Effect of pharmacologic autonomic blockade on ventriculoatrial conduction

Effect of PharmacologicAutonomicBlockade on VentriculoatrialConduction ANNE HAMILTON

DOUGHERTY, MD, ROBERT L. RINKENBERGER, MD, and GERALD V. NACCARELLI, MD

To determine the influence of autonomic tone on retrograde ventriculoatrial (VA) conduction, incremental atrial and ventricular pacing was performed before and after pharmacologic autonomic blockade In 28 patients. VA conduction during ventricular pacing was demonstrated, wlth highest frequency In patients capable of I:1 atrioventrlcular (AV) conduction at atrial paced cycle lengths of 300 ms or less (7 of 7, 100%). In subjects with I:1 AV conduction at minimum cycle lengths of 300 to 500 ms, 14 of 21 (67 % ) demonstrated VA conduction in the control state; however, only 12 of 21 (57% ) did so after autonomic blockade. The lowest frequency was observed in those capable of I:1 AV conduction at minimum cycle lengths of 505 ms or

more before and after autonomic blockade (2 of 7, [29 % 1, p 10.02 compared with values in the first group). No change In the mean minimum ventricular paced cycle length at which I:1 VA conduction could be maintained was demonstrated after autonomic blockade. In lndivldual subjects, incremental change in this cycle length after autonomic blockade correlated positively with the corresponding change in minimum atrial cycle length at which I:1 AV conduction could be maintained (r = 0.62, p
A mong patients with normal anterograde atrioventricular (AV] nodal conduction, retrograde ventricu-

tion.8-*0 Furthermore, it is known that the effect of atropine on retrograde conduction correlates positively with that on anterograde conduction.’ A systematic assessmentof the effect of the autonomic nervous system upon VA conduction, however, has not previously been done. Therefore, this work was designed to determine the balance of sympathetic and parasympathetic modulation on VA conduction in resting humans and the relation of this interaction to AV nodal conduction properties.

loatrial [VA] conduction has been demonstrated in 66% during ventricular pacing. The probability of having intact VA conduction, however, diminishes progressively with increasing degrees of anterograde AV nodal and His-Purkinje dysfunction.l-3 VA conduction, however, is not a fixed property, as suggested by the occurrence of pacemaker-mediated tachycardia in patients who have had VA block.4p5Modulation by the autonomic nervous system of VA conduction, which may account for this phenomenon, has been demon- Methods Patient selection: The study population comprised strated by acute reversal of retrograde block in occasional patients after administration of atropine or iso- 35 patients undergoing clinical electrophysiologic testproterenol.5-7 The effects of propranolol and atropine ing as part of their routine medical care (Table I]. Exon the retrograde limb in reciprocating tachycardia clusion criteria were medical contraindication to adwithin the AV node also suggest autonomic modula- ministration of either atropine or propranolol and documentation of an accessoryAV connection, based on ventricular preexcitation during sinus or atrialFrom the Department of Internal Medicine, Division of Cardiol- paced rhythm, eccentric retrograde atria1 activation ogy University of Texas Medical School at Houston, Houston, during ventricular pacing or supraventricular tachy Texas. Manuscript received November 1, 1985; revised manu- cardia, or atria1 preexcitation during supraventricular tachycardia following ventricular extrastimuli delivscript received January 13,1986, accepted January 14,1986. ered during the His-bundle refractory period.*lJ2 Address for reprints: Anne Hamilton Dougherty, MD, DiviSubjects were assigned to 1 of 3 groups on the basis sion of Cardiology, The University of Texas Medical School at Houston, P.O. Box 20708, Houston, Texas 77225-0708. of control AV nodal conduction properties.13J4Clini1274

June 1, 1986

TABLE I

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Patient Characteristics 4% W)

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R Sex

Cardiovascular

Diagnosis

EP Results

Group I 1 2 3 4 5 6 7

34F 22M 47M 30M 45M 27F 64M

MVP, syncope MVP, VT PAF, SVT SVT sss Ventricular ectopy Cardiac arrest, PAF

JMin PCL I:1 AV JMin PCL 1:l AV EAVC EAVC, dual AVN EAVC EAVC, dual AVN JMin PCL 1:i AV

