Electrophysiologic Effects of Atropine on

Atrioventricular Conduction Studied by

His Bundle Electrogram

MASOOD AKHTAR, MD

ANTHONY N. DAMATO, MD

ANTHONY R. CARACTA, MD

WIUJAM P. BATSFORD, MD

MARK E. JOSEPHSON, MD

SUN H. LAU, MD

Staten Ishnd, New York

From the Cardiopulmonary Laboratory, U. S. Public Health Service Hospital, Staten island, N. Y. This work was supported in part by the Federal Health Program Service, U.S. Public Health Service Project Py 73-l and National Heart and Lung Institute Project HE 12536-04. Manuscript accepted June 26, 1973.

Address for reprints: Masood Akhtar, MD, Cardbpulmonary Labcratoty, U. S. Public Health Service Hospital. Staten Island, N. Y. 10304.

The electrophysiologlc effects of atropine were studied with His bundle recordings in 14 patients. Admlnistration of atropine, 0.5 mg intrave- nousfy, produced a moderate degree of sinus acceleration In all pa- tients (average increase 20 percent over control rate). Atrioventrfcular (A-V) nodal conduction was enhanced during both sinus rhythm and at various paced atrial rates afler administration of atropine. the paced atrlat rates at which the A-V nodal Wenckebach phenomenon oc- curred were signfflcantly higher after administration of the drug than before. Similar effects on retrograde conduction were observed during ventricular pacing. Atropine shortened both the functional and effective refractory periods of the A-V node but appeared to have no direct ef- fect on either His-PurklnJe conduction time or refractoriness. However, aberrant ventricular conduction and block within the His-Purkinje sys- tem increased during premature atrial stimulation afler atropine admin- istration. This was the result of shortening of the functional refractory period of the A-V node by atropine, which produced significantly short- er Hi-Hz intervals. The effect of atropine on the electrophysiologlc properties of the A-V conducting system was important in interpretfng the conversion of a type I gap in A-V conduction to a type II gap.

Atropine sulfate, commonly considered a safe drug, is frequently used in general medical practice. Its effects on the electrophysiologic prop- erties of the sinus1-5 and atrioventricular (A-V) nodes1r2*6 have been extensively studied. Most clinical studies have used standard electro- cardiographic recordings to assess the effects of atropine on total A- V conduction. Relatively few have considered the possible effects of atropine on the His-Purkinje system.

In this investigation we used His bundle electrograms to study the effects of atropine on the electrophysiologic properties of the A-V node and His-Purkinje system in 14 patients. A-V nodal and His- Purkinje conduction times were compared at various paced atria1 rates before and after administration of the drug. The functional and effective refractory periods of the A-V node and His-Purkinje system were also studied with use of the atria1 extrastimulus method.7*s

Materials and Methods

All 14 patients were studied in the nonsedated, postabsorptive state after informed consent had been obtained. Under local anesthesia a quadripolar catheter was introduced percutaneously into an antecubital vein and flue- roscopically positioned against the lateral wall of the right atrium. The distal two electrodes were used to pace the atrium, and the proximal electrodes to record high right atrial activity. A tripolar electrode catheter was percuta- neously introduced into the femoral vein and positioned in the tricuspid

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TABLE I

Effect of Atropine on Sinus Cycle Length and Antegrade Conduction (msec)

Case Age no. (yr) Diagnosis Atropine

Sinus

Cycle

Length A-H H-V

1 57 NHD

2 54 IHD

3 57 NHD

4 69 IHD

5 68 NHD

6 53 IHD

7 63 NHD

8 36 NHD

9 34 NHD

10 68 IHD

11 53 IHD

12 52 NHD

13 19 NHD

14 75 NHD

Before 950 105 After 840 80 Before 1200 100

After 870 80 Before 1100 80

After 950 65 Before 810 85 After 740 75 Before 860 75

After 670 60 Before 750 90

After 640 60

Before 860 85

After 750 80

Before 720 90

After 600 70

Before 800 65

After 720 60

Before 860 100 After 770 90 Before 740 80 After 610 60

Before 750 90 After 680 85

Before 680 80

After 550 70 Before 690 100

After 660 85 -

50

50

62

62

45

45

45

45

40

40

45

45

50

50

40

40

50

50

35

35

60

60

50

50 45

45

40

40

IHD = ischemic heart disease; NHD = no heart disease.

valve area to record electrical activity of the His bundle as previously described.g For ventricular pacing a bipolar catheter was inserted into another arm vein and positioned at the apex of the right ventricle.

