycardia . The retrograde accessory pathway refractory period was defined as the longest V,V,_ interval that failed to conduct over the accessory pathway and was measured on the right ventricular electrogram . The coronary sinus eleelrogram was not used to measure the V 1 V 2 interval because the ventricular electrogram at this site is frequently far field and does not display an intrinsic deflection . Refractory period measurements were made at the same site throughout the siuty . The longest paced atria] and ventricular cycle lengths failing to conduct over the accessory pathway (accessory pathway block cycle lengths) were determined using lu-ms decrerncnts to a minimal cycle length of 250 ms. If atrial or ventricular refractoriness limited the measurement of acctsrefractoriness was used as an approximation . Similarly, when 1 :1 conduction aver the accessory pathway persisted to a cycle length of 250 ms . this latter value was used as the accessory pathway block cycle length . Sludy prolecal . The procainamide infusion was begun after control accessory pathway measurements Wig. 1). Bolus doses of procainamide were given at the star of the

infusion and thereafter at I5-min intervals . The initial infusion rate of 7.5 mglmin increased every 15 min, doubling with the first two increments and increasing by 50% with the final two increments . The total duration of the infusion was 75 min and the total dose of procatnamide was 3,265 .5 mg. At each measurement period, anterograde and retrograde accessory pathway effective refractory period and block cycle length were determined . Atria) pacing was performed first in eight patients and ventricular pacing first in seven patients . Blood procainamide levels were measured at the start and finish of each electrophysiologic measurement period. Because the difference (mean di(lecence 0,68 t 0.58 pmol!liler) between procainamide levels before and after each measurement period was not significantly different from zero, the mean of these two measurements was used °nr analysis. Blood pressure was measured with an attn cuff every 10 nlin and at the end of each electrophysielagic measursmcntperiod . The study was termirat_d if symptoms of toxicity occurred or the systolic blood pressure decreased to <911 mm Hg. Dais analyst, The effect of procainamide on the acres . spry pathway was analyzed as follows. Absolute changes in accessory pathway variables were compared with repeated measures analysis of variance (6). Measures at baseline were compared with paired r tests. Second, the concentrations of procainamide resulting in 508 proiongattan of refractoriness and block cycle length (EC w) were calculated by using nonlinear curve-fitting methods (sigmoid plot subroutine, Graphpad program, ISI) (Fig. 2). Because measures of potency demonstrate a ag-normal distribution (7), ECm was expressed as geometric mean values with a range of ± I SEComparisons of log EC ro measurements were made with paired t tests. Finally, the probability of persistence of accessory pathway conduction in the anterograde and retrograde directions duriugprocainamide infusion was estimated by the Kaplan-Meier product lime melhod . Comparison between anterograde and retrograde conduction was then performed with the generalized Wilcoxon test (8). All p values were two-tailed and were considered significant at a level of0-o5 . Apart from EC sn, all other continuous variables were reposed as arithmetic mean ± SE .



120

LEITCUETAL. DIFFERENTIAL EFFECT OF

[ACC Cot . 19 . No, I ra..ary 199E-111-54

PROCAINAMIDE

Results

Figere 2. Patient 10 . Curve modeling of the proporlional change is retrograde accessory pathway effective refractory period . To determine the concentration of procainamide resulting in 50% probnga . lion of accessory pathway nfracloriness IEC> o1. the (allowing assumptions were made : 1) The maximal acressory pathway en'eclive refractory period was considered to be equal to the sinus cycle length because changes greater than the sinus cycle length could not be measured. 2) By this reasoning . control measurements of accessory pathway refractoriness were considered to represent zero prolongation of refractoriness and sinus cycle length to represent 100% prolongation of refrectoriness . 3) The percent prolongation of accessory pathway refractoriness at each drug level was thus dcacribed by the ratio (ERP4 ERP~(ISCL-ERPj . where ERPu and ERP, arc, respe:livey, the accessory pathway refractory period at the drug level and in the control period and SCL is the sinus cycle length at the time of measurement . A similar analysis was performed for accessory pathway block cycle length . Doseresponse curves wen calculated by using nonlinear cunofming methods. The EC„ value for retrograde accessory pathway effec live refractory period in this patient was 35.5 pmolltiter.

