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Comparison of right atrial and right ventricular single and paired pacing in the canine heart
Experimental andlaboratoryreports
Comparison single
and
of right paired
atrial pacing
and
right
ventricular
in the canine
heart
David Thomas Kelly, M.B., Ch.B., M.R.A.C.P.’ Cape Town, South Africa
R
ight ventricular (RV) pacing either from an endocardial catheter’ or epicardial electrodes2 are the usual methods of sustained electrostimulation of the heart. When this is used, asynchrony of contraction occurs between atrium and ventricle and normal atria1 transport function is lost. Because of this, atrialtriggered pacemakers have been designed and used.’ The atria1 contribution to ventricular output has been shown to be important in the isolated preparation,* during fast and slow rates experimentally5 and in patients with myocardial decompensation.6 When no disease is present and the cardiovascular system intact, the transport function of the atrium is thought to be unimportant6 but most physiological experiments7v8 suggest that asynchronous pacing lowers stroke volume and external stroke work. Paired pacing is where the heart is repetitively excited by 2 selectively spaced electrical stimuli. The first will cause depolarization and mechanical contraction and the second, occurring after the absolute refractory period, results in a second depolarization but is mechanically ineffective. This is known as postextrasystolic
potentiation (PESP) and is a powerful inotropic stimulus. This phenomenon has been observed in mammalian heart muscle for many years. The history and development has been reviewed by CranefieId.g,lo PESP can only be satisfactorily elicited from the ventricles? as when the 2 stimuli are applied to the atrium the second may be delayed in the A-V node and fail to depolarize the ventricle. Paired pacing does not increase the output and external work of the normal heart, but strikingly improves the hemodynamic parameters in the failing heart. l2 Little data, however, is available on the effect of paired pacing in the normal heart when it is suddenly exposed to a stress which is insufficient to cause decompensation. The purpose of this report is to compare the effects of right atria1 (RA) pacing with single and paired RV pacing and to see if any further hemodynamic differences could be detected during increased afterload. Method Sixteen mongrel dogs weighing between 1.5 and 24 kilograms were studied, Each dog underwent right thoracotomy under
From
the Cardiac Clinic, Department of Medicine, Groote Schuur Hospital and the University of Cape Town, and the Cardiovascular-Pulmonary Research Group supported in the Department of Medicine by the Council for Scientific and Industrial Research. Supported by a grant from the Cardiovascular-Pulmonary Research Group, Council for Scientific and Industrial Research. Received for publication Jan. 26, 1968. *Research Fellow, Cardiovascular-Pulmonary Research Group.
206
American Heart Journal
Fehrnary,
1969
Vol.
77. No.
2, pp. 206-213
vollrmc Number
77 2
Right atrial and right ventricular pacing in dogs
thiopentone anesthesia. The pericardium was opened and alcohol injected into the region of the sinus node which was later crushed and sutured to achieve sinus arrest. Pacemakers were sewn to the superior right atrium and the anterior surface of the right ventricle. The dogs were allowed to recover and between 24 and 48 hours later were anesthetized with 15 mg. per kilogram of pentobarbitone initially and maintained on a constant infusion of approximately 0.05 mg. per kilogram per minute throughout the experiment. All the dogs were intubated and breathed O2 spontaneously through a Manley respirator. Catheters were placed in left ventricle and thoracic aorta for recording pressures via a Statham P23D strain gauge with zero point, 8 cm. above the table top; the first derivative of the left ventricular pressure was recorded via the catheter on a R.C. differentiating circuit. The percentage change of the peak level with different pacing was calculated. These plus the electrocardiograms were recorded photographically on a N.E.P. Honeywell recorder. Cardiac output was measured after an injection of 1.25 mg. of cardiogreen into the right atrium via a catheter and a constant volume syringe (Clay-Adams Aupette) and sampling via a femoral artery using a Waters densitometer X302 with ;I Sanborn computer and constant withdrawal (38.9 cc. per minute) Harvard pump, All blood was reinfused. The densitometer and computer were previously calibrated using the dog’s blood and a preselected dye concentration. At the end of the experiment, a further calibration with the dog’s blood was done to assess if the effect of background dye was important. The heart was paced at 3 milliamperes using a transistorized batterydriven pulse generator capable of delivering single or paired stimuli (Medtronics Inc., Model 583A). Throughout each experiment the rate was constant. In 8 dogs, after 4 minutes of right atria1 single pacing (RASP) dual outputs, left ventricular pressure and its first derivative dp/dt, the left ventricular end-diastolic pressure and aortic pressure were recorded. Single pacing was then commenced from the RV electrode (RVsp) and after 4 minutes the same records were taken.
207
Following this, RAsp was restarted and observations made to ensure that a steady state persisted. The sequence was repeated except that right ventricular paired pacing (RVpp) replaced RVsp. When the 3 types of pacing had been measured in the control state, angiotensin was infused to increase the afterload, and after 8 minutes, when the pressure had increased significantly and was stable, all measurements were again recorded during the types of pacing. In order to ensure that changes in the types of pacing did not alter the circulatory state of the dogs, 8 further animals were similarly studied except that only 2 types of pacing were compared in the same manner (i.e., 4 RAsp to RVsp and 4 RAsp to RVpp before and during angiotensin). In all dogs, single RV pacing was possible without atria1 interference and paired pacing was accomplished with a stimulus interval between 160 and 210 msec. at 5 volts which was usually twice the diastolic threshold. After cessation of paired pacing
Table I. RA and XV single pacing (mean value in 12 dogs) Type of pacing RA RVsp
~kiz$q
%P
100 92
1.7 2.1
144 135
3.1 3.5
Angiotensin RA P
RVsp values
24 21 24 21
( %~~ 32 25 46 38
Table II. RA single and RV paired pacing (mean values in 12 dogs) of pacing
TYPO
RA RVPP
Angiotensin RA
RVPP P value
‘&&.l”““~s~~~~ 94 93 139 140 >o.os
1.9 1.1 2.6 1.6
23 23
27
23 24 >o.os
43 44 >o.os
27
208
Am. Heart 1. Febnwy, 1969
Kelly
ANGIOTENSIN
CONTROL
I8Oi I701605
ANGIOTENSIN
CONTROL
I
I I
RA
RV SINGLE
RA
RV
PACING
Fig. IA. The difference in pressure RV single pacing during control (afterload).
