1298 lACC Vol. 3. NO.5May 1984:1298-307

Electrophysiologic Basis for the Suppression by Amiodarone ofOrthodromic Supraventricular Tachycardias ComplicatingPre-excitation Syndromes

GREGORY K. FELD, MD, KOONLAWEE NADEMANEE, MD, FACC, JAMES WEISS, MD,

WILLIAM STEVENSON, MD, BRAMAH N. SINGH, MD, DPhil, FACC

Los Angeles, California

Ten patients with refractory recurrent supraventriculartachycardia were found by electrophysiologic study tohave bypass tracts and orthodromic atrioventricularreentrant tachycardia. All had failed to respond to con­ventional antiarrhythmic therapy and were thereforetreated with oral amiodarone (l,600 to 2,000 mg/day for2 weeks, then 800 to 1,200 mg/day for another 2 weekswith subsequent 200 to 600 mg/day maintenance doses).During or after the fourth week of therapy, electro­physiologic study was repeated. In 9 of 10 patients,supraventricular tachycardia could not be reinduced byprogrammed stimulation. In the remaining patient, non­sustained supraventricular tachycardia (>10 beats, last­ing <30 seconds) with a slower basic cycle length thanthat during the control period was provoked. Significantincreases in the effective refractory period of the acces-

Numerous studies (1-9) recently provided convincing evi­dence for the marked effectiveness of the long-term admin­istration of amiodarone in the prophylactic control of ven­tricular and supraventricular tachyarrhythmias resistant toconventional antiarrhythmic therapy. Rosenbaum et al. (I)

first observed that the drug might also be remarkably ef­fective in controlling the supraventricular tachyarrhythmiasthat complicate the Wolff-Parkinson-White syndrome.However, subsequent studies (10-15) using varying doseregimens reported variable effects on orthodromic parox­ysmal supraventricular tachycardia. No study has utilized

From the Departments of Cardiology and Medicine. Wadsworth Vet­erans Administration Medical Center and Center for Health Sciences. LosAngeles, California. This study was supported by grants from the MedicalResearch Service for the Veterans Administration and the American HeartAssociation. Greater Los Angeles Affiliate. Los Angeles. California.Manuscript received May 9. 1983; revised manuscript received October31. 1983. accepted December 15, 1983.

Address for reprints: Koonlawee Nadernanee, MD. Cardiology Section(691/111 E). Wadsworth Veterans Administration Medical Center. Wilshireand Sawtelle Boulevards. Los Angeles. California 90073.

© 1984 by the American College of Cardiology

sory pathway in both the anterograde (+26%, P < 0.05)and retrograde (+40%, p < 0.02) directions were noted,the magnitude of change being independent of the con.trol effective refractory period. There were also signif­icant increases in the effective refractory period of theright atrium (+ 24%, P < 0.01) and the right ventricle(+ 15%, P < 0.01) during long-term therapy withamiodarone.

Over a mean follow-up period of 20 months, symp­tomatic control of the arrhythmia occurred in all pa­tients; in only one patient treatment with amiodaronecould not be continued because of side effects. Thesedata establish the electrophysiologic basis for the effec­tiveness of amiodarone in the prophylactic control ofrefractory paroxysmal supraventricular tachycardiacomplicating the bypass tract syndromes.

initial high dose treatment to attain optimal "arniodaroni­zation" (16) before evaluating the electrophysiologic cor­relates of long-term maintenance treatment with amiodaroneto prevent recurrences of paroxysmal supraventriculartachycardia in previously resistant cases.

The main objectives of the present study, therefore, wereto determine the electrophysiologic effects correlating withsuppression by amiodarone of inducible supraventriculartachycardia in previously resistant cases and to define therole of the drug in the long-term prophylactic control ofrefractory orthodromic paroxysmal supraventricular tachy­cardia complicating accessory pathway syndromes.

MethodsPatients. Ten male patients with paroxysmal supraven­

tricular tachycardia developing in association with an ac­cessory pathway were studied. Their ages ranged from 22to 74 years (mean 43). The accessory pathway was left­sided in six patients and right-sided in four, having a para-

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septal location in six and a free wall location in four (Table1). In all cases, recurrent sustained episodes of paroxysmalsupraventricular tachycardia had been documented electro­cardiographically; all had been refractory to one or moreantiarrhythmic drugs previously administered (Table 1). Be­fore the electrophysiologic studies were done and amioda­rone was administered, a complete history and physicalexamination, complete blood count; serum biochemistryprofile, liver function, pulmonary and thyroid function tests,two-dimensional echocardiogram and 12 lead electrocar­diogram were obtained. Informed written consent was ob­tained from all patients; the protocol for use of amiodaronewas approved by the Committee for the Use of HumanSubjects for Research in 1979.