Baseline stwllea. The accessory pathway was located in the left lateral AV anulus in 13 of the 15 patients and in the left pesteraseptal AV anulus in 2 patients. At baseline . the anterograde accessory pathway effective refractory period was tot significaally different from the retrograde accessory pathway effective refractory period (282 :t 7 vs . 266 ! 9 ms. respectively, p = 0.08) (Table I) . Exact measurements of accessory yathway refractory period in the anterograde direction were made in 13 patients and in the retrograde direction in II patients. There was no difference in the shortest cycle length maintaining 1 :1 conduction over the accessory pathway in the anterograde and retrograde directions (288 * 15 vs . 283 s 9 ms, p = 0.66). In nine patients . exact measurements could be made anterogradely and refrogradely. Mean procainamide concentration during the procailro mide infusion is shown in Figure 3. During the infusion, there were significant dose-dependent decreases in mean blood pressure (P < 0.101) and sinus cycle length (p < 0 .001) (Fig . 4) . In four patients, the study was terminated before completion of the fifth procainamide dose level either because of complete anterugtade and retrograde accessory pathway block (Iwo patients) or because symptoms of toxicity with hypolension occurred (two patients) . The cumaIative dose of procaummide given ranged from 26 .7 to 52.8 mglkg (mean 39.9 ± 2 .1), Fdects of proeilna lde on Me pceemm y ralktray. Absolute changes in accessory pathway effective refractory period and black cycle length during the infusion are shown in

Table 1 . Control Accessory Pathway Measurements and Effects of Intravenous Procainamide in 15 Patients pt No. I

260

2

300

3 4 5 6 7

6290 260 2n 260 320 s270 340

R S 10 11 12 13

280 310 275 275

14

260

Is

270

Mean

281 .7 6.6

SE

CaotrulMcawremcnts RERP ABCL

RRCL

Log ECw AERP

260 310 5230 285 265 270 320 .24n

761

290 <2F0 720 20) <250 3+0 5250

AERP

<_250 280 320 <220 240 220 270 266 8.5

250 410 <250 260 30D <256 420 <25D 290

Sw 3110 761 .5 <2A 280 <250

275 340 260 <240 <250 <250 287 .7

282 .7

14 .9

9.1

Log EC,o ARCL

1 .31

tar EC„ REAP t.7

1 .17

1.48

III

103 0.77

1.61 1 .66

.88 1 0-73

1-9 1.64

.98 156

L55 -

0.75 1 .49

1.53 -

1 .54

1 .55

1 .1 1 .26 2.51 1.47 1 .74

1 .42 1 .91

1 .62 1 .1 1 .26 2.33 1,44 1 .73

1 .48 1 .39 1 .62

1 .81

14

172

0.11

0 .13

007

2 .135 2 .74 2.06

1 .44 0 .13

1 .3

I-11

EC, ROLL 1 .78 1 .47

2 .13 2 .03 1 .89

P-o .nl AECL=auterepdeacaarayy .rhwayblockcyckkngrh :AERP=eulemnsadeea'adivernranoyperiod :EC,,=conccmrafanotpc .e,ie,ewki,gin Hn6 probngatioO of -,A: w = sent; RECL = retrograde accessory pathway Noel cycle knelt : RERP - rewptde nrri., rc6.nmy p ,,d. P . 0.08

p = 0.66

p=0.02



IAOC Val . 19, n.. I bath PM:118-2r

LEITCH ET AL. DIFFERENTIAL EFFECT OF PROCAB)AMIDE

121

.w ntd. a ....&1 orr Figure 1 . Mean procainamide blood level in the 15 patients during the five infusion periods . The error burs denote standard error .

Figure S . Amerograde accessory pathway effective refrac-

tory period and Mock cycle length increased to a greater extent than retrograde accessory pathway effective refrac-

a

t

2

tory period and block cyck length (interaction term p = 0 .03 prnenln.mide

fog both effective refractory period and block cycle length) . Concentrations of procainamide resulting in 5th prolongation of anterograde and rdrvpaade measurements (EC,,I could be calculated in I I patients. In three patients, anteregrade and retrograde ECro measurerrnnts coed rat be dete pined because prexinamide had insufficient effects on both anterograde and retrograde accessory pathway refractoriness. In one patient, anterograde EC,,, measurements could be determined, but procainamide had an insuScient affect

Figure 5.

