Electrophysiologic effects of isoproterenol on cardiac conduction system in man

Electrophysiologic effects of isoproterenol on cardiac conduction system in man

Guillermo Vargas, M.D. Masood Akhtar, M.D. Anthony N. Damato, M.D. Staten Island. .V. Y.

The effects of sympathomimetic drugs on the electrophysiologic properties of the cardiac conduction system have been the subject of previous studies.‘-:: It is well accepted that these agents accelerate sinus rate, enhance A-V nodal conduction, and increase the discharge rate of idioven- tricular pacemakers. Some controversy exists re- garding effects of isoproterenol (ISOP) on the His-Purkinje system. Previous studies in isolated animal preparations’ and intact human heart”-’ indicate that isoproterenol has no appreciable influence on His-Purkinje conduction. However, in a recent study8 it was reported that isoprotere- no1 consistently facilitated His-Purkinje conduction in patients with either normal or prolonged control values as evidenced by a decrease in the H-V interval following drug administration.

Electrophysiologic studies were performed in 16 patients utilizing His bundle electrograms and the effects of isoproterenol on atrioventricular conduction and refractoriness were evaluated. The well-known effects of isoproterenol on sinus rate and A-V nodal conduction were consistently observed. Isoproterenol in the doses infused (1 mcg. per minute) did not appear to have any effect on His-Purkinje conduction time. The purpose of this report is to present results obtained in these patients and to discuss some of the reasons which might explain existing discrepancies.

From the Cardiopulmonary Laboratory, United States Public Health Service Hospital, Staten Island, N. Y.

This work was supported in part by the Bureau of Medical Services, IJnited States Public Health Service Project Py 74-l and National Heart and Lung Institute Project HE 12536-04.

Received for publication July 18, 1974.

Reprint requests: Dr. Anthony N. Damato, Cardiopulmonary Labora- tory, United States Public Health Setice Hospital, Staten Island, N. Y. 10304.

Materials and methods

Right-heart catheterization was performed in 16 patients in the postabsorptive, nonsedated state. The nature of the study was explained and a signed consent was obtained. Bundle of His electrograms were recorded as previously de- scribed, using a tripolar electrode catheter which was percutaneously introduced into the right femoral vein and fluoroscopically positioned in the region of the tricuspid valve.” A quadripolar electrode catheter was percutaneously introduced into an antecubital vein and advanced to the high right atrium near its junction with the superior vena cava. The distal two electrodes were used to stimulate the right atrium and the proximal two electrodes used to record a high right atria1 electrogram. Intracardiac electrograms as well as electrocardiographic Leads I, II, HI, and V, and time lines generated at 10 and 100 msec. were simultaneously displayed on a multichannel oscilloscope and relayed to a magnetic tape recorder. The records were subsequently repro- duced at paper speeds of 150 and 200 mm. per second. Electrical stimulation was accomplished using a programmed digital stimulator which delivered impulses of 1.5 msec. at approximately twice diastolic threshold. The functional properties of the A-V conduction system were determined at one or more basic atria1 cycle lengths using the atria1 extrastimulus method.“‘. it The right atrium was stimulated at a predetermined basic cycle length (A,A,) and, following every eight basic drive beat, a premature atria1 impulse (A,) was introduced at progressively decreasing A,A, intervals to the point of atria1 refractoriness. Careful attention was paid to the grounding of all equipment. After completing the control studies, isoproterenol was given by continuous intrave-

July, 1975. Vol. 90, No. 1, pp. 25-34 American Heart ~Jwrnal 25

Vargas, Akhtar, and Damato

Table I. Clinical data and A-V conduction during sinus rhythm before and after isoproterenol

No. Age Sex Diagnosis Resting ECG

5 6 7 8 9

10 11 12

13 14 15 16

Sinus cycle length (msec.)

Before After

A-H interval H-V interval (msec.) (msec.)