Atria1 pacing was accomplished by using a programmed digital stimulator that delivered rectangular impulses of I .5 msec duration at approximately twice diastolic threshold. Ventricular pacing was accomplished in a similar way using the lowest milliamperage that permitted reliable capture. Refractory period studies were performed with the atria1 extrastimulus method.7,8

Three to four standard electrocardiographic leads (I, II, III, Vr) were simultaneously recorded.

All tracings were displayed on a multichannel oscillo- scope and recorded on magnetic tape. The recordings were subsequently reproduced at a paper speed of 150 mm/set. Intracardiac electrograms were recorded at a filter frequen- cy setting of 40 to 500 Hz. Care was taken to insure the grounding of all equipment.

After control values were obtained, 0.5 mg of atropine sulfate was administered intravenously and studies were repeated 5 to 10 minutes after injection. The A-H interval, used as an approximation of A-V nodal conduction time, was measured from the onset of the low right atria1 electro- gram to the beginning of the His deflection (normal values

for our laboratory 60 to 140 msec). The H-V interval repre- sented His-Purkinje conduction time and was measured from the onset of the His bundle deflection to the begin- ning of ventricular depolarization (normal values for our laboratory 30 to 55 msec). During ventricular pacing with retrograde conduction the interval from the stimulus arti- fact to the beginning of the low right atria1 electrogram was taken as a measure of ventriculoatrial conduction time.

Definitions for relative, functional and effective refracto- ry periods of the various components of the A-V conduc- tion system have been previously published.iO

Results

Table I provides the essential clinical data on the 14 patients in this study. All patients had sinus rhythm and normal P-R intervals; none was taking medication. Patients with the so-called sick sinus syndrome were excluded from the study.

Sinus cycle: Administration of atropine, 0.5 mg, resulted in an acceleration of the sinus rate in all pa- tients (Table I). The average increase was 15 beats/ min (a 20 percent decrease in sinus cycle length).

A-V Conduction Studies

Antegrade conduction: Administration of atro- pine resulted in significant enhancement of A-V nodal conduction in all 13 patients studied,* as shown by shortening of the A-H interval duriug sinus rhythm (Table I) and at various paced atria1 rates. For example, at a paced atria1 rate of 100 beats/min the mean A-H interval measured 113.3 msec (stan- dard error of the mean 9.9 msec) during the control period and 80.0 f 4.2 msec after administration of at- ropine (P <O.OOl). Similarly, in six patients with a paced atria1 rate of 150/min the mean decrease in the A-H interval was 33 f 16 msec after administration of atropine (P X0.005). In seven patients faster rates of atria1 stimulation resulted in A-V nodal conduc- tion of the Wenckebach type during the control peri- od. The average atria1 rate at the onset of the ante- grade A-V nodal Wenckebach phenomenon was 133 beatslmin before administration of atropine. After atropine, five of the seven patients demonstrated 1:l A-V conduction up to.an atria1 rate of 160 beatslmin. Two patients who had an earlier onset of the A-V nodal Wenckebach phenomenon (at atria1 rates of 110 and 120 beats/min, respectively) during the con- trol period also demonstrated the phenomenon after atropine administration, but at a much faster atria1 rate (150 beats/min in each case). Atropine produced no changes in the H-V interval during antegrade conduction studies.

Retrograde conduction: Retrograde conduction studies were performed in three patients (Cases 6, 11 and 13). At any given paced ventricular rate, retro- grade conduction time was less after administration of atropine. The ventricular rate at which the retro-

l Individual patient data on atrioventricular conduction and refrac- tory periods before and after administration of atropine are available on request.

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FIGURE 1. Case 11. Effect of atro- pine on retrograde conduction. Panel A shows sinus rhythm in which the sequence of atrial activation is from Ihe hiih to the low right atrium. Panel B demonstrates that at a paced ven- tricular cycle length of 400 msec a 3:2 retrograde A-W nodal Wencke- bath type of block with concealed reentry occurs repetitiveiy. Note the low to hiih sequence of right atriai activation. Panel C shows that after administration of atropine 1:l retro- wade conduction occurs at the same paced cycle length of 400 msec. Each panel shows from top to bottom standard eiectrocardiographic leads I, II, Ill, VI, hi right atrlai electrogram (HRA). His bundle electrogram (i-BE) and tima iines (T) recorded at 10 and 100 msec. CL = cycle length; S = stimulus artifact.

- _ -

a

grade Wenckebacb phenomenon occurred after atro- pine was greater than in the control period (Fig. 1).