Electrophysiologic study. After discontinuation of anyprevious medication for at least 5 half-lives, the patientsunderwent electrophysiologic study in the postabsorptivenonsedated state. Endocardial electrode catheters (USCI)were placed in the high lateral right atrium, coronary sinus,right ventricular apex and His bundle region of the inter­ventricular septum (17,18). Pacing was performed using aMedtronic 5325 programmable stimulator. Recordings fromsurface electrodes I, aVF, VI and endocardial electrodes inthe right atrium, coronary sinus, His bundle and the rightventricle were obtained on an Electronics for Medicine re­corder (VR-12). Refractory periods of the right atrium,atrioventricular (AV) node, right ventricle and accessory

pathway were determined using single premature stimuli(S IS2) with scanning during diastole with stimuli of increas­ing prematurity, each delivered after an eight beat pacingsequence (Medtronic 5325) with a cycle length (SISI) 10to 20% above the normal sinus rate during the control pe­riod. The same basic cycle length was then used in eachpatient during amiodarone treatment. Refractory periods weredefined as previously described (18,19), and tachycardiainduction is summarized herein:

Tachycardia induction. Ventricularpacing at two or morebasic cycle lengths (S,SI), 10 to 25% above sinus cyclelength, was followed by single premature stimuli (S,S2) withscanning during diastole until the refractory period of theright ventricle was reached. If supraventricular tachycardiawas not produced, double premature stimuli (SIS2S3) weredelivered after two or more basic cycle lengths (SISI)' Thediastole was scarined with the double stimuli, with the short­ening of the interval between S2 and S3 initially and thenwith that between SI and S2 until both S2 and S3 approachedthe right ventricular effective refractory period. If supra­ventricular tachycardia was not induced by these measures,rapid ventricular pacing at increasing rates was used untilretrograde ventriculoatrial (VA) block occurred or untilsupraventricular tachycardia was induced.

Atrial pacing from the right atrium and coronary sinuswas then performed using the S,S2 and S,S2S3 technique ina manner identical to that described for ventricular pacing.

Table 1. Clinical Characteristics and Location of Accessory Pathways in 10 Patients WithOrthodromic Paroxysmal Supraventricular Tachycardia

Previously

Location of Duration of Used

Age (yr) Accessory Tachycardia Antiarrhythmic

Case &Sex Pathways* (yr) Agents

26M Left-sided 15 0, PAparaseptal

2 27M Right-sided 5 P,PAparaseptal

3 74M Left-sided 5 D, P, °parasepta1

4 54M Right-sided 28 PA. P, Dparaseptal

5 38M Left lateral 5 PA, P, Dwall

6 34M Right-sided 7 O,D, Pparaseptal

7 63M Left lateral 25 Qwall

8 66M Left lateral 42 D.Q,Pwall

9 22M Right-sided 4P, °

paraseptal10 43M Left lateral 3 v: 0, PA

wallMean 43 14

*Demonstrated by electrophysiologic studies (see Table 2). D = digoxin: F = female: M = male; P =

propranolol: PA = procainamide; Q = quinidine; V = verapamil.

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If supraventricular tachycardia was not induced, rapid atrialpacing was then undertaken at increasing rates until anter­ograde block or supraventricular tachycardia was produced.Atrial fibrillation was not routinely induced in our patients.

Tachycardia induction was performed during long-termtreatment with amiodarone in a manner identical to thatperformed during the control study in each patient.

Location of bypass tracts. The tachycardia cycle lengthand the activation sequence of the reentrant tachycardia weredetermined from endocardial and surface lead recordingsobtained during pacing and supraventricular tachycardia (20).The location of the bypass tracts was defined on the basisof the endocardial retrograde (VA) activation sequence dur­ing ventricular pacing and supraventricular tachycardia asfollows:

A) Left ventricular lateral wall-activation of the leftatrium first (distal coronary sinus electrode), then low rightatrium (His bundle electrode) and high right atrium.