Before After Before After

65 M Systemic hypertension Normal 59 M Systemic hypertension Normal 65 M ASHD RBBB + LAD 81 M ASHD RBBB + LAD

First-degree A-V block

42 M NHD Normal 52 M ASHD RBBB + LAD 56 M ASHD Normal 52 F NHD Normal 39 M NHD Normal 53 M ASHD RBBB 57 M ASHD Normal 61 M ASHD Sinus

bradycardia 32 M Systemic hypertension Normal 62 F Systemic hypertension Normal 54 M Systemic hypertension LBBB 59 M ASHD LBBB

Mean:

P-value:

1,100 870 125 92 52 52 1,060 615 112 102 48 48

795 720 100 92 52 52 780 565 135 125 so so

940 700 118 105 40 40 1,025 890 85 58 38 38

940 665 75 65 40 40 610 490 110 95 58 58 910 795 95 so 45 45 900 570 75 65 40 40 635 395 70 45 32 32

1,200 715 70 60 50 50

830 630 95 70

1,100 800 100 70 850 710 120 105 820 530 85 60

906 f 165 666 k 136 98 f 20 80 i 22

P < 0.001 P < 0.001

60 60 40 40 50 50 80 80

ASHD, atherosclerotic heart disease; NHD, no heart disease; LAD, left axis deviation of more than -30’; LBBB, left bundle branch block; and RBBB, right bundle branch block.

nous infusion (microdrops), and electrophysiologic measurements were repeated ten minutes after the infusion was stabilized at the desired rate of 1 mcg. per minute. The procedure was well tolerated and no adverse effects were noted.

Definition of terms. Antegrade conduction. A-H interval was used as an approximation of A- V nodal conduction time and was measured from the onset of the low atria1 electrogram to the onset of the His bundle electrogram (normal values for our laboratory, 60 to 140 msec.). H-V interval represented conduction time within the His-Purkinje system and was measured from the onset of the His bundle deflection to the earliest onset of ventricular activity as noted either on the ECG or HBE tracing (normal values for our laboratory, 30 to 55 msec).

Antegrade refractory periods.” A,, H,, and V, represents atrial, His bundle, and ventricular depolarizations of the basic atria1 drive. A,, H,, and V, represent atrial, His bundle, and ventricular depolarizations of the premature atria1 beats. Effective refractoryperiod (ERP) of the atrium is defined as the longest S,S, interval at which S,

fails to depolarize the atrium, S representing the stimulus artifact. ERP of the AVN is defined as the longest A,A, interval at which A, fails to propagate to the His-Purkinje system (HPS). Functional refractory period (FRP) of the AVN is defined as the shortest H,H, interval that results from any A,A2. ERP of the HPS is defined as the longest H,H, interval at which H, fails to conduct to the ventricles. Relative refractory period (RRP) of the HPS is generally defined as the longest H,H, interval at which H2 conducts to the ventricles with a longer H-V interval than the basic drive beat or results in an aberrant QRS complex. However, the detection of minor degrees of aberrant ventricular conduction was more difficult to determine and was subject to greater observer error. Therefore, for the purpose of this study, the longest H,H, interval resulting in definite bundle branch block pattern, QRS axis shifts of more than 30° in the frontal plane, or H- V prolongation was taken as the RRP of the HPS. Although it is recognized that the HPS is a trifascicular system, in the absence of multiple recording sites along individual fascicles it is

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Electrophysiologic effects of zcynroterrnol

Table II. Antegrade refractory period data

Atrium A-V node His-Purkinje sytcm

ERP FRP ERP RR? Patient A trial ‘. ------

NO. cycle length Before After Before After Before After Hefow / A/b I

8 9

10

11

12

13

14

700 310 300 475 375

600 300 290 460 350

500 270 260 470 340

600 300 260 380 335

500 250 260 355 330

600 270 290 345 345

500 270 250 350 330

600 260 240 545 375

650 270 240 570 370

600 230 260 445 370

550 260 250 440 380 700 290 250 390 350

600 270 250 360 350

500 250 230 355 340 450 240 230 445 380

600 270 260 415 355 500 250 260 400 340

700 240 250 430 365

550 240 250 350 330 500 220 250 450 315

550 220 210 330 315

500 220 230 320 305

450 230 230 315 300

700 270 230 410 345 600 270 230 395 320

600 250 220 395 350

500 220 210 385 315 700 270 240 510 410

600 260 220 490 350 500 220 210 465 330

All values (other than patient number) are in milliseconds. In patients Nos. 4. 15. and 16, no refractory period studies were performed.

impossible to measure the ERP versus the RRP of any given fascicle. Thus, for the purposes of this study it was elected to consider the HPS as a single functioning unit.