between RA and and angiotensin
RV SINGLE
ANGIOTENSIN
CONTROL
RA
RV
RA PACING
Fig. 1C. The difference in stroke work between RA and RV single pacing during control and angiotensin (afterload).
when KAsp was substituted, the blood pressure dropped and the end-diastolic pressure rose transiently but returned to normal within 2 minutes. As no difference was noted between dogs who had 3 types of pacing and dogs who had only 2, results were pooled giving 12 in each category. From the figures for cardiac output, systemic mean pressure, left ventricular euddiastolic pressure and rate, stroke volume and stroke work were calculated from the following formula: Stroke work (Gm./hI.) SINGLE Fig. 1B. The difference and RV single pacing (afterload).
PACING
in stroke volume between RA during control and angiotensin
=
SV(JI~XJ’I__---
LVED)x 100
1.36
where SV, stroke volume c.c.s.; MAI’, mean aortic pressure mm. Hg; and LVED, left ventricular end-diastolic pressure mm. Hg measured during expiration.
Right atria1 and right ventricular pacing in dogs
CONTROL
r I 5
2101 I 200190180170-
I I I I
Id I ? ISOL%140- I k! 2 Y $
Ix>I to-
.
.
130I I I
ANGIOTENSIN
i T TIA i i T Tf---: T T i i T 5b
60’ RASP
Fig. and
RV PP
ZA. The difference RVpp during control
RASP
ANGIOTENSIN
CONTROL
I
9o-7 80-
209
I
I 70-
s da 60z P y 50& L 40- ‘L. b
WPF
1-: * :A
20
>
in pressure between RAsp and angiotensin infusion.
IO
a
i*
30i
I
RASP
The mean aortic pressure was measured by electrical integration.
4c b-r
&
WPFJ
RASP
Fig. 2B. The difference in stroke RAsp and RVpp during control infusion.
Results
Results for RA to RV single pacing are shown in Table I and for RA to RV paired pacing in Table II. In Fig. lA, where RA pacing is compared to single RV pacing in 12 dogs, the blood pressure decreases slightly with a mean drop of 7.2 mm. Hg (1 to 16 mm. Hg range) and after angiotensin 8.7 mm. Hg (0 to 18 mm. Hg range). Stroke volume (Fig. 1B) is similarly compared and the average decrease is 14 per cent. This is unchanged by angiotensin. Stroke work (Fig. 1 C) shows a further decrease of 35 per cent control and 37 per cent angiotensin. The average rise in LVED pressure with RV single pacing is 0.46 and 0.44 mg. with increased afterload and the percentage decline of dp/dt was 14 and 16 per cent, respectively. Thus in all measured parameters, the RA pacing was superior to RVsp and in terms
WPP
CONTROL
volume between and angiotensin ANGIOTENSIN
l-
3c
r 9! ,,, 2o v) IO’-
RASP
RVPP
Fig. ZC. The difference RAsp and RVpp during infusion.
RASP
RVPP
in stroke work between control and nngiotensin
210
Fig. 3. during a slight paired RA and the LV
Kelly
Left ventricular pressure pulses and dp/dt the types of pacing. RV single pacing shows decline in peak pressure and dp/dt. RV pacing shows enhancement as compared to a small second mechanical event is seen on pulse.
stroke work this is statistically significant. When RA pacing is compared to RVpp before and after angiotensin, no striking differences are seen. Average systemic pressure (Fig. 2A) dropped by 1.3 and 0.5 mm. Hg when after-load was applied. Stroke volume (Fig. 2B) increased by 3 and 6 per cent and stroke work (Fig. 2C) by 5.5 and 8 per cent. All this variation is within the limits of experimental error and is not statistically significant. The first differential of the left ventricular pressure, however, showed a 20 per cent increase with paired pacing and increased to 30 per cent when afterload was present. The end-diastolic pressure declined 1.1 and 1.5 mm. Hg during increased afterload. The types of pacing are illustrated in Fig. 3. of
Discussion
The cardiac output may fluctuate widely in anesthetized dogs.13J4 Pentobarbitone was used as the anesthetic and while this had an anticholinergic action it does not interfere greatly with the sympathetic system.15p16 The dog was lightly anesthetized to
Fig. 4. Showing event to cause seen and after
“natural” rhythm when no electrical the normal P wave in the atrium is atria1 pacing when it reappears.