B) Left ventricular paraseptal-low right atrium, leftatrium and high right atrium.

C) Right ventricular paraseptal-low right atrium, highright atrium and left atrium.

Drug treatment protocol. Only patients with sustained,inducible supraventricular tachycardia refractory to otherantiarrhythmic drugs were treated. After electrophysiologicstudy, treatment was started with oral amiodarone, initiallyat 1,600 to 2,000 mg (in two divided doses)/day for 2 weeks.The dose was then decreased to 800 to 1,200 mg for another2 weeks, at or after which time electrophysiologic studywas repeated. The dose was then decreased to 200 to 400mg/day in all patients. In one patient, amiodarone was dis­continued after 2 months because of fever and pulmonaryinfiltrates, which resolved spontaneously on cessation ofamiodarone. During the treatment period, patients' labo­ratory determinations were repeated at regular intervals toassess evidence of impending toxicity, the development ofwhich was also monitored clinically.

Statistical analysis. Data are presented for individualpatients as well as for the study group as a whole as meanvalues ± 1 standard deviation. Statistical significance ofthe difference of means before and during treatment wasdetermined by the Student's two-tailed t test for paired datawith probability (p) < 0.05 as the limit of significance.

ResultsThe overall data with respect to the effects of amiodarone

on the inducibility of paroxysmal supraventricular tachy­cardia and on the electrophysiologic variables of the heartare summarized in Table 2 and illustrated in Figures I through5.

Effects on inducible supraventricular tachycardia.Before amiodarone was given, sustained supraventriculartachycardia was inducible in all 10 patients by programmed

electrical stimulation of the heart (Table 2). During therapywith amiodarone, supraventricular tachycardia became non­inducible in 9 of 10 patients. In the remaining patient, oneepisode of supraventricular tachycardia occurred sponta­neously during electrophysiologic study but was not re­producibly inducible; it was nonsustained (> 10 beats, last­ing <30 seconds) and had a cycle length that was 130 ms(300 versus 430 ms) longer than it was before amiodaronewas started (Fig. 1).

Effect on the refractoriness of the accessory path.way. In all seven patients in whom the anterograde con­duction over the accessory pathway could be demonstratedduring the control electrophysiologic study, the effectiverefractory period (anterograde) was lengthened (Table 2).

In patients in whom the exact value for the effective re­fractory period could be determined, the mean ± standarddeviation of the effective refractory period (anterograde) ofthe accessory pathway was 293 ± 30 ms before amiodaroneand 368 ± 26 ms (+ 26%, P < 0.05) during amiodaronetreatment. The corresponding values for the retrograde ef­fective refractory period of the accessory pathway beforeand during amiodarone therapy were 277 ± 29 ms and 388± 72 ms, respectively (+40%, P < 0.02).

Figure 2 illustrates the increase in the anterograde re­fractory period of the accessory pathway plus prolongationof conduction in the AV node and prevention of supraven­tricular tachycardia by amiodarone. During control electro­physiologic study anterograde block of the accessory path­way occurs at SIS2 coupling intervals of 290 ms duration.Anterograde conduction through the AV node then occurswith retrograde conduction through the accessory pathwayand induction of supraventricular tachycardia. Amiodaroneincreased the anterograde effective refractory period of theaccessory pathway to 390 ms (not shown) and markedlyprolonged the atrio-His conduction time (450 ms) at similarSIS2 coupling intervals (300 ms). Retrograde conductionthrough the accessory pathway is then followed by antero­grade AV node block, thus preventing induction of supra­ventricular tachycardia.

Figure 3 illustrates the increase in retrograde refractoryperiod of the accessory pathway produced by amiodarone.During control electrophysiologic study, retrograde blockoccurs at S I S2 intervals of 310 ms. The retrograde effectiverefractory period of the accessory pathway is increased to400 ms after administration of amiodarone.

Effect of amiodarone on effective refractory periodof atrium, right ventricle and AV node (Table 2).Amiodarone increased the effective refractory period in allthe tissues. The increase in the mean effective refractoryperiods was 24% (p < 0.01) in the atrium and 15% (p <0.01) in the right ventricle. Although the anterograde ef­fective refractory period of the AV node was increased byamiodarone, it could not be measured in most cases becauseof anterograde conduction through the accessory pathway.

