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Electrophysiologic effects of isoproterenol on cardiac conduction system in man
Electrophysiologic cardiac conduction
effects of isoproterenol system in man
on
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 idioventricular pacemakers. Some controversy exists regarding 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 isoprotereno1 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 Service Hospital, Staten
Laboratory, Island, N. Y.
United
States
Public
This work was supported in part by the Bureau of Medical IJnited States Public Health Service Project Py 74-l and Heart and Lung Institute Project HE 12536-04. Received
for publication
July
Health Services, National
18, 1974.
Reprint requests: Dr. Anthony N. Damato, tory, United States Public Health Setice Y. 10304.
Cardiopulmonary Hospital, Staten
July, 1975. Vol. 90, No. 1, pp. 25-34
LaboraIsland, N.
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 described, 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 reproduced 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-
American
Heart
~Jwrnal
25
Vargas,
Table
Akhtar,
and
Damato
I. Clinical data and A-V conduction during sinus rhythm before and after isoproterenol Sinus cycle length (msec.)
No.
Age
Sex
Diagnosis
65 59 65 81
M M M M
Systemic Systemic ASHD ASHD
5 6 7 8 9 10 11 12
42 52 56 52 39 53 57 61
M M M F M M M M
NHD ASHD ASHD NHD NHD ASHD ASHD ASHD
13 14 15 16
32 62 54 59
M F M M
Systemic Systemic Systemic ASHD
Resting
hypertension hypertension
hypertension hypertension hypertension
ECG
Before
Normal Normal RBBB + LAD RBBB + LAD First-degree A-V block Normal RBBB + LAD Normal Normal Normal RBBB Normal Sinus bradycardia Normal Normal LBBB LBBB
1,060 795 780
940 1,025 940 610 910
900 635 1,200 830
heart
disease;
870 615 720 565
125 112
700 890 665 490 795 570 395 715
118
135
85 75 110
95 75 70 70 95 100
800
850 710 820 530 906 f 165 666 k 136
no heart
disease;
LAD,
left axis deviation
of more
H-V
After
100
120 85 98 f 20
P < 0.001 NHD,
interval (msec.)
Before
630
1,100
P-value: atherosclerotic
After
1,100
Mean:
ASHD,
A-H
interval (msec.)
Before
After
92 102 92 125
52 48 52 so
52 48 52 so
105 58 65 95 so 65 45 60
40 38 40 58 45 40 32 50
40 38 40 58 45 40 32 50
70 70 105 60 80 i 22
60 40 50 80
60 40 50 80
P < 0.001 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 AV 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,
26
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 HV 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
July,
1975,
Vol.
90, No.
1
Electrophysiologic
II. Antegrade refractory
Table
Patient NO.
A trial cycle length
8 9 10
effects of zcynroterrnol
period data A-V node
Atrium ERP
His-Purkinje ERP
FRP Before
After
700 600
310
300
475
375
380
< 300
425
300
290
460
390
< 290
500
270
< 260 < 260
43u 42.5
300 250
470 380
400
600 500
260 260
350 340
260
355
330
600
270
290
345
500 600
270 260
250 240
350 545
345 330
650
270
600 550 700
230 260
240 260
< 260
270
< 290
300
280 260
370 395
375
450
570 445
370 370
500
< 240
330
< 260 < 250
250 250
440
390
380 350
600
290 270
250
360
350
500 450
250 240
230 230
355 445
340 380
600 500
270 250
260 260
415
355 340
700
240
250
550 500
240
250 250
400 430 350
335
< 290 < 270
< 250
400
270
< 250 < 230
365 430
300
230
340 340
< 260 < 260
370
280
385
240 400
< 250 260
330
315 305
< < < <
220 220
< 210 < 230
355 335
230
290
< 230 i 330 < 230
480 465
47,s 455 385 420
230
320
700 600
230 270 270
230 230 230
315 410
13
600
250
220
395 395
350
280
< 220
400
14
500 700
220 270
210 240
385 510
315 410
280 370
< 210 < 240
430 535
600 500
260
220 210
490
350 330
370 400
< 220
530 480
12
All values In patients
(other Nos.
220
than patient number) are in milliseconds. 4. 15. and 16, no refractory period studies
465
were
Results
The essential clinical and electrophysiologic data are presented in Tables I and II. None of the patients were taking any cardioactive medications 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.
Heart
Journal
300 345 320
270
270
325 345 320
525 520 470
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.
American
420
<
220
500 450
3% 356
330 315
365
210
550
220 220
300 250
450 330
11
‘.-----/ A/b I
After
< < <
After
Hefow
Before
335
Before
sytcm
RR?