Results

The essential clinical and electrophysiologic data are presented in Tables I and II. None of the patients were taking any cardioactive medica- tions at the time of the study. Fifteen patients had P-R intervals of normal duration and one patient (No. 4, Table I) had first-degree A-V block with a wide QRS complex.

Sinus cycle length. In all patients, ISOP resulted in sinus acceleration. (Fig. 1). The average decrease in sinus cycle length was 240 msec., p-value (0.001 (Table I). The mean sinus cycle length measured 906 msec., c 165 msec.

380 < 300

390 < 290

400 < 260

< 300 < 260

< 250 < 260

< 270 < 290

300 280 450 260

500 < 240

330 < 260

335 < 250

< 290 < 250

< 270 < 250 270 < 230

300 230

340 < 260 340 < 260

370 280

< 240 < 250 400 260

< 220 < 210 < 220 < 230

< 230 < 230 < 270 i 330

290 < 230

280 < 220

280 < 210 370 < 240

370 < 220 400 270

400 3%

365 356

430 420

355 335

385

330

325 345

320

480 47,s 465 455

400 385

430 420

535 525

530 520 480 470

425

43u 42.5

370

395

during the control period and 666 msec. + 136 msec. following isoproterenol administration.

Antegrade conduction studies (Table I). A - Vnode. ISOP facilitated A-V nodal conduction as indicated by a shortening of A-H intervals during sinus rhythm (16 patients) and at various paced atria1 rates (14 patients). The average decrease in A-H interval during sinus rhythm was 17 msec. (range, 5 to 33 msec.), p-value <O.OOl. The shortening of A-H intervals after ISOP was more pro- nounced at the faster-paced atria1 rates. For example, in 14 patients who demonstrated a 1:l atrioventricular response at a paced atria1 cycle length of 500 msec. (heart rate of 120 per minute), the average decrease in A-H interval following isoproterenol was 62 msec. (range 18 to 210 msec.), p-value (0.001. Furthermore, in 12 patients the onset of A-V nodal Wenckehach type

American Heart Journal 27


Fig. 1. Effect of isoproterenol on sinus rate, A-V nodal, and His-Purkinje conduction. Tracings in each panel from top to bottom are standard ECG Leads I, 11,111, V,, high right atria1 electrogram (HRA), His bundle electrogram (HBE), and time lines at 10 and 100 msec. Panel A shows sinus rhythm during the control period. The sinus cycle length measures 780 to 750 msec. The A-H and H-V intervals measure 130 and 90 msec., respectively. Note prolonged P-R and aberrant QRS complex (right bundle branch block and left posterior hemiblock pattern). After isoproterenol (panel B) there is acceleration of the sinus rate, a decrease in the A-H interval (115 msec.), and an unchanged H-V interval (90 msec.) and QRS complex.

of conduction during rapid atria1 pacing was significantly delayed after ISOP (Fig. 2). Four of these 12 patients demonstrated 1:l atrioventricular response up to paced atria1 rates of 200 beats per minute following ISOP, whereas in the control period the onset of A-V nodal Wencke- bath phenomenon occurred at average atria1 rates of 165 beats per minute. In the remaining eight patients, A-V nodal Wenckebach type of conduction occurred at an average atria1 rate of 141 beats per minute (range, 130 to 170 per minute) during the control period and 175 beats per minute (range, 160 to 190 per minute) after ISOP. In the remaining two patients, a 1: 1 atrioventricular response occurred up to maximum atria1 paced rates of 200 beats per minute both before and after the drug administration.

His-Purkinje system. In all patients, His-

Purkinje conduction time (H-V interval) remained unchanged following ISOP, both during sinus rhythm (16 patients) and at various paced atria1 rates (14 patients). The H-V intervals during sinus rhythm were within normal range in 12 patients and prolonged in four patients (Table I, Fig. 1).

Antegrade refractory period studies, 13 patients (Table II).

ATRIUM. For the entire group of 13 patients, including all cycle lengths, the ERP of the atrium averaged 296.6 msec. during the control and 323 msec. after ISOP. These differences did not achieve a statistical significance (p-value >0.2) since both decrease and increase in atria1 ERP was observed after ISOP. As, for example, when the atria1 ERP was measured in 10 patients at a basic atria1 cycle length of 600 msec. the ERP of

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Electrophysiologic effects of i.~s~pwtrr~nol

the atrium decreased by 10 to 40 msec. in eight patients and increased by 20 and 30 msec. in the remaining two patients.