Group II 8 9 IO 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 2? 28

46M 15F 19M 55F 67M 75M 22F 64F 18M 41M 75F 75M 43F 75F 64M 39M 68M 59M 79F 18M 74M

VT, AV Wenckebach MVP, syncope Downs, syncope Episodic CHB Syncope, ventricular ectopy Near syncope, PAF, AR MVP Syncope, SVT, SH Syncope, bradycardia Syncope, bradycardia MVP. near syncope MVP, VT, MR Cardiac arrest sss CAD, MVP, VT, SH Syncope, asystole Syncope, VT Syncope Syncope, SH Syncope sss

Normal Normal Dual AVN CSH Normal Normal Dual AVN AVNRT, SRT Normal Normal AVNRT Normal Dual AVN ~SNRT VT Normal Normal ~SNRT CSH Dual AVN Normal --

Group Ill 29 30 31 32 33 34 35

61M 38M 33M 46M 10M 76M 50M

VT, patent foramen ovale SH, SVT, PAF MVP, ventricular ectopy MVP, SVT MVP, VT, 2O AV block Syncope Syncope

TMin PCL 1:l tMin PCL I:1 TMin PCL 1:l fSNRT,t Min tSNRT,t Min TMin PCL I:1 TMin PCL 1:l

AV, AV AV PCL PCL AV, AV,

VT

1:l AV, 1 H-V, NJT 1:l AV dual AVN, CSH VT

AR = aortic regurgitation; AVNRT = atrioventricular (AV) nodal reentrant tachycardia; CAD = coronary artery disease; CHB = complete AV block; CSH = carotid sinus hypersensitivity; dual AVN = dual AV nodal physiology; EAVC = enhanced AV nodal conduction; EP = electrophysiologic; Min PCL 1:i AV = minimal cycle length I:1 AV; MR = mitral regurgitation: MVP = mitral valve prolapse; SH = systemic hypertension; NJT = nonparoxysmal junctional tachycardia; PAF = paroxysmal atrial fibrillation; SNRT = sinus node recovery time; SRT = sinus node reentrant tachycardia; SSS = sick sinus syndrome: SVT = supraventricular tachycardia; VT = ventricular tachycardia.

cal characteristics are described in Table I. Group I consisted of 7 patients (mean age 3% f 15 years) in whom 1:l AV conduction could be maintained at atrial-pacing lengths of 300 ms or less. Group II consisted of 21 patients (mean age 52 f 23 years, difference not significant [NS] compared with group I) in whom 1:l anterograde conduction was recorded at minimum paced cycle lengths between 300 and 500 ms. Group III was comprised of 7 patients (mean age 45 -f. 21 years, NS compared with groups I and II) in whom 1:l AV conduction could only’be maintained at cycle lengths longer than 500 ms. Study protocol: All cardioactive drug therapy was withdrawn for at least 5 half-lives before the control study. Electrophysiologic evaluation of anterograde

AV and retrograde VA conduction was performed as outlined later. Atropine (0.03 mg/kg over 2 minutes) and propranolol (0.15 mg/kg at a rate of 1 mg/min) were administered intravenously.13J5J6 After autonomic blockade, electrophysiologic testing was promptly repeated. To examine the individual contributions of the sympathetic and parasympathetic limbs, intermediate electrophysiologic testing was assessed after only atropine in 8 patients, and after only propranolol in 9 patients before total autonomic blockade. Serial testing was performed with minimal delay to ensure continuing pharmacologic effect throughout the protocol. Electre~hysiQl~gic ~~o~ea~re: Patients were stu ied in the nonsedated, postabsorptive state, as previ-

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TABLE ii

Eiectrophysioiogic

Results

Group I (n = 7) Control Autonomic blockade Group II (n = 21) Control Autonomic blockade Group III (n = 7) Control Autonomic blockade

Minimum CL 1:l VA

Predicted Intrinsic CL

Minimum CL 1:i AV

720 f 45 585 f 40t

... 623 f 52

270 zk 21 307 f 27”