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
27
Vargas, Akhtar, and Damato
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 Wenckebath 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-
28
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 pa-
tients (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
July, 1975, Vol. 90, No. 1
Electrophysiologic
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 determination 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.); pvalue 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
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
American
Heart
Journal
effects of i.~s~pwtrr~nol
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,ervals).‘ 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 suggested 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 unchanging catheter position is indicated by the constancy of both the H-V interval measurements and the amplitude of the atria1 electrogram recordings. (3) Variations in paper speed can cat&seartifactual changes in all interval measurements, especially when time lines are inscribed t.very 1,000
29
Vargas,
Akhtar,
and
Damato
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.
30
July, 1975, Vol. 90, No. 1
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
Vargas,
Akhtar,
and
Damato
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.
32
July, 1975, Vol. 90, No. 1
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)).
American
Heart
Journal
33
Vargas,
Akhtar,
and
Damato
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 significant 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.
2. 3.
4.
5.
6.
7.
8.
9.
Summary
The effects of isoproterenol (ISOP) on the functional properties of the A-V conduction system were studied in 16 patients using Hisbundle 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 1.
34
Wallace, A. G., and Sarnoff, sympathetic nerve stimulation heart, Circ. Res. 14:86, 1964.
10.
11.
12.
13.
14.
15.
16. S. J.: Effects of cardiac on conduction of the
Alanis, J., Gonzales, H., and Lopez, E.: The electrical activity of the bundle of His, J. Physiol. 142:127, 1958. Nathanson, M. H., and Miller, H.: The action of norepinephrine, epinephrine, and isopropyl-norepinephrine on the rhythmic function of the heart, Circulation 6:238, 1952. Kassebaum, D. G., and Van Dyke, A. R.: Electrophysiological effects of isoproterenol on Purkinje fibers of the heart, Circ. Res. 19:940, 1966. Damato, A. N., Lau, S. H., Helfant, R. H., Stein, E., Berkowitz, W., and Cohen, S. I.: Study of atrioventricular conduction in man using electrode catheter recordings of His bundle activity, Circulation 39:287, 1969. Damato, A. N., Lau, S. H., Helfant, R. H., Stein, E., Paton, R., Scherlag, B. J., and Berkowitz, W. D.: A study of heart block in man using His bundle recordings, Circulation 39:297, 1969. Lister, J. W., Stein, I., Kosowsky, B., Lau, S. H., and Damato, A. N.: Atrioventricular conduction in man. Effect of rate, exercise, isoproterenol, and atropine on the P-R interval, Am. J. Cardiol. 16516, 1965. Dhingra, R. C., Winslow, E., Pouget J., Rahimtoola, S., and Rosen, K. M.: The effect of isoproterenol on atrioventricular and intraventricular conduction, Am. J. Cardiol. 32:629, 1973. Scherlag, B. J., Lau, S. H., Helfant, R. H., Berkowitz, W. D., Stein, I, and Damato, A. N.: Catheter technique for recording His bundle activity in man, Circulation 39:13, 1969. Krayer, O., Mandoki, J. J. and Mendez, C.: Studies on veratrum alkaloids. XVI. The action of enineuhrine and of veratramine on the functional refractory period of the atrioventricular transmission in the heart-lung preparation of the dog, J. Pharmacol. Exp. Ther. 103:412, 1951. Goldreyer, B. N. and Bitter, J. T., Jr.: Spontaneous and induced re-entrant tachycardia, Ann. Intern. Med. 70~87, 1969. Wit, A. L., Weiss, M. B., Berkowitz, W. D., Rosen, K. M., Steiner, C., and Damato, A. N.: Patterns of atrioventricular conduction in the human heart, Circ. Res. 27:345, 1970. Schwartz, S. P., and Schwartz, L. S.: Adam-Stokes syndrome during normal sinus rhythm and transient heart block, AM HEART J. 57:849, 1959. Zoll, P. M., Linenthal, A. J., Gibson, W., Paul, M. H., and Norman, L. R.: Intravenous drug therapy of StokesAdams disease. Effects of sympathomimetic amines on ventricular rhythmicity and atrioventricular conduction, Circulation 17:325, 1958. Schumacher, E. E., and Schmock, C. L.: Control of certain cardiac arrhythmias with isopropylnorepinephrine, AM HEARTJ.~~:~~~, 1954. El-Nahas, M. M., and Johnson, A. M.: Clinical evaluation of oral long-action isoprenaline in treatment of heart block, Br. Med. J. 2:735, 1966.