avoid significant myocardial depression and a slow continuous infusion was used to achieve a steady state. About 1 hour after induction of anesthesia, the output was stable and thus measurements could be commenced. The dogs were allowed time to recover from the operation to prevent further variations in output due to recent thoracotomy. The sinus node was obliterated so that paired and single pacing could be established at the same slower rate, also without electrical stimulation no significant atria1 contraction was seen (Fig. 4). Thus, the atria1 pacemaker when used could control the rate and cause synchronous atria1 mechanical contraction but, when RV pacing was instituted, no significant variation in the left ventricular pressure pulse usually seen in asynchronous pacing could be found. When external stroke work is used as a parameter of myocardial function, the rate must be constant, otherwise, the spontaneous fluctuation in rate found in the anesthetized dog plus bradycardia caused by increased afterload will cause a very significant change in stroke volume due to rate alone and invalidate comparisons which should depend on output changes, Accordingly, the rate was constant throughout the experiment. Angiotensin was used to increase the
Vollcmc
77
A’mnbcu 2
Right atria1 and right ventricalnr pacing in dogs
afterload and provide significant ventricular stress. While this drug has some inotropic action in the papillary muscle preparation” when the cardiovascular system is intact, there is no significant myocardial or venous action.‘8 The drug is short-acting and has no significant tachyphylaxis during an acute experiment.‘” The amount of drug infused varied between 4 to 14 pg per minute depending on the weight and individual response of the dog. The blood pressure was elevated to a single constant level in each experiment between 25 and 70 mm. Hg above control levels. When a normal ventricle is subjected to an increased afterload, the rate slows and output falls, the heart dilates and the end-diastolic pressure rises. If the load is within the range of physiological compensation all these tend to return to normal.20 This decline in LVED pressure with increment of aortic pressure is thought to reflect decreased ventricular size and increased contractility. 21 Recent work suggests, however, that part of this decline may he due to stress relaxation of series viscous components of the ventricle consequent on increased afterload.22 From serial observations, it was found that in 8 minutes a steady state was reached and measurements were taken after this. When RVsp was used, blood pressure and stroke volume declined. As the numerical value of LVED pressure is small in comparison with systemic mean pressure stroke work reflects mainly these 2 parameters. In this preparation during an acute experiment, therefore, stroke work is less and thus the loss of atria1 contraction is a significant factor. Pacemakers applied to different anatomical sites in the ventricle may cause variation in hemodynamic findings. 23 The abnormal depolarization of the right ventricle from an epicardial electrode on the anterior surface may be responsible for a less efficient contraction than that initiated through the normal conducting pathway. This may cause some asynergy of contraction of the left ventricle and may contribute to the lower hemodynamic findings. Using the present experimental technique, however, the contribution of this factor cannot be assessed.
211
In both control aud afterload heart, the difference was of the same order showing that stress within the range of physiological compensation did not further aggravate the differences caused by loss of atria1 contraction. When RA pacing is compared to RVpp, no significant difference is seen. From Fig. 2C, it would appear that paired pacing confers slight benefit during afterload but this is not statistically significant. Other experiments, where afterload is increased sufficiently to cause decompensation, show that paired pacing results in a marked improvement. When a comparison is made between RV paired and single pacing, because the stroke work is the same as RA pacing, paired pacing is hemodynamically better than single pacing. In both types of RV pacing, atria1 contraction is not a contributory factor. The dp/dt is increased and the LVED pressure decreased with paired pacing suggesting that the velocity of contraction plus diastolic compliance or end-diastolic volume has altered. This is a known result of paired pacing.21 The decline in dp/dt seen with RVsp is due to multiple factors, among them a lower systemic pressure, an abnormal ventricular depolarization, plus the loss of atria1 transport function. The inotropic stimulus of I’ESP will only compensate for the loss of atria1 contraction in the normal heart and will not elevate output or pressure above this. Because PESP causes moderate increase in oxygen consumption25 which in turn reflects enhanced velocity of contraction,26 and as external work is not increased, normal rhythm with synchronous atrial contraction will be more efficient even when the sinus node is not destroyed, as in this preparation, because repetitive ventricular stimuli will be conducted retrograde to depolarize the sinus node and interfere with atria1 contraction.27 Paired pacing, while altering the force velocity characteristics of muscle contraction,*j produces no improvement of the heart, as judged by its external work as a pump, when the myocardium is normal or when significant physiological stress, which can normally be compensated for, is present, thus this powerful inotropic stimulus serves no useful purpose. This is also found with the digitalis
212
Am. Eicart J. Frbvztary, 1969
Kelly
glJ.cosides which, apart from the rise in oxygen consumption found with paired pacing, tend to produce similar effects when given in therapeutic dosage. Measurable improvements found in the failing heart with powerful inotropic stimuli cannot be demonstrated in the normal situation. The intricate regulatory systems which maintain pressures and flows at optimal levels in spite of stress such as change in afterload is a homeostatic mechanism” which nullifies the effect of PESP which would otherwise upset the normal hemodynamic balance.
provei~~eiit cardiuni.
iii the
uor~nal
illyo-
I wish to thank Professor V. Schrire and Professor C. N. Barnard for their help and encouragement and Miss E. E. Firth for her technical assistance. I am most grateful for the financial assistance received from the Council for Scientific and Industrial Research. This work was done during the tenureship of a C.S.I.R. Senior Research Officer’s post in the Cardiovascular-Pulmonary Research Group.
1.