Changes in

a

4

a

date level

accessory pathway effective refractory period

(upper pond) and black cycle kngth linear pod) during procrinamide infusion . The anterograde refractory period and block cycle length increased to a greater extent than did the retrograde refractory period and block cycle length (both p = 0 .031.

In the remaining II patients, the EC, value for the anterograde accessory pathway effective refractory period was less than the EC ro value for the retrograde accessory

on retrograde refractoriness to allow retrograde EC w

measurements to be determined .

Ion

FIfoee4. Mean blood pressure (BP) and sinus cycle length (ml) during procainamide infusion. There were significant decreases in both sinus cycle lend; tp < 0.001) and mean blood pressure (p < 0A01) . The error bars denote standard error .

no non

405

70



122

LEITCH 91 AL.

UACC Vd . 19, No. I hoary 149711d-24

DIPFEREIMAL EFFECT OF PROCAINAatLE

theanterogadedirection (25,11-4.6 . O.I31 anioUliter)was less than in the retrograde direction (52 .5 1-4,28 a 0.071 penopfiter. p = O.Oq . For all 15 patients . the probability of persistence of accessory pathway conduction in the anterograde direction was less than in the retrograde direction (p = 004) Mg, 61. By the 3rd dose level, anterogade preexcitation was no longer present in six patients, whereas retrograde conduction over the accessory pathway did not disappear in any patient. In no patient was retrograde accessory pathway conduction abolished before anterograde accessory pathway conduction .

-RnaorllaeE 0a-

i 4 PFCCA toalat: mig tFVrL tat clot um un lIP) _ .. IPI 151 z

rcaaams tm1 !mI

o rn !et-

Masot 6. Kaplalt•M eier plot for probability of persistence of accessory pathway conduction in the anteronrade f • . . ) and retrograde (-) directions. The diBercnec between antarpgrade and relrograde accessory pathway conduction was significant (p = 0.04) • pathway refractory period (27 .3 [log - 4 .56 '- 0 . i31 vs. 64.6 1-4,19 ± 0.111 pmoldliter, respectively, p = 0 .02) (Table 1) . Similarly, ECre for accessory pathway block cycle length in

Discussion Prrcaiwmlde effect an nnhrograde veia retrograde ow duclion. This study demonstrates that intravenous procain . amide exerts a greater effect on anterogade than an retrograde accessory pathway refroctminess . This differential effect implies that changes in anterograde pre-excitation after procainamide do not predict the therapeutic effect of the drug in preventing orthodromic AV reentry . In some instances, induction of orthodramic AV reentry may even be facilitated by procainamide (Fig . 7). This phenomenon can occur if there is marked prolongation of anterograde a=sscary pathway refractoriness without concomitant changes in retrograde accessory pathway refractoriness. In combine-

Flgere 7. Example of proarrhythmia during prucainamide infusion . A. At baseline, during

atrial incremental racing, amegrade aeoessnry pathway conduction persisted to a cycle length of w250ms. Orthodramic reciprocating wchycasdia was not imiucible by atria] stimulation . O . At the third pmeeinamtde dose, anterograde accessory pathway conduction blacks at a cycle length of 400 ms. but retry

grade accessory pathway condtetion is only minimally affected . Onhodromic atrioventricularrachycardia utilizing the k8 lateral aces • nary pathway as the retrograde limb is in-

rolls

sto

duced by atrial pacing after aaterograde accessory pathway conduction blocks . CSd = distal surtmary sinus; CSp = proximal coronary sinus : HOE = His bundle electrugmm : HRA = high right atrium; RVA = right venIncular apex .