Refractory Period Studies

Atrium: Atropine had no consistent effect on the effective refractory period of the atrium in the 11 pa- tients studied. In nine patients the effect of atropine on the effective refractory period of the atrium was studied at a cycle length of 600 msec. In four (Cases 3, 9, 11 and 14), the effective refractory period de- creased by 10 to* 20 ‘msec and in three (Cases 2,5 and 6), it increased by 10 msec; in two patients (Cases 1 and 7), no change occurred.

A-V node: During the control period, the effective refractory period of the A-V node could be deter- mined in only six patients. In the remaining five, the

effective refractory period of the atrium was encoun- tered first. Administration of atropine decreased the effective refractory period of the A-V node in all six patients by a mean of more than 51.5 -+ 37.3 msec (P <O.OOl). After atropine, the actual or smallest value for the effective refractory period of the A-V node could not be determined since atria1 refractoriness was encountered first in all instances. Figure 2 exem- plifies the effect of atropine on the effective refracto- ry period of the A-V node. In all patients atropine shortened the functional refractory period at one or mnre cycle lengths. The mean value for the function- al refractory period of the A-V node was 417.9 f 10.7 msec during the control period and 371.2 f 6.4 msec after administration of atropine (P <O.OOl). The shortening of the functional refractory period after

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A CONTROL

B AFTER ATROPINE 0.5mg IV

C AFTER ATROPINE 0.5mg IV

atropine was greater at longer basic atria1 cycle lengths.

His-Purkinje system: Atropine in the dose used did not appear to have a direct effect on refractori- ness of the His-Purkinje system (Fig. 3). However, H-V prolongation and aberrant ventricular conduc- tion during premature atria1 stimulation occurred more frequently after administration of atropine than in the control period, especially at atria1 cycle lengths of 700 msec and greater (Fig. 4). This in- creased frequency was caused by the enhanced A-V nodal conduction induced by atropine which, at any

FIGURE 2. Case 1. Effect of atropine on the effective refractory period of the A-V node. In the control period (panel A) the effective refractory pe- riod of the A-V node is reached at an A 1 -A2 interval of 360 msec. After ad- ministration of atropine (panel B), the premature atria1 beat (AZ) conducts to the ventricle at the same AI-A2 in- terval of 360 msec. The HI-HP inter- val measures 365 msec and there is aberrant ventricular conduction of a left bundle branch block type with an Hz-V2 interval of 65 msec. The de- gree of shortening of the effective re- fractory period of the A-V node is further exemplified by the fact that conduction to the ventricles occurred at an AI-A2 interval of 315 msec (panel C). Abbreviations in this and subsequent figures as in Figure 1.

given atria1 coupling interval, resulted in an Hi--H* interval shorter than that of the control period. The shorter Hi--Hz interval permitted the impulse of the premature atria1 beat to be conducted during the rel- ative refractory period of the His-Purkinje system. In five patients (Cases 1, 2, 6, 7 and 9) the relative re- fractory period of the His-Purkinje system was en- countered after administration of the drug but not before.

Figure 5 is representative of two patients who had no aberrant ventricular conduction when the basic cycle length of atria1 stimulation was reduced during

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FIGURE 3. Case 14. Effect of atropine on the effective refractory period of His-Purkinje sys- tem. In paneb A through D the atrial cycle length is constant at 650 msec. Before adminis- tration of atropine, at an AI-A2 interval of 370 msec. a premature atrial beat (As) conducts to the ventricles with a longer H-V interval (50 msec. panel A) than that of the basic drive. The HI-Hs interval is 420 msec, which is outside the effective but within the relative refractory period of the His-Purkinje system. By decreasing the Al-As interval by 10 msec (panel B) A2 reach- es the His-Purkinje system during its effective refractory period (410 msec) and blocks within this system. After administration of atropine, As blocks withit the His-Purkinje system (panel D) at the same HI-H2 interval of 410 msec as that of the control period (panel B). As shown in panel C. A2 conducted to the ventricles during its relative refractory period (H2-V2 interval, 50 msec).

CONTROL

A-1

AFTER ATROPINE 0.5mg IV

the control period but who manifested aberrant con- system could be determined only after administra- duction at the shorter cycle lengths after administra- tion of atropine (Fig. 6 and 7). tion of atropine.