Summary Sixteen mongrel dogs were previously prepared by destruction of the sinus node at right thoracotomy to obliterate significant atria1 contraction and pacemakers were implanted to the right atrium and right ventricle. After surgical recovery, the dogs were anesthetized with pentobarbitone. Aortic pressure, left ventricular pressure plus its first derivative were measured. Cardiac output was sequentially determined using a Waters densitometer and Sanborn computer via a femoral artery sampling of indocyanine green injected into the right atrium. Stroke volume and work were calculated during single pacing of the right atrium and right ventricle and during paired pacing of the right ventricle, all at constant rates. The 3 types of pacing were measured at rest and during infusion of angiotensin to increase the afterload. Results show that single RA pacing is hemodynamically superior to single RV pacing in all instances as greater stroke volume and work is achieved, and the difference is due to loss of atria1 contraction. During increased afterload within the limits of physiological compensation no further difference was found. Paired pacing of the right ventricle lowers the LVED pressure and increases dp/dt of the left ventricular pulse but stroke work is the same as seen with RA pacing. The inotropic stimulus of paired pacing compensates for the acute loss of atria1 contraction as seen with RVsp but even with increased afterload no further im-
is detected
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
REFERENCES Harris, A., Bluestone, R., Busby, E., Davies, G., Leatham, A., Siddons, H., and Sowton, E.: The management of heart block, Brit. Heart J. 27:469, 196.5. Chardack, W. M., Gage, A. A., and Greatback, W.: Correction of complete heart block, J. Thoracic & Cardiovas. Surg. 42:814, 1961. Nathan, D. A., Center, S., Samet, P., and WU, C. Y.: The application of an implantable synchronous pacer for the correction of StokesAdams attacks, Ann. New York Acad. SC. 111:1093, 1964. Gilmore, J. P., Sarnoff, S. J., Mitchell, J. H., and Linden, R. J.: Synchronicity of ventricular contraction. Observations comparing haemodynamic effects of atria1 and ventricular pacing, Brit. Heart J. 25:299, 1965. Nakano, J.: Effects of atria1 and ventricular tachycardias on the cardiovascular dynamics, Am. J. F’hysiol. 206:547, 1964. Bechimol, A., Ellis, J. G., and Grey Dimond, E.: Haemodynamic consequences of atrial and ventricular pacing in patients with normal and abnormal hearts, Am. J. Med. 39:911, 1965. Snyder, J., and Wood, E. H.: The effects of heart rate on atrial contribution to cardiac output in dogs with complete heart block, Fed. Proc. 21:137, 1962. Martin, K. H., Cobb, A., Lau, S. H., and Samson, \Xi. I?. : Reduction of cardiac output caused by asynchronous ventricular pacing in man, Circulation 30:122, 1964. Cranefield, P. F.: The force of contraction of extrasystoles and the potentiation of force of the postexirasystolic contractions: a historical review. Bull. New York Acad. Med. 41:419, 1965. Cranefield, P. F.: Paired pulse stimulation and postextrasystolic potentiation, Prog. Cardiovas. Dis. 8:446, 1966. Katz, L. N.: Effects of artificially induced paired and coupled beats, Bull. New York Acad. Med. 41:428, 1965. Goetz, R. H., Jallah, E. M., and Goetz, V. M.: Circulatory dynamics of paired pacing in hypovolemic and cardiogenic shock, AM. HEART J. 73:506, 1967. Howell, E. D., and Horvath, S. M.: The reproducibility of cardiac output measurements in the dog, J. Appl. Physiol. 14:421, 1959. Vogt, D. G., Honusek, G., Schieve, J. F., Hull, H. B., and Saperstein, I,. A.: Spontaneous vnri-
Right
15.
16.
17.
18.
19.
20.
21.
22.
atriczl und right
ability of cardiac output in the dog, Am. J. Physiol. 181:337, 1955: Nash. C. B.. Davis. F.. and Woodburv. R. A.: Cardiovascular effects ‘of anaesthetic *doses of Pentobarbital sodium, Am. J. Physiol. 185:107, 1956. Shabetai, R., Fowler, N. O., and Hurlburt, 0.: Hemodynamic studies of dogs under pentobarbital and morphine chloralase anesthesia, I. Sure. Res. 3:263. 1963. -Koch-Weser, J.: The nature of the inotropic action of angiotensin on the ventricular myocardium, Circulation Res. X6:230, 1966. Fowler, N. O., and Holmes, J. C.: Coronary and myocardial actions of angiotensin, Circulation Res. 14:191, 1964. Olmsted, F., and Page, I. H.: Haemodynamic aspects of prolonged infusion and angiotensin into unanaesthetized dogs, Circulation Res. 16:140, 1965. Goodyear, A. V. N., Goodkind, J., and Landry, A. B.: Ventricular response to a pressure load, Circulation Res. 10:885, 1962. Sarnoff, S. J., Mitchell, J. H., Gilmore, J. P., and Remensnyder, J. P.: Homeometric autoregulation in the heart, Circulation Res. 8:1077, 1960. Sonnenblick, E. H., Ross, J., Covell, J. W., and Braunwald, E.: Alterations in resting length tension relations of cardiac muscle induced by
changes
ventricular
in
contractile
pacing
force,
in dogs
Circulation
213
Res.
19:980, 1966. 23.
24.
25.
26.
27.
Lister, J. W., Klotz, D. H., Jomain, S. L., Stucky, J. H., and Hoffman, B. F.: Effect of pacemaker site on cardiac output and ventricular activation in dogs with complete heart block, Am. J. Cardiol. 14:494, 1964. Bartelstone, H. J., Scherlag, B. J., Hoffman, B. F., and Craneheld, P. F.: Demonstration of variable diastolic compliance associated with paired stimulation of the dog heart, Bull. New York Acad. Med. 41:616, 1965. Ross. f.. Ir.. Sonnenblick. E. H.. Kaiser. G. A.. From&r; P. L., and Braunwaid, E.: Elect& augmentation of ventricular performance and oxygen consumption by repetitive application of paired electrical stimuli. Circulation Kes. 16:332, 1965. Sonnenblick, E. H., Ross, J., Covell, J. W., Kaiser, G. A., and Braunwald, E.: Velocity of contraction as a determinant of myocardial oxygen consumption, Am. J. Physiol. 209:919, 1965. Sarnoff, S. J., Gilmore, J. P., Daggett, \\‘. hl., Mansfield, P. B., McDonald, Ii. H. J., and Weisfeldt, N. L.: Net potassium loss and changes in oxygen and ventricular performance during paired stimulation of the heart, Bull New York Acad. Med. 41:602, 1965.