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Table 2. Effects of Long-Term Amiodarone Therapy on the Electrophysiologic Variables and Inducibility of SupraventricularTachycardia in Patients With Accessory Pathways

Effective Refractory Period (ms) InducibilityofSVT at

AP Ante AP Retro RV Atria AV Node EPS

Case C A C A C A C A C A C A

I <300 340 <320 410 220 280 240 330 NA NA Yes No2 320 380 <350 410 250 285 210 270 NA NA Yes No3 < 240 360 <240 550 240 270 240 280 NA NA Yes No4 NA NA 250 320 220 260 300 310 < 315 340 Yes No5 250 370 240 500 220 240 210 280 220 300 Yes No6 310 330 < 280 <310 210 240 210 250 240 > 330 Yes No7 NA NA 31 0 440 250 290 250 360 NA NA Yes Yes*8 290 390 310 400 260 280 NA NA NA NA Yes No9 NA NA 280 350 250 270 260 300 NA NA Yes No

10 <260 <340 270 320 210 250 215 260 NA NA Yes NoTotals 293 368 277 388 233 267 237 293

± 30 ± 26 ± 29 ± 72 ± 19 ± 18 ± 30 ± 35 10(n = 4) (n = 4) (n = 6) (n = 6) (n = 10) (n = 10) (n = 9) (n = 9)

*Nonsustained. A = during amiodarone therapy; Ante = anterograde; AP = accessory pathway; AV = atrioventricular; C = control; EPS =electrophysiologic study; NA = not applicable or could not be done; Retro = retrograde; RV = right ventricle; SVT = supraventricular tachycardia.

An example of AV node anterograde conduction block aftertreatment with amiodarone is shown in Figure 2.

Figures 4 and 5 further demonstrate the effects of amio­darone on AV node and ventricular refractoriness and in­duction of supraventricular tachycardia. In Figure 4, atrialpacing with progressively premature stimuli (A\A2) producesnondecremental conduction through the accessory pathway(VIV2) until the effective refractoryperiod is reached. Whenthe effective refractory period of the accessory pathway isreached, anterograde conduction through the AV node witha prolonged atrio-His interval occurs. Retrograde conduc­tion through the accessory pathway results in induction ofsupraventricular tachycardia. Amiodarone prolongs the an­terograde AV node refractory period to an extent where AVnode block occurs before the anterograde effective refrac­tory period of the accessory pathway is reached, thus pre­venting the induction of supraventricular tachycardia. Theanterograde effective refractory period of the accessorypathway is also increased. During ventricular pacing (Fig.5), amiodarone prolongs the functional refractory period ofthe right ventricle to a point outside the tachycardia zonenoted during controlelectrophysiologicstudy in this patient,thus preventing the induction of supraventricular tachycardia.

Long-term clinical outcome and drug side effects. In9 of 10 patients, the recurrence of spontaneous supraven­tricular tachycardia was suppressed 100% after the first monthof amiodarone therapy over a mean duration of therapy of20 months (range 10 to 29). In one patient, amiodarone hadto be discontinued after 2 months of therapy because of theonset of fever, pulmonary infiltrates and elevated serumlevels of hepatic enzymes. The nine patients remaining on

long-term therapy (200 to 400 mg/day) have been free ofclinically significant side effects.

DiscussionThe reentrant nature of orthodromic paroxysmal supra­

ventricular tachycardia in patients with accessory pathwaysis now well defined (20-22) . The reentrant circuit incor­porates the atrioventricular (AV) node and His bundle (andbranches) as the anterograde limb and the anomalous tractas the retrograde limb, while atrial and ventricular tissuesprovide the final proximal and distal common pathways forthe initiation and perpetuation of the tachycardia. Thus, therational approach for its control is to prolong refractorinessor conduction, or both, in one or more components of theentire reentrant circuit or to eliminate the trigger mechanism(for example, ventricular or supraventricular extrasystoles)initiating the arrhythmia. Different antiarrhythmic com­pounds have been shown to exhibit variable potencies inthis regard (23- 29).

Inconsistency in amiodarone's effects on supraven­tricular tachycardia. In the case of amiodarone, the suc­cess rate varying between 33 and 100% (1,3 , 10- 15) is note­worthy because the electrophysiologic properties of thedrugduring long-term administration are reasonably uniform (5,7).It lengthens repolarization and effective refractoryperiod inall cardiac tissue (5,7,30,31). One might, therefore, expecta greater consistency in the overall therapeutic effects ofamiodarone in orthodromic paroxysmal supraventriculartachycardia than has been reported (10,12, 13- 15).