In three patients (Cases 2, 3 and 14), at basic atria1 In one patient (Case 3) atropine converted a type I gap in

cycle lengths of 800, 700 and 550 msec, respectively, A-V conduction11J3 (Fig. 8) into a type II gap13 (Fig. 9). In panel B of Figure 8 a relatively late premature atria1 depo-

the effective refractory period of the His-Purkinje larization (Al-A2 interval 445 msec) is initially blocked

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AFTER ATROPINE 0.5mg I V

.- II / j 1 1 j 1 i j j ( 1 --I , j ’ ; : 1 [ / ; 1 I ; 1 1.;

FIGURE 4. Case 3. Effect of atropine on the functional refractory period of the A-V node and the resultant His-Purkinje conduction. Atrial cycle lengths are constant at 900 msec. In the control period (panel A), a premature atrial beat (A*) introduced at an AI-A, interval of 420 msec en- counters A-V nodal delay (A*-H2 interval 230 msec). The resultant HI-H2 interval is 560 msec, and normal ventricular activation occurs with a normal H-V interval of 45 msec. After administration of atropine (panel B), the premature atrial beat results in a shorter HI-HP interval (450 msec) caused by enhancement of A-V nodal conduction time (AZ-H2 interval 100 msec). The premature atrial beat is conducted during the rela- tive refractory period of the His-Purkinje system as evidenced by the markedly prolonged H2-V2 interval (195 msec) and aberrant ventricular ac- ttvaiion of a left bundle branch block type.

within the His-Purkinje system. The effective refractory period of the His-Purkinje system occurs at an HI-HZ in- terval of 510 msec. In panels C and D, A-V conduction re- sumes because earlier premature atria1 depolarizations en- counter greater A-V nodal delay and the resultant HI-HZ intervals (545 and 515 msec, respectively) are outside the effective refractory period of the His-Purkinje system.

Figure 9 (same patient) illustrates a type II gap in A-V conduction after administration of atropine. In panel 3, a premature atria1 impulse (AZ) blocks within the His-Purk- inje system at an HI-H:! interval of 490 msec. In panel C, an earlier premature atria1 depolarization was conducted to the ventricles although the Hi-Hz interval of 430 msec was less than in panel B. In panel D, block again occurred with- in the His-Purkinje system when the Al-As interval was decreased and the resultant Hi-H2 interval was shortened to 415 msec. This form of gap in A-V conduction has been explained as follows: In panel B, the premature atria1 im- pulse encounters an area of maximal refractoriness within the distal His-Purkinje system. In panel C, it encounters

conduction delay in the proximal portion of the His-Purk- inje system which allows recovery of the distal area thereby permitting ventricular excitation. The Hz-V2 interval is prolonged at 135 msec. In panel D, the premature atria1 im- pulse is again blocked because it encounters the effective refractory period of the proximal portion of the His-Purk- inje system.

Discussion

In this study we used a relatively small dose of at- ropine to avoid marked increases in sinus rate. With larger doses of 1 mg or more, it is not always possible to obtain refractory period studies at comparable cycle lengths before and after administration of the drug. In addition, if significant sinus acceleration were produced by a larger drug dose, the shorter cycle lengths would decrease the relative and effec- tive refractory periods of the His-Purkinje system to such a degree that the indirect effects of atropine on

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FIGURE 5. Case 2. Aberrant ventric- ular conduction elicited by atropine. Pand A: At a basic cycle length of 850 msec (AI-AI) and premature atrial coupling (AI-AZ) of 440 msec, AP conducts to the ventricles aber- rantly (right bundle branch block and right axis +1200). The premature atrial beat conducts with a longer H-V (l-l92 75 msec) interval than that of the basic atrial beats (HI-V1 interval 82 msec). As shown in panel B, decreasing the basic atrial cycle m by 50 msec (AI-A1 interval 800 msec) abolishes ventricular ab- erration and H-V prolongation al- thou& then AI-AZ and H,-Hz intervals are the same in both pmels A and B d&ng ihe control period. Panel C: After administration of atroplne, at a basic atrial cycle length (AI-A, inter- val 800 msec) similar to that of panel B, ventricular aberration (right bundle branch block) with H-V prolongation (H.92 interval 75 msec) resumes. The aberrancy occurs because of a decrease in the functional refractory period of the A-V node (HI-Hi 470 msec) permitting A2 to conduct to the His-Purkinje system during its relative refractory period.

EWORE ATROPINE

BEFORE AWINE

AFTER AlROPlNE 05mg IV

these variables would be obscured. We did not ob- serve the initial slowing of sinus rate occasionally seen with administration of atropine.

The well known effects of atropine on the sinoatri- al and A-V nodes were observed in all patients. Fur- thermore, the predictable shortening of both the functional and effective refractory periods of the A-V node was consistently seen.