July,
1975,
Vol.
90, No.
1
effects of isoproterenol system in man
on
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 idioventricular pacemakers. Some controversy exists regarding 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 isoprotereno1 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 Service Hospital, Staten
Laboratory, Island, N. Y.
United
States
Public
This work was supported in part by the Bureau of Medical IJnited States Public Health Service Project Py 74-l and Heart and Lung Institute Project HE 12536-04. Received
for publication
July
Health Services, National
18, 1974.
Reprint requests: Dr. Anthony N. Damato, tory, United States Public Health Setice Y. 10304.
Cardiopulmonary Hospital, Staten
July, 1975. Vol. 90, No. 1, pp. 25-34
LaboraIsland, N.
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 described, 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 reproduced 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-
American
Heart
~Jwrnal
25
Vargas,
Table
Akhtar,
and
Damato
I. Clinical data and A-V conduction during sinus rhythm before and after isoproterenol Sinus cycle length (msec.)
No.
Age
Sex
Diagnosis
65 59 65 81
M M M M
Systemic Systemic ASHD ASHD
5 6 7 8 9 10 11 12
42 52 56 52 39 53 57 61
M M M F M M M M
NHD ASHD ASHD NHD NHD ASHD ASHD ASHD
13 14 15 16
32 62 54 59
M F M M
Systemic Systemic Systemic ASHD
Resting
hypertension hypertension
hypertension hypertension hypertension
ECG
Before
Normal Normal RBBB + LAD RBBB + LAD First-degree A-V block Normal RBBB + LAD Normal Normal Normal RBBB Normal Sinus bradycardia Normal Normal LBBB LBBB
1,060 795 780
940 1,025 940 610 910
900 635 1,200 830
heart
disease;
870 615 720 565
125 112
700 890 665 490 795 570 395 715
118
135
85 75 110
95 75 70 70 95 100
800
850 710 820 530 906 f 165 666 k 136
no heart
disease;
LAD,
left axis deviation
of more
H-V
After
100
120 85 98 f 20
P < 0.001 NHD,
interval (msec.)
Before
630
1,100
P-value: atherosclerotic
After
1,100
Mean:
ASHD,
A-H
interval (msec.)
Before
After
92 102 92 125
52 48 52 so
52 48 52 so
105 58 65 95 so 65 45 60
40 38 40 58 45 40 32 50
40 38 40 58 45 40 32 50
70 70 105 60 80 i 22
60 40 50 80
60 40 50 80
P < 0.001 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 AV 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,
26
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 HV 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
July,
1975,
Vol.
90, No.
1
Electrophysiologic
II. Antegrade refractory
Table
Patient NO.
A trial cycle length
8 9 10
effects of zcynroterrnol
period data A-V node
Atrium ERP
His-Purkinje ERP
FRP Before
After
700 600
310
300
475
375
380
< 300
425
300
290
460
390
< 290
500
270
< 260 < 260
43u 42.5
300 250
470 380
400
600 500
260 260
350 340
260
355
330
600
270
290
345
500 600
270 260
250 240
350 545
345 330
650
270
600 550 700
230 260
240 260
< 260
270
< 290
300
280 260
370 395
375
450
570 445
370 370
500
< 240
330
< 260 < 250
250 250
440
390
380 350
600
290 270
250
360
350
500 450
250 240
230 230
355 445
340 380
600 500
270 250
260 260
415
355 340
700
240
250
550 500
240
250 250
400 430 350
335
< 290 < 270
< 250
400
270
< 250 < 230
365 430
300
230
340 340
< 260 < 260
370
280
385
240 400
< 250 260
330
315 305
< < < <
220 220
< 210 < 230
355 335
230
290
< 230 i 330 < 230
480 465
47,s 455 385 420
230
320
700 600
230 270 270
230 230 230
315 410
13
600
250
220
395 395
350
280
< 220
400
14
500 700
220 270
210 240
385 510
315 410
280 370
< 210 < 240
430 535
600 500
260
220 210
490
350 330
370 400
< 220
530 480
12
All values In patients
(other Nos.
220
than patient number) are in milliseconds. 4. 15. and 16, no refractory period studies
465
were
Results
The essential clinical and electrophysiologic data are presented in Tables I and II. None of the patients were taking any cardioactive medications 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.
Heart
Journal
300 345 320
270
270
325 345 320
525 520 470
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.
American
420
<
220
500 450
3% 356
330 315
365
210
550
220 220
300 250
450 330
11
‘.-----/ A/b I
After
< < <
After
Hefow
Before
335
Before
sytcm
RR?