LEITCH ET AL . DIFFERENTIAL EFFECT OF PROCAJNAMIDF

JACC Vat. 19. No. 1 January 1992:118-24

lion with the vagolytic effect of procainamide . the net result may be to facilitate induction of tachycardia (2-51 . This mechanism may explain the reports (4,9,10) of incessant tachycardia and proorrhythmia after procainamide in patients with the WotlT Parkinson-White syndrome . Masaremeniofaccemarypathwayconduction . Threedifferent approaches to the measurement of the effect of proeanamide on the accessory pathway were used in this study . These were I) measurement of absolute change in accessory pathway variables (Fig . 5): 21 measurement of proportional changes in accessory pathway variables by curve-modeling techniques (Fig . 2) ; and 3) estimation of the probability of accessory pathway conduction by KaplanMeier analysis (Fig. hi. This latter analysis was performed because of the technical limitations of measuring anterograde and retrograde accessory pathway refractoriness at electraphysiologie study. The Kaplan-Meiee analysis required only an assessment of the presence or absence of accessory pathway conduction . which could be determined in all patients at each drug level . This analysis demonstrated important qualitative differences in the response of the accessory pathway, which were confirmed by the absolute changes in accessory pathway measurements . The results from curve modeling of the individual dose-response curves allowed some quantitative estimate of the differential effect of procainamide- It is important to note that all three approaches yielded congruent results, Possible mechanisms far the differential effect of prorainadIe . Several observations suggest that there are fundamental differences between anterograde and retrograde accessory pathway conduction and that the safety margin for conduction in the retrograde direction is higher than that in the anterograde direction . Unidirectional retrogradely conducting pathways have been found far more frequently than have unidirectional anterogradely conducting pathways(11) . Spontaneous loss of pre-encitation has also been reported (12) with continued retrograde accessory pathway conduction . One report (13) of accessory pathway ablation suggested that it may be easier to abolish anterograde than retrograde accessory pathway conduction with direct current ablation . Finally, in a large series of patients (141 . there was only a weak relation between anterograde and rctrograde accessory pathway block cycle lengths . Differences between anterograde and retrograde conduction might result from accessory pathway geometry with anisatropic conduction (15). discontinuous propagation (t6) and -impedance mismatch" (17-19) . Evidence against this latter hypothesis has been presented in an airial myocardial model of accessory pathways (19) . In that model, procainamide did not exert a differential efiecL an bidirectional conduction ; however, there may be substantial differences between the model and actual accessory AV pathways. Alternatively, the observations in this study could he explained by the presence of closely separated multiple accessory pathways or branching networks of fibers (14,20) In some patients . A second concealed accessory pathway

123

might continue to conduct after a bidirectional pathway had blacked . Although patients with clearly demonstrable multiple accessory pathways were excluded from this study, the techniques used did not have sufficient resolution to demonstrate discrete but closely located (I to 2 coal accessory pathways . Observations during radiofrequency ablation suggest that closely separated accessory pathways may occur relatively often (20). At baseline, the anterograde accessory pathway refractory period leaded to be longer than the retrograde acces . sory pathway refractory period, although this did not achicse statistical significance . Because the response of an accessory pathway to procainamide may depend on the initial refractory period (5), the differential response may also reflect differences in anterograde and retrograde accessory pathway conduction and refractoriness at baseline. Limitations of the Judy. Exact measurements of accessory pathway refractory period and block cycle length could not he made in all patients . Retrograde accessory pathway refractory period measurements were made on the tight ventricular electrogrem, which may have slight! ; overestimated differences between anterograde and retrograde measurements as a result of ventricular conduction delay . This factor would not affect the measurement of accessory pathway block cycle length . There were significant decreases in blood pressure and sinus cycle length during the procaine • mide infusion, in keeping with the known vasodilator and vagolytic properties of the drug (21). These autonomic changes may have modulated the direct effects of procainamide on the accessory pathway (22-24) . Our study also had a relatively small sample size and did not include patients in whom retrograde accessory pathway conduction was not clearly distinguishable from normal ventriculoarial con, duction. Therefore, these findings may not apply to all patients with the Wolll Parkinson-White syndrome . Finally, it is possible that our results would not be replicated with oral procainamide because of the actions of its metabolite, N-acetyl procainamide. Nonetheless, these data demonstrate a systematic differential effect of procainamide on anterograde and retrograde accessory pathway refractoriness . The greater margin of safety for retrograde conduction after procainamide may influence drug selection, depending en the mechanism of the symptomatic arrhythmia . we dunk Sheila Duo, for preparation of sire masNSCrwt-

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3Z9

LEITCHE'TAL. DIFFERENTIAL EFFECT OF PR(H'AINAMIOE

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