Comparison single
and
of right paired
atrial pacing
and
right
ventricular
in the canine
heart
David Thomas Kelly, M.B., Ch.B., M.R.A.C.P.’ Cape Town, South Africa
R
ight ventricular (RV) pacing either from an endocardial catheter’ or epicardial electrodes2 are the usual methods of sustained electrostimulation of the heart. When this is used, asynchrony of contraction occurs between atrium and ventricle and normal atria1 transport function is lost. Because of this, atrialtriggered pacemakers have been designed and used.’ The atria1 contribution to ventricular output has been shown to be important in the isolated preparation,* during fast and slow rates experimentally5 and in patients with myocardial decompensation.6 When no disease is present and the cardiovascular system intact, the transport function of the atrium is thought to be unimportant6 but most physiological experiments7v8 suggest that asynchronous pacing lowers stroke volume and external stroke work. Paired pacing is where the heart is repetitively excited by 2 selectively spaced electrical stimuli. The first will cause depolarization and mechanical contraction and the second, occurring after the absolute refractory period, results in a second depolarization but is mechanically ineffective. This is known as postextrasystolic
potentiation (PESP) and is a powerful inotropic stimulus. This phenomenon has been observed in mammalian heart muscle for many years. The history and development has been reviewed by CranefieId.g,lo PESP can only be satisfactorily elicited from the ventricles? as when the 2 stimuli are applied to the atrium the second may be delayed in the A-V node and fail to depolarize the ventricle. Paired pacing does not increase the output and external work of the normal heart, but strikingly improves the hemodynamic parameters in the failing heart. l2 Little data, however, is available on the effect of paired pacing in the normal heart when it is suddenly exposed to a stress which is insufficient to cause decompensation. The purpose of this report is to compare the effects of right atria1 (RA) pacing with single and paired RV pacing and to see if any further hemodynamic differences could be detected during increased afterload. Method Sixteen mongrel dogs weighing between 1.5 and 24 kilograms were studied, Each dog underwent right thoracotomy under
From
the Cardiac Clinic, Department of Medicine, Groote Schuur Hospital and the University of Cape Town, and the Cardiovascular-Pulmonary Research Group supported in the Department of Medicine by the Council for Scientific and Industrial Research. Supported by a grant from the Cardiovascular-Pulmonary Research Group, Council for Scientific and Industrial Research. Received for publication Jan. 26, 1968. *Research Fellow, Cardiovascular-Pulmonary Research Group.
206
American Heart Journal
Fehrnary,
1969
Vol.
77. No.
2, pp. 206-213
vollrmc Number
77 2
Right atrial and right ventricular pacing in dogs
thiopentone anesthesia. The pericardium was opened and alcohol injected into the region of the sinus node which was later crushed and sutured to achieve sinus arrest. Pacemakers were sewn to the superior right atrium and the anterior surface of the right ventricle. The dogs were allowed to recover and between 24 and 48 hours later were anesthetized with 15 mg. per kilogram of pentobarbitone initially and maintained on a constant infusion of approximately 0.05 mg. per kilogram per minute throughout the experiment. All the dogs were intubated and breathed O2 spontaneously through a Manley respirator. Catheters were placed in left ventricle and thoracic aorta for recording pressures via a Statham P23D strain gauge with zero point, 8 cm. above the table top; the first derivative of the left ventricular pressure was recorded via the catheter on a R.C. differentiating circuit. The percentage change of the peak level with different pacing was calculated. These plus the electrocardiograms were recorded photographically on a N.E.P. Honeywell recorder. Cardiac output was measured after an injection of 1.25 mg. of cardiogreen into the right atrium via a catheter and a constant volume syringe (Clay-Adams Aupette) and sampling via a femoral artery using a Waters densitometer X302 with ;I Sanborn computer and constant withdrawal (38.9 cc. per minute) Harvard pump, All blood was reinfused. The densitometer and computer were previously calibrated using the dog’s blood and a preselected dye concentration. At the end of the experiment, a further calibration with the dog’s blood was done to assess if the effect of background dye was important. The heart was paced at 3 milliamperes using a transistorized batterydriven pulse generator capable of delivering single or paired stimuli (Medtronics Inc., Model 583A). Throughout each experiment the rate was constant. In 8 dogs, after 4 minutes of right atria1 single pacing (RASP) dual outputs, left ventricular pressure and its first derivative dp/dt, the left ventricular end-diastolic pressure and aortic pressure were recorded. Single pacing was then commenced from the RV electrode (RVsp) and after 4 minutes the same records were taken.
207
Following this, RAsp was restarted and observations made to ensure that a steady state persisted. The sequence was repeated except that right ventricular paired pacing (RVpp) replaced RVsp. When the 3 types of pacing had been measured in the control state, angiotensin was infused to increase the afterload, and after 8 minutes, when the pressure had increased significantly and was stable, all measurements were again recorded during the types of pacing. In order to ensure that changes in the types of pacing did not alter the circulatory state of the dogs, 8 further animals were similarly studied except that only 2 types of pacing were compared in the same manner (i.e., 4 RAsp to RVsp and 4 RAsp to RVpp before and during angiotensin). In all dogs, single RV pacing was possible without atria1 interference and paired pacing was accomplished with a stimulus interval between 160 and 210 msec. at 5 volts which was usually twice the diastolic threshold. After cessation of paired pacing
Table I. RA and XV single pacing (mean value in 12 dogs) Type of pacing RA RVsp
~kiz$q
%P
100 92
1.7 2.1
144 135
3.1 3.5
Angiotensin RA P
RVsp values
24 21 24 21
( %~~ 32 25 46 38
Table II. RA single and RV paired pacing (mean values in 12 dogs) of pacing
TYPO
RA RVPP
Angiotensin RA
RVPP P value
‘&&.l”““~s~~~~ 94 93 139 140 >o.os
1.9 1.1 2.6 1.6
23 23
27
23 24 >o.os
43 44 >o.os
27
208
Am. Heart 1. Febnwy, 1969
Kelly
ANGIOTENSIN
CONTROL
I8Oi I701605
ANGIOTENSIN
CONTROL
I
I I
RA
RV SINGLE
RA
RV
PACING
Fig. IA. The difference in pressure RV single pacing during control (afterload).