Present study . Our results show that when the drug isgiven orally for at least 4 weeks (in our patients at a high

1302 FEW ET AL.AMIODARONE IN ORTHODROMIC BYPASS TRACTTACHYCARDIA

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AVF

Figure 1. Case 7. Effect of long-termamiodarone administration on the in­ducibility of supraventricular tachy­cardia in a patient with a bypass tractsubject to recurrent orthodromic par­oxysmal supraventricular tachycardia.Upper panel, Induction of supraven­tricular tachycardia by atrial pacingbefore amiodarone was started. Lowerpanel, Spontaneous supraventriculartachycardia occurs during electro­physiologic study after two prematureventricular complexes. With amioda­rone, the supraventricular tachycardiawas nonsustained with a tachycardiacycle length longer than that undercontrol conditions. The tachycardiacould not be reinduced by pacing. I,AYF, Y I = surface electrocardio­graphic leads; A = atrial deflection;Ae = retrograde deflection; DCS =distal coronary sinus electrogram; Hor HBE = His deflection or His bun­dle electrogram, respectively;HRA =high right atrial electrogram; PCS =proximal coronary sinus electrogram;S = stimulus; Y = ventriculardeflection.

'.-c • .. - ... =' =

loading dosage), it leads to a significant increase in theeffective refractory period of the atria, AV node, ventricleand accessory pathways (anterograde and retrograde). Inour 10 patients, this was associated with the near completesuppression of the tendency for electrically inducible supra­ventricular tachycardia. Furthermore, over a mean follow­up period of 20 months on maintenance doses (200 to 400m/day), the drug was uniformly effective in eliminatingrecurrences of paroxysmal supraventricular tachycardia, withside effects occurring in only one patient.

Previous studies. Such a response is in line with the lessstandardized approach to dosage regimen used by Rosen­baum et al. (I) and others (3,32). Of particular significanceis the preliminary report by Rasmussen and Berning (II),who found amiodarone-induced increases in the refractoryperiod in the atrium, AV node and accessory pathway as afunction of duration of treatment in six patients with in­ducible supraventricular tachycardia. Their initial dose ofamiodarone was 600 mg/day for 10 to 14 days, followedby 400 mg/day until the appropriate response had been ob­tained, after which the dose was reduced to 250 to 400

mg/day. They repeated electrophysiologic study in four suchpatients after 26 to 85 days of treatment; induction of supra­ventricular tachycardia was prevented in all four patients.

These data, which are comparable with our own, are incontrast to those of Wellens et al. (10), who found thatamiodarone prevented inducible supraventricular tachy­cardia in only 5 of 15 patients. Nevertheless, the drug in­variably prolonged the tachycardia cycle length in those inwhom it was reinducible. As in our study, Wellens et al.(10) noted a marked increase in the effective refractoryperiod of the accessory pathway in the anterograde direction;however, they found a less striking effect on this variablein the retrograde direction. By contrast, we found a greaterincrease in the effective refractory period in the retrograde(40%) than in the anterograde (26%) direction, in additionto the somewhat larger increase in the right ventricular ef­fective refractory period (about 34 ms) than that (23 ms)reported by Wellens et al. (10).

Dosage regimen and duration of therapy. The differ­ences between our data and those of Rasmussen and Berning(II) and Wellens et ai. (10) may be due to the differing

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Figure 2. Case 8. Changes in atrioven­tricular (AV) conduction and tachycardiainduction before and after long-termarniodarone therapy in another patient witha bypass tract. Upper panel, Control re­cordings during atrial stimulation dem­onstrating ventricular pre-excitation.Middle panel, Control recordings show­ing the anterograde effective refractoryperiod of the accessory pathway duringatrial premature stimulation, anterogradeconduction through the AV node and in­duction of supraventricular tachycardia.Lower panel, Note that amiodaronelengthened the anterograde effective re­fractory period of the accessory pathwayand AV conduction, thus preventing in­duction of supraventricular tachycardia byanterograde AV node block. RV = rightventricular electrogram; other abbrevia­tions as in Figure I.