361 f 45 383 f 54

862 f 261 704 f 197t

. . 680 f 87

410 zk 59 393 f 59

474 i 146 (n = 14) 465f93(n= 12)

659 i 78

584 f 65 451 k 100’

540 (n = 2) 520 (n = 2)

Spontaneous SCL

1000 f 727 f

184 199+

Compared with control: * p (0.02; t p <0.002; AV = atrioventricular; VA = ventrlculoatrial.

t p 10.001.

ously described.14 Cardiac stimulation was performed with either a Medtronic 5325 or a 2332 stimulator, using a 1.8-ms pulse width at an amplitude of twice late diastolic threshold. Spontaneous cycle length, AH and HV intervals were measured to the nearest 5 ms from the electrogram recorded in the vicinity of the bundle of His during sinus rhythm. AH and HV intervals were also measured during atria1 pacing at cycle lengths slightly shorter than the spontaneous cycle length, and then at progressively shorter cycle lengths until 1:l AV conduction was no longer maintained. The shortest atria1 paced cycle length at which 1:l anterograde conduction was observed was defined as minimum cycle

5

length i:l AV conduction. AV nodal refractory period determinations were made using scanning single extrastimuli at 1 or more cycle lengths. Ventricular pacing was begun at cycle lengths just shorter than the spontaneous cycle length and continued at progressively shorter cycle lengths until the onset of VA block, ventricular refractoriness or hemodynamic compromise. Minimum cycle length 1:l VA conduction was defined as the shortest ventricular paced cycle length at which it was recorded. Because of obscuration by the ventricular electrogram, retrograde His deflections could not be consistently identified at all cycle lengths. Therefore, VA intervals were measured in the high right atria1 electrogram from stimulus artifact to rapid atria1 deflection at each cycle length.17 Ventricular and VA conduction system refractory periods were determined at 1 or more ventricular paced cycle lengths with single extrastimuli scanning the diastolic period. Discontinuous AV or VA conduction curves were identified during either incremental pacing or extrastimulus testing, as previously described.1*-20 Statistical analysis: Group data are presented as mean f standard deviation (SD). Comparisons between groups were made by analysis of variance, confirmed with the Newman-Keuls multiple range test, or by the Students t test. Adjustments in the t statistic for unequal variance were made when appropriate. Those comparisons between control and autonomic blockade observations were made by the paired t test or by the Wilcoxon signed rank test. Prevalance of VA conduction by groups was compared using the Fischer exact test.

.E 200 .s 22

Results

l l l

Group Group Group

I (n=7) II (n=Zl) Ill (n=7)

Compared to C: *p =.Ol **p =.02

700

600 0 g L

500

2 _

400

.

0’ a

300

100

p
p<.ool

I

I

C

AB

FIGURE 1. Minimum cycle length (PCL) I:1 atrioventricuiar (AV) conduction during control (C) and autonomic blockade (AB) states. Although the means of groups I and iii become more “normal” with autonomic blockade, both remain significantly different from group ii.

Heart rate: Electrophysiologic results are summarized in Table II. Spontaneous cycle length was not significantly different in groups I, II and III, before or after autonomic blockade. Compared with control, significant shortening of mean cycle length followed autonomic blockade in each group to intervals not significantly different from the intrinsic sinus cycle lengths predicted for age.15 Atrioventricular conduction: Four of 7 group I subjects met all 3 criteria for enhanced AV nodal conduction as previously described.21J2Discontinuous AH in-

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terval curves during incremental atria1 pacing or atria1 extrastimulus pacing, suggestive of dual AV nodal physiology, were observed in 2 group I patients, 6 group II, a& ; grc;r-, III ;clicnt. 17fthese. ? grouo I and 2 group II subjects had clinical or inducible AV nodal reciprocating tachycardia. The effect of autonomic blockade on minimum cycle length 1:l AV conduction is demonstrated in Figure 1. In groups I and III, significant changes in anterograde conduction were observed, shifting the means into the normal range; however, both remained significantly different from that of group II (p
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Prevalence

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(VA) Conduction -VA

+VA Group I(n = 7)' Control Autonomic blockade Group II (n = 21) Control Autonomic blockade Group III (n = 7)’ Control Autonomic blockade Total (n = 35) Control Autonomic blockade