between RA and and angiotensin
RV SINGLE
ANGIOTENSIN
CONTROL
RA
RV
RA PACING
Fig. 1C. The difference in stroke work between RA and RV single pacing during control and angiotensin (afterload).
when KAsp was substituted, the blood pressure dropped and the end-diastolic pressure rose transiently but returned to normal within 2 minutes. As no difference was noted between dogs who had 3 types of pacing and dogs who had only 2, results were pooled giving 12 in each category. From the figures for cardiac output, systemic mean pressure, left ventricular euddiastolic pressure and rate, stroke volume and stroke work were calculated from the following formula: Stroke work (Gm./hI.) SINGLE Fig. 1B. The difference and RV single pacing (afterload).
PACING
in stroke volume between RA during control and angiotensin
=
SV(JI~XJ’I__---
LVED)x 100
1.36
where SV, stroke volume c.c.s.; MAI’, mean aortic pressure mm. Hg; and LVED, left ventricular end-diastolic pressure mm. Hg measured during expiration.
Right atria1 and right ventricular pacing in dogs
CONTROL
r I 5
2101 I 200190180170-
I I I I
Id I ? ISOL%140- I k! 2 Y $
Ix>I to-
.
.
130I I I
ANGIOTENSIN
i T TIA i i T Tf---: T T i i T 5b
60’ RASP
Fig. and
RV PP
ZA. The difference RVpp during control
RASP
ANGIOTENSIN
CONTROL
I
9o-7 80-
209
I
I 70-
s da 60z P y 50& L 40- ‘L. b
WPF
1-: * :A
20
>
in pressure between RAsp and angiotensin infusion.
IO
a
i*
30i
I
RASP
The mean aortic pressure was measured by electrical integration.
4c b-r
&
WPFJ
RASP
Fig. 2B. The difference in stroke RAsp and RVpp during control infusion.
Results
Results for RA to RV single pacing are shown in Table I and for RA to RV paired pacing in Table II. In Fig. lA, where RA pacing is compared to single RV pacing in 12 dogs, the blood pressure decreases slightly with a mean drop of 7.2 mm. Hg (1 to 16 mm. Hg range) and after angiotensin 8.7 mm. Hg (0 to 18 mm. Hg range). Stroke volume (Fig. 1B) is similarly compared and the average decrease is 14 per cent. This is unchanged by angiotensin. Stroke work (Fig. 1 C) shows a further decrease of 35 per cent control and 37 per cent angiotensin. The average rise in LVED pressure with RV single pacing is 0.46 and 0.44 mg. with increased afterload and the percentage decline of dp/dt was 14 and 16 per cent, respectively. Thus in all measured parameters, the RA pacing was superior to RVsp and in terms
WPP
CONTROL
volume between and angiotensin ANGIOTENSIN
l-
3c
r 9! ,,, 2o v) IO’-
RASP
RVPP
Fig. ZC. The difference RAsp and RVpp during infusion.
RASP
RVPP
in stroke work between control and nngiotensin
210
Fig. 3. during a slight paired RA and the LV
Kelly
Left ventricular pressure pulses and dp/dt the types of pacing. RV single pacing shows decline in peak pressure and dp/dt. RV pacing shows enhancement as compared to a small second mechanical event is seen on pulse.
stroke work this is statistically significant. When RA pacing is compared to RVpp before and after angiotensin, no striking differences are seen. Average systemic pressure (Fig. 2A) dropped by 1.3 and 0.5 mm. Hg when after-load was applied. Stroke volume (Fig. 2B) increased by 3 and 6 per cent and stroke work (Fig. 2C) by 5.5 and 8 per cent. All this variation is within the limits of experimental error and is not statistically significant. The first differential of the left ventricular pressure, however, showed a 20 per cent increase with paired pacing and increased to 30 per cent when afterload was present. The end-diastolic pressure declined 1.1 and 1.5 mm. Hg during increased afterload. The types of pacing are illustrated in Fig. 3. of
Discussion
The cardiac output may fluctuate widely in anesthetized dogs.13J4 Pentobarbitone was used as the anesthetic and while this had an anticholinergic action it does not interfere greatly with the sympathetic system.15p16 The dog was lightly anesthetized to
Fig. 4. Showing event to cause seen and after
“natural” rhythm when no electrical the normal P wave in the atrium is atria1 pacing when it reappears.