A-V NODE. ERP; During the control period the ERP of the A-V node could be determined in only 11 gatients at one or more atria1 cycle lengths. In the remaining two patients atria1 refractoriness exceeded that of the A-V node and limited deter- mination of the latter parameter. ISOP decreased the ERP of the A-V node in five of the 11 patients (Fig. 3) by an average of 106 msec. (range 20 to 190 msec.), p-value tO.O1. In the remaining six patients ISOP decreased the A-V nodal ERP to such a degree that the ERP of the atrium was encountered first. The actual or lowest value for the ERP of the A-V node could not be achieved and in these six patients is expressed as less than the ERP of the atrium (Table II).

FRP; In all patients, isoproterenol significantly decreased the FRP of the A-V node (Fig. 4) at all cycle lengths except one (Table II). The average decrease was 72 msec. (range lo-200 msec.); p- value t0.001.

HIS-PURKINJE SYSTEM. RRP; In five patients (and 12 cycle lengths), the RRP of the HPS could be determined before and after isoproterenol. A consistent shortening of the RRP of the HPS was seen after drug administration (Fig. 5). The value for this parameter at 12 cycle lengths, measured 433.7 msec., S.E.M. (standard error of the mean) 19 msec., during the control period and 422.9 msec., S.E.M. 19.4 msec., after ISOP (p-value <O.OOl). In three patients (eight cycle lengths), the RRP of the HPS could only be demonstrated after the drug but not before. These results are not unexpected if one considers that ISOP by decreasing the FRP of the A-V node allows achievement of shorter H,H, intervals.

ERP; The ERP of the HPS could not be determined in any patient in this study since complete block within the His-Purkinje system did not occur either during the control or after drug infuwon.

Discussion

Administration of ISOP almost invariably results in simultaneous acceleration of the sinus node pacemaker and enhanced A-V nodal conduction, L ’ L ’ * effects which were consistently observed in the present study. Although not previously shown, ISOP consistently decreased

both the functional and effective refractory periods of the A-V node.

Kassebaum and Van Dyke’ demonstrated in isolated lamb Purkinje fibers that ISOP did not change conduction velocity. Similarly,, Wallace and Sarnoff’ reported that sympathetic nerve stimulation in the intact dog heart produced little or no change of conduction velocity in the Purkinje system. In a recent study using His bundle electrograms, it was reported that ISOP consistently decreased HP conducrion time (range 1 to 16 msec.) in patients with either normal or prolonged HP conduction [H-V int,er- vals).‘ We were unable to confirm these lat.ter observations. In the present study, H-V intervals remained unchanged after ISOP in the entire group which included four patients with prolonged H-V intervals. Several possible reasons can be put forth which may explain some of the discrepancies between the results of this study and those reported by Dhingra and associates.’

(1) Part of the discrepancy may be related to the amount and rate of infusion of isoproterenol. In the study by Dhingra and associates,’ infusion was adjusted to achieve a sinus rate i)f between 100 to 120 per minute, whereas in the present study, measurements were obtained after several minutes of a constant infusion of i mcg. per minute. The average sinus rates aftr>r infusion were 104 beats per minute during t,ht* study by Dhingra and associates” and 90 beats per minute during the present study. It cannot he stated for certain whether isoproterenol in doses greater than those used in the present st,udy will affect His-Purkinje conduction time.

(2) Changes in catheter position such that a proximal right bundle branch potential and not a bundle of His potential is recorded afttkr isoproterenol infusion can result in an apparent shortening of the H-V interval. This possibility is sug- gested by a change to a lower amplitude atria1 electrogram when an RB potential is recorded as appears to be the case in panels A and B of Fig. 1, of reference 8. In the present study, atI unchang- ing catheter position is indicated by the constan- cy of both the H-V interval measurements and the amplitude of the atria1 electrogram recordings.