57

0 (II%\ 0 co%\

, ;iix::; 7(100%) 14 (67%) 12 (57%)

7(33%) 9(43%)

2(29%) 2 (29%)

5(71%) 5(71%)

23(66%) 21(60%)

12 (34%) 14 (40%)

* p <0.02.

returned to 427 f 121 ms after blockade (NS compared with control). A weakly positive correlation (r = 0.46, p
@ Group . Group * Group

700 600

I (n=7) II (n=12) III (n=2)

1

i

1

C

A8

URE 2. Minimum cycie length (PCL) I:1 ventrie conduction during control (C) and autonomic blockad Patients with VA block during either state Rave been significant change was observed with blockade, either overall ar within any group; however, the dift~ren~es between groups in bath states are signifi~snt.

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VENTRICULOATRIAL

CONDUCTION

patients. Of the 3 patients with a discordant response, none had discontinuous VA conduction curves to suggest dual VA pathways.

I 4 1000

-I

1

IA

Discussion

0 -> SCL

C A A!3 FIGURE 3. Serial testing of minimum cycle length (PCL) 1:l ventricufoatriaf (VA) conduction during control (C), atroplne (A) and complete autonomic blockade (AB) states In 6 subjects. Data points represented as open squares mark the spontaneous sinus cycle length in subjects with VA block at ail paced cycle lengths. Block was reversed In 3 of 5 subjects wlth atropine, but returned after complete blockade. in the remaining 3 patients, minlmum cycle length 1:i VA signiffcantfy shortened (p
This work suggests that retrograde VA conduction is modulated by the autonomic nervous system in a balanced fashion, as previously described with AV nodal conduction.16 As in the case with anterograde conduction, P-adrenergic blockade with propranolol lengthens the minimum cycle length to which 1:l VA conduction can be maintained, whereas muscarinic blockade with atropine enhances retrograde conduction.. These influences may result in the temporary creation of, or reversal of, VA block, respectively. As shown by 1 of our subjects, however, this effect may be ma$ked by the change in heart rate, which limits the ability to test for VA conduction at comparable rates.’ Although either sympathetic or parasympathetic influences may predominate in a given subject at a particular time, the net effect is similar in direction to, but smaller in magnitude than, the autonomic effect on anterograde conduction. The characteristics of VA conduction are closely related to those of anterograde conduction, as previously demonstrated. 7,23Patients capable of rapid AV conduction are, in general, more likely to be capable of rapid VA conduction as well. Conversely, those with slower anterograae conduction are most likely to exhibit either VA block or retrograde conduction only at slower rates. The concordance of autonomic effect on anterograde and retrograde conduction in 18 patients suggests functional proximity of the 2 systems. Both spontaneous cycle length and AV nodal conduction became more “normal” with autonomic blockade in group III, suggesting vagal predominance on both sinus node automatic@ and AV nodal function.

200 3 ..

lb0

6 a E .-z .2

0 -> SCL I

I

I

a

0

-100

-200

I

C P AB FIGURE 4. Serial testing of mfnfmum cycle length (PCL) 1:l ventricufoatriaf (VA) conductfon during control (C), propranofof (P) and complete autonomic blockade (AB) states in 9 subjects. Data pofnts represented as open circles mark the spontaneous sinus cycle length @CL) in patients with VA block at ail pacing cycle lengths. Significant lengthening of mfnlmum cycle length 1:l VA (p
-100

-50

A Minimum

0

50

100

PCL 1 :l AV

FIGUBE 5. incremental change in minimum cycle length (PCL) 1:l ventrfcufoatriaf (VA) conduction compared with change In minimum cycle length 1:l atrioventricular (AV) conduction after autonomic blockade (r = 0.62, n = 21, p <0.005). Patients with VA block during either control or autonomic blockade states are excluded.