avoid significant myocardial depression and a slow continuous infusion was used to achieve a steady state. About 1 hour after induction of anesthesia, the output was stable and thus measurements could be commenced. The dogs were allowed time to recover from the operation to prevent further variations in output due to recent thoracotomy. The sinus node was obliterated so that paired and single pacing could be established at the same slower rate, also without electrical stimulation no significant atria1 contraction was seen (Fig. 4). Thus, the atria1 pacemaker when used could control the rate and cause synchronous atria1 mechanical contraction but, when RV pacing was instituted, no significant variation in the left ventricular pressure pulse usually seen in asynchronous pacing could be found. When external stroke work is used as a parameter of myocardial function, the rate must be constant, otherwise, the spontaneous fluctuation in rate found in the anesthetized dog plus bradycardia caused by increased afterload will cause a very significant change in stroke volume due to rate alone and invalidate comparisons which should depend on output changes, Accordingly, the rate was constant throughout the experiment. Angiotensin was used to increase the
Vollcmc
77
A’mnbcu 2
Right atria1 and right ventricalnr pacing in dogs
afterload and provide significant ventricular stress. While this drug has some inotropic action in the papillary muscle preparation” when the cardiovascular system is intact, there is no significant myocardial or venous action.‘8 The drug is short-acting and has no significant tachyphylaxis during an acute experiment.‘” The amount of drug infused varied between 4 to 14 pg per minute depending on the weight and individual response of the dog. The blood pressure was elevated to a single constant level in each experiment between 25 and 70 mm. Hg above control levels. When a normal ventricle is subjected to an increased afterload, the rate slows and output falls, the heart dilates and the end-diastolic pressure rises. If the load is within the range of physiological compensation all these tend to return to normal.20 This decline in LVED pressure with increment of aortic pressure is thought to reflect decreased ventricular size and increased contractility. 21 Recent work suggests, however, that part of this decline may he due to stress relaxation of series viscous components of the ventricle consequent on increased afterload.22 From serial observations, it was found that in 8 minutes a steady state was reached and measurements were taken after this. When RVsp was used, blood pressure and stroke volume declined. As the numerical value of LVED pressure is small in comparison with systemic mean pressure stroke work reflects mainly these 2 parameters. In this preparation during an acute experiment, therefore, stroke work is less and thus the loss of atria1 contraction is a significant factor. Pacemakers applied to different anatomical sites in the ventricle may cause variation in hemodynamic findings. 23 The abnormal depolarization of the right ventricle from an epicardial electrode on the anterior surface may be responsible for a less efficient contraction than that initiated through the normal conducting pathway. This may cause some asynergy of contraction of the left ventricle and may contribute to the lower hemodynamic findings. Using the present experimental technique, however, the contribution of this factor cannot be assessed.
211
In both control aud afterload heart, the difference was of the same order showing that stress within the range of physiological compensation did not further aggravate the differences caused by loss of atria1 contraction. When RA pacing is compared to RVpp, no significant difference is seen. From Fig. 2C, it would appear that paired pacing confers slight benefit during afterload but this is not statistically significant. Other experiments, where afterload is increased sufficiently to cause decompensation, show that paired pacing results in a marked improvement. When a comparison is made between RV paired and single pacing, because the stroke work is the same as RA pacing, paired pacing is hemodynamically better than single pacing. In both types of RV pacing, atria1 contraction is not a contributory factor. The dp/dt is increased and the LVED pressure decreased with paired pacing suggesting that the velocity of contraction plus diastolic compliance or end-diastolic volume has altered. This is a known result of paired pacing.21 The decline in dp/dt seen with RVsp is due to multiple factors, among them a lower systemic pressure, an abnormal ventricular depolarization, plus the loss of atria1 transport function. The inotropic stimulus of I’ESP will only compensate for the loss of atria1 contraction in the normal heart and will not elevate output or pressure above this. Because PESP causes moderate increase in oxygen consumption25 which in turn reflects enhanced velocity of contraction,26 and as external work is not increased, normal rhythm with synchronous atrial contraction will be more efficient even when the sinus node is not destroyed, as in this preparation, because repetitive ventricular stimuli will be conducted retrograde to depolarize the sinus node and interfere with atria1 contraction.27 Paired pacing, while altering the force velocity characteristics of muscle contraction,*j produces no improvement of the heart, as judged by its external work as a pump, when the myocardium is normal or when significant physiological stress, which can normally be compensated for, is present, thus this powerful inotropic stimulus serves no useful purpose. This is also found with the digitalis
212
Am. Eicart J. Frbvztary, 1969
Kelly
glJ.cosides which, apart from the rise in oxygen consumption found with paired pacing, tend to produce similar effects when given in therapeutic dosage. Measurable improvements found in the failing heart with powerful inotropic stimuli cannot be demonstrated in the normal situation. The intricate regulatory systems which maintain pressures and flows at optimal levels in spite of stress such as change in afterload is a homeostatic mechanism” which nullifies the effect of PESP which would otherwise upset the normal hemodynamic balance.
provei~~eiit cardiuni.
iii the
uor~nal
illyo-
I wish to thank Professor V. Schrire and Professor C. N. Barnard for their help and encouragement and Miss E. E. Firth for her technical assistance. I am most grateful for the financial assistance received from the Council for Scientific and Industrial Research. This work was done during the tenureship of a C.S.I.R. Senior Research Officer’s post in the Cardiovascular-Pulmonary Research Group.
1.