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
27
Vargas, Akhtar, and Damato
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 Wenckebath 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-
28
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 pa-
tients (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
July, 1975, Vol. 90, No. 1
Electrophysiologic
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 determination 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.); pvalue 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
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
American
Heart
Journal
effects of i.~s~pwtrr~nol
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,ervals).‘ 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 suggested 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 unchanging catheter position is indicated by the constancy of both the H-V interval measurements and the amplitude of the atria1 electrogram recordings. (3) Variations in paper speed can cat&seartifactual changes in all interval measurements, especially when time lines are inscribed t.very 1,000
29
Vargas,
Akhtar,
and
Damato
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.
30
July, 1975, Vol. 90, No. 1
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
Vargas,
Akhtar,
and
Damato
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.
32
July, 1975, Vol. 90, No. 1
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)).
American
Heart
Journal
33
Vargas,
Akhtar,
and
Damato
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 significant 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.
2. 3.
4.
5.
6.
7.
8.
9.
Summary
The effects of isoproterenol (ISOP) on the functional properties of the A-V conduction system were studied in 16 patients using Hisbundle 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 1.
34
Wallace, A. G., and Sarnoff, sympathetic nerve stimulation heart, Circ. Res. 14:86, 1964.
10.
11.
12.
13.
14.
15.
16. S. J.: Effects of cardiac on conduction of the
Alanis, J., Gonzales, H., and Lopez, E.: The electrical activity of the bundle of His, J. Physiol. 142:127, 1958. Nathanson, M. H., and Miller, H.: The action of norepinephrine, epinephrine, and isopropyl-norepinephrine on the rhythmic function of the heart, Circulation 6:238, 1952. Kassebaum, D. G., and Van Dyke, A. R.: Electrophysiological effects of isoproterenol on Purkinje fibers of the heart, Circ. Res. 19:940, 1966. Damato, A. N., Lau, S. H., Helfant, R. H., Stein, E., Berkowitz, W., and Cohen, S. I.: Study of atrioventricular conduction in man using electrode catheter recordings of His bundle activity, Circulation 39:287, 1969. Damato, A. N., Lau, S. H., Helfant, R. H., Stein, E., Paton, R., Scherlag, B. J., and Berkowitz, W. D.: A study of heart block in man using His bundle recordings, Circulation 39:297, 1969. Lister, J. W., Stein, I., Kosowsky, B., Lau, S. H., and Damato, A. N.: Atrioventricular conduction in man. Effect of rate, exercise, isoproterenol, and atropine on the P-R interval, Am. J. Cardiol. 16516, 1965. Dhingra, R. C., Winslow, E., Pouget J., Rahimtoola, S., and Rosen, K. M.: The effect of isoproterenol on atrioventricular and intraventricular conduction, Am. J. Cardiol. 32:629, 1973. Scherlag, B. J., Lau, S. H., Helfant, R. H., Berkowitz, W. D., Stein, I, and Damato, A. N.: Catheter technique for recording His bundle activity in man, Circulation 39:13, 1969. Krayer, O., Mandoki, J. J. and Mendez, C.: Studies on veratrum alkaloids. XVI. The action of enineuhrine and of veratramine on the functional refractory period of the atrioventricular transmission in the heart-lung preparation of the dog, J. Pharmacol. Exp. Ther. 103:412, 1951. Goldreyer, B. N. and Bitter, J. T., Jr.: Spontaneous and induced re-entrant tachycardia, Ann. Intern. Med. 70~87, 1969. Wit, A. L., Weiss, M. B., Berkowitz, W. D., Rosen, K. M., Steiner, C., and Damato, A. N.: Patterns of atrioventricular conduction in the human heart, Circ. Res. 27:345, 1970. Schwartz, S. P., and Schwartz, L. S.: Adam-Stokes syndrome during normal sinus rhythm and transient heart block, AM HEART J. 57:849, 1959. Zoll, P. M., Linenthal, A. J., Gibson, W., Paul, M. H., and Norman, L. R.: Intravenous drug therapy of StokesAdams disease. Effects of sympathomimetic amines on ventricular rhythmicity and atrioventricular conduction, Circulation 17:325, 1958. Schumacher, E. E., and Schmock, C. L.: Control of certain cardiac arrhythmias with isopropylnorepinephrine, AM HEARTJ.~~:~~~, 1954. El-Nahas, M. M., and Johnson, A. M.: Clinical evaluation of oral long-action isoprenaline in treatment of heart block, Br. Med. J. 2:735, 1966.
July,
1975,
Vol.
90, No.
1