Atropine appeared to have no direct effect on His- Purkinje conduction time or refractoriness. The greater frequency of His-Purkinje conduction delay,

aberrant ventricular conduction and block within the His-Purkinje system after Bdministration of atropine can be explained by the enhanced A-V nodal conduc- tion (shorter AZ-HZ interval) at a given atria1 prema- ture coupling interval, resulting in shorter HI-HZ in- tervals. At these shorter HI-H2 intervals the prema- ture atrial impulse entered the His-Purkinje system during its relative or effective refractory period, or both. Thus, atropine may be used to determine the relative (Fig. 2, 4 and 5).and effective (Fig. 6 and 7) refractory periods of the His-Puikinje system in pa-

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FIGURE 6. Case 2. Effective refractory peri- od of the His-Purkinje system after adminis- tration of atropine. In both panels, the atrial cycle length is constant at 800 msec. In panel A, As is conducted with a prolonged A-V nodal conduction time (A2-H2 interval 190 msec). The resultant HI-H2 interval is outside the relative and effective refractory periods of the His-Purkinje system, and therefore normal ventricular activation oc- curs. As shown in panel 8, atropine short- ens the A-V nodal conduction time of the premature atriil beat (A2-t-l2 interval 125 msec). The resultant HI-HP interval is within the effective refractory period of the His- Purkinje system, and therefore block wtthin this system occurs.

FIGURE 7. Case 3. Effective refractory period of the His-Purkinje system after administration of atropine. At a basic cycle length of 700 msec, the effective refractory period of the A- V node occurred at an AI-A:, interval of 355 msec (panel A). Panel B shows that atropine shortened A-V nodal conductin of the basic beat (AI-HI 80 msec) and the effective refrac- tory period of the A-V node. At the same AI-AZ interval (355 msec), A2 is conducted to and blocked within the His-Purkinje system.

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FIGURE 8. Case 3. Typical type I gap in A-V conduc- tion occurred during the control period. The atrial cycle length is constant at 900 msec and the Al-A2 interval of the premature beat is progressively decreased in pads A through D. In panel 6, the effective refracto- ry period of the His-Purkinje system is reached at an HI-H2 interval of 510 msec. Thereafter (paneb c and D), conduction to the ventricles is resumed at shorter AI-As intervals. The more premature atrial beats en- counter greater A-V nodal delay (235 and 245 msec). The resultant HI-H2 intervals (545 and 515 msec) are now outsii the effective refractory period of the His- Purfdnje system, and conduction to the ventricles oc- curs.

tients who, during control studies, have relatively long functional and effective refractory periods of the A-V node that prevent such determinations.

In most patients the dual actions of atropine (sinus acceleration and enhancement of A-V nodal conduc- tion) occur together. For this reason the drug is gen- erally useful. for treating (1) sinus bradycardia with or without first degree heart block, (2) the A-V nodal

Wenckebach phenomenon, and (3) some cases of 2:l A-V nodal block. However, under certain circum- stances atropine may increase the severity or shift the site of A-V block. If the electrocardiographic pat- tern of type I second degree heart block is due to delay in the His-Purkinje system rather than delay in the A-V node, atropine may result in a higher degree of block. The increased severity occurs because (1)

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FIGURE 9. Case 3. Atropine converts a type I gap in A-V conduction to a type II gap. Atrial cycle lengths are constant at 900 msec. Atropine short- ened A-V nodal conduction time (A,-f-f, interval) of the basic beat to 70 msec. The premature coupling interval is progressively decreased in panels A through D. In panel 6, the effective refractory peri- od of same portion of the His-Purkinje system is reached at an HI-Hz interval of 490 msec. In panel C, A-V conduction resumes at shorter A,-AP and HI-HZ intervals. In panel D, the effective refractory period of the His-Purkinje system is again encoun- tered at an HI-HP interval of 415 msec.

sinus acceleration and enhanced A-V nodal conduc- tion result in shorter H-H intervals, and (2) atropine has no direct enhancing effect on His-Purkinje con- duction. Figure 7 suggests the possibility that in 2:l A-V block atropine may change the site of block from the A-V node to the His-Purkinje system. Shift in the site of block is more likely to occur after pre- mature atria1 beats. A functional form of 2:l block below the His bundle was seen more frequently after administration of atropine.12

The mechanism involved in type I and type II gaps in A-V conduction have been previously present- ed.11J3 The occurrence of gap phenomena depends

upon a state of differential refractoriness within the A-V nodal and His-Purkinje systems and does not by itself indicate abnormality in the conducting system. The functional nature of the phenomena is further emphasized by the fact that the conduction gaps may be unmasked by drugs that enhance A-V nodal con- duction (Fig. 8 and 9) or obscured by drugs, such as sympathetic beta receptor blocking agents, that prolong A-V nodal conduction.”

Acknowledgment

We acknowledge the technical assistance of Stephen Ru- dich, PhD, Audrey Pederson and Mary Vecchione.

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