(3) Variations in paper speed can cat&se artifac- tual changes in all interval measurements, espe- cially when time lines are inscribed t.very 1,000



30 July, 1975, Vol. 90, No. 1

Fig. 2. Effect of ISOP on A-V nodal conduction. Panel A demonstrates 1:l atrioventricular response at a paced atria1 cycle length of 500 msec. during the control period. The A-H and H-V intervals measure 200 and 50 msec., respectively. S denotes stimulus artifact. Upon decreasing the atria1 cycle length to 470 msec. (panel B), a 3:2 A-V nodal Wenckebach type of conduction results, as indicated by progressive prolongation of the A-H interval (from 170 to 220 msec.) and block of the third atria1 impulse in the A-V node. Panel C shows 1:l A-V conduction after ISOP at an atria1 cycle length of 370 msec. A 4:3 A-V nodal Wenckebach is shown in panel D after ISOP. Note the decrease in atria1 cycle length necessary to produce A-V nodal Wenckebach type of conduction following ISOP (from 470 to 340 msec.) and also the unchanged H-V intervals.

Electrophysiologic effects of’ isnm-oterend

Fig. 3. Effect of ISOP on the effective refractory period of the A-V node. At an atria1 cycle length of 600 msec. and an A,A2 of 460 msec., A,conducts with an A,H, of 370 msec. during the control (panel A). Upon decreasing the A,AI to 450 msec. (panel B), A, blocks proximal to the bundle of His which defines the effective refractory period of t,he A-V node before ISOP. Panel C demonstrates marked shortening of the A-V nodal effective refractory period following ISOP such that A, is still able to conduct at an A,A, interval of 270 msec. Finally, panel D demonstrates the effective refractory period of the A-V node after ISOP which has decreased by 190 msec. compared to the control period. Note also marked shortening of A-V nodal conduction time of the basic drive beats after ISOP (from 289 msec. to 75 msec.), and unchanged His-Purkinje conduction time.

American Heart Jourml 31


32

Fig. 4. The effect of ISOP on the A-V nodal functional refractory period. Basic atria1 cycle length is constant at 600 msec. in all panels. During the control period (panel A) at an atria1 coupling interval of 480 msec., Al conducts within an A2H, of 345 msec. The resulting H,H, interval of 545 msec. defined the functional refractory period of the A-V node in this patient at this cycle length. Further decrease in A,A, interval (panel B) results in prolongation of H,H, interval of 550 msec. Panel C demonstrates the functional refractory period of the A-V node following ISOP (H,H, 375 msec.); at an A,A% of 330 msec.

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Electrophysiologic effects of isoprcderend

Fig. 5. Effect of ISOP on the relative refractory period of the His-Purkinje system. Basic atria1 drive is cowtan! at 700 msec. Before ISOP, Al results in minor aberration at an H,H, interval of 405 msec. (panel A) and right bundle branch block pattern at an H,H, interval of 400 msec. (panel B). Following ISOP. similar degrees of vrntrict:lar aberrations could be produced at shorter H,H, intervals, i.e., 400 and 385 msec.. respectively (panelc. (’ and I)).



msec.8 This problem can be minimized, although not completely eliminated, by recording (as was done in this study) continuous time lines at 10 and 100 msec. intervals and using the time scale which is at the same perpendicular level as the interval to be measured.

The magnitude of decrease in the RRP of the His-Purkinje system (5 to 15 msec.) following isoproterenol represented a statistically signifi- cant 1 to 4 per cent change from control values. The ERP of the HPS could not be reached in any of the patients in this study even though ISOP, by virtue of decreasing the functional refractory period of the A-V node, permitted the attainment of shorter H,H, intervals than in the control.

This in part resulted from the fact that ISOP significantly decreased the sinus cycle length in all patients which of itself produces a rate-related decrease in the ERP of the HPS.

Summary

The effects of isoproterenol (ISOP) on the functional properties of the A-V conduction system were studied in 16 patients using His- bundle recordings and the atria1 extrastimulus technique. In all patients, ISOP at an infusion rate of 1 mcg. per minute resulted in sinus acceleration and enhancement of A-V nodal conduction, but had no effect on His-Purkinje conduction time. ISOP significantly decreased both functional and effective refractory periods of the A-V node. The relative refractory period of the His-Purkinje system decreased by a small amount in five patients in whom the parameter could be compared before and after the drug.

The authors gratefully acknowledge the assistance of Anne Mazzella, Mary Vecchione, Audrey Pedersen, Etta Jones, Theresa Halloran, and Florence DaCasto. Photography services were provided by Kenneth Donohue.

REFERENCES

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Electrophysiologic effects of isoproterenol on cardiac conduction system in man