Summary Sixteen mongrel dogs were previously prepared by destruction of the sinus node at right thoracotomy to obliterate significant atria1 contraction and pacemakers were implanted to the right atrium and right ventricle. After surgical recovery, the dogs were anesthetized with pentobarbitone. Aortic pressure, left ventricular pressure plus its first derivative were measured. Cardiac output was sequentially determined using a Waters densitometer and Sanborn computer via a femoral artery sampling of indocyanine green injected into the right atrium. Stroke volume and work were calculated during single pacing of the right atrium and right ventricle and during paired pacing of the right ventricle, all at constant rates. The 3 types of pacing were measured at rest and during infusion of angiotensin to increase the afterload. Results show that single RA pacing is hemodynamically superior to single RV pacing in all instances as greater stroke volume and work is achieved, and the difference is due to loss of atria1 contraction. During increased afterload within the limits of physiological compensation no further difference was found. Paired pacing of the right ventricle lowers the LVED pressure and increases dp/dt of the left ventricular pulse but stroke work is the same as seen with RA pacing. The inotropic stimulus of paired pacing compensates for the acute loss of atria1 contraction as seen with RVsp but even with increased afterload no further im-
is detected
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REFERENCES Harris, A., Bluestone, R., Busby, E., Davies, G., Leatham, A., Siddons, H., and Sowton, E.: The management of heart block, Brit. Heart J. 27:469, 196.5. Chardack, W. M., Gage, A. A., and Greatback, W.: Correction of complete heart block, J. Thoracic & Cardiovas. Surg. 42:814, 1961. Nathan, D. A., Center, S., Samet, P., and WU, C. Y.: The application of an implantable synchronous pacer for the correction of StokesAdams attacks, Ann. New York Acad. SC. 111:1093, 1964. Gilmore, J. P., Sarnoff, S. J., Mitchell, J. H., and Linden, R. J.: Synchronicity of ventricular contraction. Observations comparing haemodynamic effects of atria1 and ventricular pacing, Brit. Heart J. 25:299, 1965. Nakano, J.: Effects of atria1 and ventricular tachycardias on the cardiovascular dynamics, Am. J. F’hysiol. 206:547, 1964. Bechimol, A., Ellis, J. G., and Grey Dimond, E.: Haemodynamic consequences of atrial and ventricular pacing in patients with normal and abnormal hearts, Am. J. Med. 39:911, 1965. Snyder, J., and Wood, E. H.: The effects of heart rate on atrial contribution to cardiac output in dogs with complete heart block, Fed. Proc. 21:137, 1962. Martin, K. H., Cobb, A., Lau, S. H., and Samson, \Xi. I?. : Reduction of cardiac output caused by asynchronous ventricular pacing in man, Circulation 30:122, 1964. Cranefield, P. F.: The force of contraction of extrasystoles and the potentiation of force of the postexirasystolic contractions: a historical review. Bull. New York Acad. Med. 41:419, 1965. Cranefield, P. F.: Paired pulse stimulation and postextrasystolic potentiation, Prog. Cardiovas. Dis. 8:446, 1966. Katz, L. N.: Effects of artificially induced paired and coupled beats, Bull. New York Acad. Med. 41:428, 1965. Goetz, R. H., Jallah, E. M., and Goetz, V. M.: Circulatory dynamics of paired pacing in hypovolemic and cardiogenic shock, AM. HEART J. 73:506, 1967. Howell, E. D., and Horvath, S. M.: The reproducibility of cardiac output measurements in the dog, J. Appl. Physiol. 14:421, 1959. Vogt, D. G., Honusek, G., Schieve, J. F., Hull, H. B., and Saperstein, I,. A.: Spontaneous vnri-
Right
15.
16.
17.
18.
19.
20.
21.
22.
atriczl und right
ability of cardiac output in the dog, Am. J. Physiol. 181:337, 1955: Nash. C. B.. Davis. F.. and Woodburv. R. A.: Cardiovascular effects ‘of anaesthetic *doses of Pentobarbital sodium, Am. J. Physiol. 185:107, 1956. Shabetai, R., Fowler, N. O., and Hurlburt, 0.: Hemodynamic studies of dogs under pentobarbital and morphine chloralase anesthesia, I. Sure. Res. 3:263. 1963. -Koch-Weser, J.: The nature of the inotropic action of angiotensin on the ventricular myocardium, Circulation Res. X6:230, 1966. Fowler, N. O., and Holmes, J. C.: Coronary and myocardial actions of angiotensin, Circulation Res. 14:191, 1964. Olmsted, F., and Page, I. H.: Haemodynamic aspects of prolonged infusion and angiotensin into unanaesthetized dogs, Circulation Res. 16:140, 1965. Goodyear, A. V. N., Goodkind, J., and Landry, A. B.: Ventricular response to a pressure load, Circulation Res. 10:885, 1962. Sarnoff, S. J., Mitchell, J. H., Gilmore, J. P., and Remensnyder, J. P.: Homeometric autoregulation in the heart, Circulation Res. 8:1077, 1960. Sonnenblick, E. H., Ross, J., Covell, J. W., and Braunwald, E.: Alterations in resting length tension relations of cardiac muscle induced by
changes
ventricular
in
contractile
pacing
force,
in dogs
Circulation
213
Res.
19:980, 1966. 23.
24.
25.
26.
27.
Lister, J. W., Klotz, D. H., Jomain, S. L., Stucky, J. H., and Hoffman, B. F.: Effect of pacemaker site on cardiac output and ventricular activation in dogs with complete heart block, Am. J. Cardiol. 14:494, 1964. Bartelstone, H. J., Scherlag, B. J., Hoffman, B. F., and Craneheld, P. F.: Demonstration of variable diastolic compliance associated with paired stimulation of the dog heart, Bull. New York Acad. Med. 41:616, 1965. Ross. f.. Ir.. Sonnenblick. E. H.. Kaiser. G. A.. From&r; P. L., and Braunwaid, E.: Elect& augmentation of ventricular performance and oxygen consumption by repetitive application of paired electrical stimuli. Circulation Kes. 16:332, 1965. Sonnenblick, E. H., Ross, J., Covell, J. W., Kaiser, G. A., and Braunwald, E.: Velocity of contraction as a determinant of myocardial oxygen consumption, Am. J. Physiol. 209:919, 1965. Sarnoff, S. J., Gilmore, J. P., Daggett, \\‘. hl., Mansfield, P. B., McDonald, Ii. H. J., and Weisfeldt, N. L.: Net potassium loss and changes in oxygen and ventricular performance during paired stimulation of the heart, Bull New York Acad. Med. 41:602, 1965.