;-~_-4-4-....!L..::::::=:::::==::::::::r=--__A,--_-!....-__--===:=!:::A:

---~----::DeS

.t:, • L&

v

~,-

1304 FEW ET AL.AMIODARONE IN ORTHODROMIC BYPASS TRACT TACHYCARDIA

lACC Vol 3. No.5May 1984 1298-307

DCS

_-------'lalw,h j "'-"-

I I I I

~--.....-x,-+-

------~I

Figure 3. Case 8. An example of theprolongation of the retrograde effec­tive refractory period of the accessorypathway induced by long-term admin­istration of oral amiodarone. Upperand middle panels, Control record­ings during right ventricular pacingdemonstrating accessory pathwayconduction and the effective refractoryperiod (310 ms). Lower panel, Re­cordings during amiodarone treat­ment. The drug markedly lengthenedthe effective refractory period (400 ms)of the accessory pathway. Abbrevia­tions as in Figure I.

I--'--+---.,----....-----.~--------.-

,,!.~.d.r I

2

RV ~'.if .. 600 ~~- ~..... :.."..,.. .~ __- ,. f-- I!;j;~~_.._. --_.- - =£

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FELD ET AL.AMIODARONE IN ORTHODROMIC BYPASS TRACTTACHYCARDIA

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~80

~60 • •~40 • • •~20

~OO D O

480 D O

460 D O

V,V, 440 8(ms)

420 D O

400 DOBASELINE

380 B o SVT NOT INDUCED

360 B • SVT INDUCED

340 0 ORAL AMIODARONE

320 b o SVT NOT INDUCEDa

A,A, (rns)

Figure 4. Case6. Datafrom electrophysiologic study before andduring amiodarone treatment showing anterograde nondecrementaIconduction through theaccessory pathway during atrial prematurestimulation. When the effective refractory period of the accessorypathway is reached (a), anterograde conduction through the atrio­ventricular node with prolonged atrio-His interval occurs and in­duces reentrant supraventricular tachycardia (SVT). Amiodaroneprolongs anterograde AV nodeconduction and accessory pathwayeffective refractory period to a point outside the tachycardia zone(b), thus preventing induction of supraventricular tachycardia. A)A2

= atrial intervals; VIV2 = ventricular intervals.

dosage regimens used. Adequate' 'amiodaronization' in ourpatients and in the study by Rasmussen and Berning (11)was achieved by higher initial loading doses and by a longerduration of therapy before electrophysiologic reevaluationwas undertaken; Wellens et al. (10) utilized 600 mg/day ofamiodarone for 7 days followed by 300 mg/day for another7 days, at which time repeat electrophysiologic study wasperformed .

The elimination half-life of chronically administeredamiodarone is exceedingly long and variable (33) and ad­equate amiodaronization is thus a function not only of dose,but also of duration of therapy. Thus, it is unlikely that asteady state drug therapy had been achieved in the patientsstudied by Wellens et al. (10). Nevertheless, their data aredirectionally similar to those from our laboratory as well asto those reported by Rasmussen and Berning (II ); theyprovide convincing evidence for the high degree of effec­tiveness of amiodarone in the prophylactic control of or­thodromic supraventricular tachycardia in patients with by­pass tracts. However, they do not indicate the precisemechanisms to account for the extraordinary efficacy of thedrug in this context. A comparison of the cardiac electro­physiologic actions of various antiarrhythmic drugs relativeto their clinical efficacy in orthodromic paroxysmal supra-

~oo (j)

480 8460 B440 B4 20 B

tl 400 aN

-e - 380 8! •! 360 8

BASELINEC

340 B o SVT NOT INDUCED0 • SVT INDUCED320 d o

30 0 • ORAL AMIODARONE

• o 5VT NOT INDUCED280 •260

",f>0 ",,,,0..,00 ..,iJ..,r;.o ..,f>0 ..,,,,0..0° r;."'o r;.r;.or;.f>0 r;.'lP -flO

VlV2 (ms)

Figure 5. Case 6. Datafrom electrophysiologic study before andduring amiodarone therapy showing retrograde nondecrementalconduction through the accessory pathway during ventricular pre­mature stimulation. A defined tachycardia zone is noted in thispatient during the control study. After amiodarone therapy, theventricular functional refractory period is prolonged to a pointoutside the tachycardia zone, thus preventing induction of supra­ventricular tachycardia. A1cA2c = retrograde A intervals; otherabbreviations as in Figure 4.

ventricular tachycardia might indicate the potential mech­anisms involved.