June 1, 1986

These findings regarding sinus node function confirm those of Desai et a1.24The effect on VA conduction in this group is difficult to analyze because only 2 of 7 patients &IlluiiA$it& 21 I.'.4 coX!W%W?. at anv WIGing cycle length, however, the effect in these 2 was balanced. as it was in the other groups. The group I subjects in this study by definition each met at least 1 of the 3 criteria that have been proposed to identify patients with enhanced AV nodal conduction2*J2 As did Benditt et a1,25we found a sympathetic predominance of modulation over anterograde conduction in this group, although the intrinsic difference between groups I and II remained significant after autonomic blockade. The slight lengthening of minimal cycle length 1:l VA after blockade, however, was not statistically significant, suggesting a more moderate or counterbalanced sympathetic effect on VA than on AV conduction. Patients with both enhanced AV conduction and rapid VA conduction may be susceptible to very rapid tachycardia rates when reciprocation within the AV node occurs, unless the rate is moderated substantially by the conduction velocity of the slower of the 2 functional anterograde pathways.2627 All reciprocating tachycardias using the VA conduction system as the retrograde limb, including AV nodal reentry, antidromic supraventricular tachycardia in Wolff-Parkinson-White syndrome, and pacemaker-mediated tachycardias, may be either facilitated or suppressed by autonomic influences that affect the rate to which VA conduction can be maintained.10 Therefore, the range of autonomic balance over which retrograde conduction can occur should be considered when planning antiarrhythmic therapy (i.e., treatment that results in VA block in the resting state may not be adequate in situations in which adrenergic tone is high). Acknowledgment: We are indebted to Masood Ahktar, MD, for his critical comments, as well as to Sandra Ogens and Lisa Douglas for their assistance in preparation of the manuscript.

efeaences 1. Schuilenburg RM. Patterns of V-A conduction in the human heart in the presence of normal and abnormal A-V conduction. In: Wellens H JJ. Lie KI, Janse M J, eds. The Conduction System of the Heart: Structure, Function and Clinical Implications. Philadelphia: Lea 8 Febiger, 1976;485-593. 2. Akhtar M, Damato AN, Batsford WP, Ruskin JN. Ogunkelu JB. A comparative analysis of antegrade and retrograde conduction patterns in man. Circulation 1975;52:766-778. 3. Shenasa M, Denker S, Mabmud R, Lehmann M. Gilbert CJ, Akhtar M. Atrioventricular nodal conduction and refractoriness after intranodal collision from antegrade and retrograde impulses. Circulation 1983;67:651-660. 4. Redd RM, Vasilomanolakis EC, Castellanet MJ, Messenger JC, Goldberg LB, Val-Mejias JE, Kennedy HL. Pacemaker re-entry syndrome (abstr]. JACC 19233:1:s74. 5. Hariman RJ. Pasquariello JL, Gomes JAC, Holtzman R, El-Sherif N. Auto-