Comparison with other agents. Numerous agents havebeen studied with respect to their electrophysiologic effectsand efficacy in suppressing inducible supraventricular tachy­cardia in the Wolff-Parkinson-White syndrome. The fre­quency of suppression of inducible tachycardia after intra­venous administration was 50% with quinidine and ajmaline(23), 75% with procainamide (23) and 70% with disopyr­amide (26,27). These class I agents acted primarily by in­creasing refractoriness in the accessory pathway and block­ing the retrograde limb of the reentrant circuit, with littleeffect on the AV node or anterograde limb (23,26,27). Bycontrast, intravenous ouabain , propranolol and verapamilwere effective in approximately 50% of patients (24,29) andaffected primarily AV node refractoriness (anterograde limb)with no effect on accessory pathway refractoriness .

Of particular significance are the data from four patientswith orthodromic paroxysmal supraventricular tachycardiastudied by Reid et al. (25) after intravenous administrationof aprindine . In all four patients, induction of supraven­tricular tachycardia was prevented by the drug which, likeamiodarone in our study, increased the effective refractoryperiod in the AV node and bypass tracts in addition to thosein the atria and ventricles. Thus, the data suggest that inorthodromic paroxysmal supraventricular tachycardia, ef­ficacy of an agent may be dependent on the degree of length­ening of the effective refractory period in the AV node

1306 FELD ET AL.AMIODARONE IN ORTHODROMIC BYPASS TRACT TACHYCARDIA

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(anterograde) as well as in the bypass tracts (retrograde).For this reason, compared with that of amiodarone or aprin­dine, a lower rate of efficacy in orthodromic paroxysmalsupraventricular tachycardia might be expected for agentswith a narrower spectrum of electrophysiologic effects (forexample, class I agents, digoxin, propranolol and verapamil).

Mechanisms of action. In our study, amiodarone wasshown to prevent induction of supraventricular tachycardiaby several potential mechanisms. These included prolon­gation of refractory periods and block of anterograde con­duction in the AV node and retrograde conduction in theaccessory pathway and, in one case, prolongation of therefractory period of the right ventricle to a point outside thetachycardia zone. The possibility must also be consideredthat in paroxysmal supraventricular tachycardia, the drugadditionally might act by the reduction of premature atrialand ventricular complexes that provide the trigger mecha­nism for the initiation of the tachycardia (34). At least forpremature ventricular complexes, amiodarone has been shownto be a powerful suppressant (4,5,16).

Implications. Orally administered amiodarone appearsto be extremely effective in suppressing inducible sustainedsupraventricular tachycardia in the Wolff-Parkinson-Whitesyndrome. The incidence of side effects with the patientreceiving the minimal dose required to suppress sponta­neously recurring paroxysmal supraventricular tachycardia(generally 200 to 400 mg/day) over a 20 month follow-upperiod was found to be low. The data suggest that the highrate of prophylactic efficacy of amiodarone in orthodromicparoxysmal supraventricular tachycardia may relate to thesignificant increases in the effective refractory period of thevarious components of the reentrant circuit, especially theAV node and the bypass tracts.

We are much indebted to Alma Gump and Lacy Goede for typing thismanuscript. We are also grateful to 10Ann Hendrickson and the technicalstaff of Electrophysiologic Laboratories at the Veterans AdministrationMedical Center, West Los Angeles and the Center for Health Sciences atthe University of California at Los Angeles, California for their assistancein the studies.

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arrhythmias associated with the Wolff-Parkinson-White syndrome byamiodarone hydrochloride. Am 1 Cardiol 1974;34:215-23.

2. Rosenbaum MB, Chiale PA, Halpern MS. Clinical efficacy of amio­darone as an antiarrhythmic agent. Am 1 Cardiol 1976;38:934-44.

3. Leak D, Eydt IN. Control of refractory cardiac arrhythmias withamiodarone. Arch Intern Med 1979;139:425-8.

4. Nademanee K, Hendrickson lA, Cannom DS, Goldreyer BN, SinghBN. Control of refractory life-threatening ventricular arrhythmias byamiodarone. Am Heart 1 1981;101:759-65.

5. Nademanee K, Hendrickson lA, Kannan R, Singh BN. Electrophys­iological effects of amiodarone in patients with life-threatening ven­tricular arrhythmias: modifications of induced ventricular tachycardia

versus suppression of spontaneously occurring tachyarrhythmias. AmHeart 1 1982;103:950-9.

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