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nomic dependence of ventriculoatrial conduction. Am J CardioI 1985;58:285291. 6. Svenson RH, ClarkM, Hall D, Elliott C, Harbold NB, Zimmern S, Austin K. Analysis of manifest and Iatent retrograde conduction in patients with AV sequential pacemakers. Implications for pacer induced tachycardias (abstr]. ;.h.cr l_o_pyc74 7. Mabmud R. Denker ST, Lehmann MH, Addas A, AkhahtarM. Unidiraciicd retrograde atrioventricular nodal block in man: determinants of reversibility by vagaI antagonism. Am Heart J 1985;110:568-574. 6. Akhtar M, Damato AN, Batsford WP, Caracta AR, Ruskin JN, Weisfogel GM, Lau SH. Induction of atrioventricular nodal reentrant tachycardia after atropine. Am J Cardiol 1975:38:286-291. 9. Wu D, Denes P, Bauernfeind R, Dhingra RC, Wyndham C, Rosen KM. Effects of atropine on induction and maintenance of atrioventricular nodal reentrant tachycardia. Circulation 1979;59:779-788. 10. Bauernfeind RA, Wyndham CR, Dhingra RC, Swiryn SP, Palileo E, Strasberg B, Rosen KM. Serial electrophysiologic testing of multiple drugs in patients with atrioventricular nodal reentrant paroxysmal tachycardia. Cirmdation 1980:62:1341-1349. 11. Wellens HJJ, Durrer D. The role of an accessory atrioventricular pathway in reciprocal tachycardia. Observations in patients with and without the Wolff-Parkinson-White syndrome. Circulation 1975;52:58-72. 12. Sellers TD, Gallagher JJ,Cope GD, Tonkin AM, Wallace AG. Retrograde atria1 preexcitation following premature ventricular beats during reciprocating tachycardia in the Wolff-Parkinson-White syndrome. Eur J Cardiol 1976;4:283-294. 13. Rahilly GT, Zipes DP, Naccarelli GV, Jackman WM, Heger JJ,Prystowsky EN. Autonomic blockade in patients with normal and abnormal atrioventricular nodal function (abstr]. Am J Cardiol 1982;49:898. 14. Jackman WM, Prystowsky EN, Naccarelli GV, Fineberg NS, Rahilly GT. Heger JJ.Zipes DP. Reevaluation of enhanced atrioventricular nodoI conduction: evidence to suggest a continuum of normal atrioventricular nodal physiology. CircuIation 1983;67:441-448. 15. Jose AD. Effect of combined sympathetic and parasympathetic bIockade on heart rate and cardiac function in man. Am J Cardiol 1966;18:476-478. 16. Prystowsky EN, Jackman WM. Rinkenberger RL. Heger JJ, Zipes DP. Effect of autonomic blockade on ventricular refractoriness and atrioventricular nodal conduction in humans: evidence supporting a direct cholinergic action on ventricular muscle refractoriness. Circ Res 1981;49:511-518. 17. Hayes DL. Furman S. Atrio-ventricular and ventriculo-atria1 conduction times in patients undergoing pacemaker implant. PACE 1983;8:38-46. 16. Denes P, Wu D, Dhingra RC, Chuquimia R, Rosen KM. Demonstration of dual A-V nodal pathways in patients with paroxysmal supraventricular tachycardia. Circulation 1973:48:549-555. 19. Wu D, Denes P, Amat-y-Leon F, Wyndham CRC, Dhingra R. Rosen KM. An unusual variety of atrioventricular nodal re-entry due to retrograde dual atrioventricular nodal pathways. Circulation 1977;56:50-59. 20. Strasberg B, Swiryn S, Bauernfeind R, Palileo E, Scagliotti D, Duffy Ce, Rosen KM. Retrograde dual atrioventricular nodal pathways. Am J CardioI 1981;48:639-648. 21. Gallagher JJ, Sealy WC, Kasell J, Wallace AG. Multiple accessory pathways in patients with the pre-excitation syndrome. Circulation 1976;54:571591. 22. Benditt DG, Pritchett ELC, Smith WM, Wallace AG. Gallagher JJ.Characteristics of atrioventricular conduction and the spectrum of arrhythmias in Lown-Canong-Levine syndrome. Circulation 1978;57:454-465. 23. Bauernfeind RA, Swiryn S, Strasberg B, Palileo E, Wyndham C, Duffy CE, Rosen KM. Analysis of anterograde and retrograde fast pathway properties in patients with dual atrioventricular nodal pathways. Am J CardioI1982;49:283290. 24. Desai JM, Scheinman MM, Strauss HC, Massie B, O’Young J. Electrophysiologic effects of combined autonomic blockade in patients with sinus node disease. Circulation 1981:63:953-960. 25. Benditt DG, Klein GJ, Kriett JM, Dunn&an A, Benson DW. Enhanced atrioventrictdar nodaI conduction in man: electrophysiologic effects of pharmacologic autonomic blockade. Circulation 1984;69:1068-1095. 26. Bauernfeind RA, Ayres BF, Wyndham CC, Dhingra RC, Swiryn SP. Strasberg B, Rosen KM. Cycle length in atrioventricular nodal reentrant paroxysmal tachycardia with observations on the town-Ganong-Levine syndrome. Am J Cardiol 1980;45:1148-1153. 27. Benditt DC, Epstein ML, Arentzen CE, Kriett JM, Klein GJ. Enhanced atrioventricuiar conduction in patients without preexcitation syndrome: relation to heart rate in paroxysmal reciprocating tachycardia. Circulation 1982x35:1474-1479.