Download Regulation of Cardiac Output by Stroke Volume and Heart Rate in

CONTROL OF CARDIAC OUTPUT/Vatner and Boettcher
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Hauge A, Bo G, Waaler BA: Interrelations between pulmonary liquid
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Regulation of Cardiac Output by Stroke Volume
and Heart Rate in Conscious Dogs
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STEPHEN F. VATNER AND DEDO H. BOETTCHER
SUMMARY We examined the relative importance of increases in stroke volume and heart rate in mediating
increases in cardiac output in response to elevations in preload, inotropic state, or a combination of these factors in
15 conscious dogs with love, physiological heart rates. Elevating preload by volume loading with saline increased left
atrial pressure by 15 mm Hg, cardiac output by 147 ± 7% from a control of 2340 ± 80 ml/min, and heart rate by 143
± 7% from a control of 62 ± 2 beats/min, but did not alter stroke volume. Similarly, volume loading with blood
increased cardiac output by 100 ± 5% and heart rate by 108 ± 10%, while stroke volume did not change
significantly. Hemorrhage in conscious dogs reduced cardiac output by 49 ± 4% and stroke volume by 75 ± 2%
while increasing heart rate by 113 ± 15%. In dogs anesthetized with pentobarbital Na, and with an open chest,
volume loading increased stroke volume by 243 ± 89% but did not alter heart rate. In conscious dogs, isoproterenol
increased cardiac output solely by increasing heart rate, failing to increase stroke volume, whereas dobutamine, a
sympathomimetic amine with less positive chronotropic action than isoproterenol, raised stroke volume by
approximately 25%. Infusion of both sympathomimetic amines in the volume-loaded state increased stroke volume
by a slightly greater amount than either volume loading or sympathomimetic amine infusion by itself. Severe exercise
also increased stroke volume by 27 ± 2%, whereas cardiac output rose by 402 ± 24%. Thus, in the conscious dog
with a low physiological heart rate, stroke volume is relatively large at rest and does not increase at all, even with
maximally tolerable volume loading, and only modest increases were observed with exercise or combined
sympathomimetic amine infusion and volume loading.
WHEREAS IT IS OBVIOUS that the cardiac pump can
increase its output only through a change in frequency or
a change in stroke volume, the relative importance of
these two factors in mediating changes in preload remains
controversial despite intense investigation of this subject
during the past century. Starling's pioneering work on the
heart-lung preparation established a dominant role for
stroke volume in mediating changes in cardiac output.'
From the Departments of Medicine, Harvard Medical School and Peter
Bent Brigham Hospital, and Department of Cardiology, Childrens Hospital Medical Center, Boston, Massachusetts, and the New England Regional
Primate Research Center, Southboro, Massachusetts.
Supported in part by U.S. Public Health Service Grants HL 15416.
17459, HL 10436, AHA 73-833, and NSG 2136.
Dr. Vatner is an Established Investigator of the American Heart
Association. Dr. Boettcher was an International Research Fellow of the
U.S. Public Health Service.
Presented in part at the Meeting of Federation of American Societies
for Experimental Biology, Atlantic City. New Jersey, April, 1975.
Address for reprints: Stephen F. Vatner, M.D., New England Regional
Primate Research Center, One Pine Hill Drive, Southboro, Massachusetts
01772.
Original manuscript received June 10, 1976; accepted for publication
December 13, 1977.
Rushmer, using a normal conscious animal model,2"'
challenged the views of Starling and concluded that stroke
volume remained roughly constant, particularly when
cardiac output rose during exercise.2 However, Rushmer
and colleagues did not examine the effects on stroke
volume of elevating preload by volume loading, a case in
which a large rise in stroke volume might be predicted.
The goal of this study was to determine the extent to
which stroke volume changed in response to marked
alterations in preload, starting from the basal state, i.e., a
reclining conscious dog with a physiological heart rate. It
was considered essential to study animals with low, physiological heart rates, since the importance of changes in
stroke volume tend to be overemphasized when the baseline heart rate is elevated, as occurs in excited animals, or
during general anesthesia. To examine responses to
marked changes in preload, trained dogs instrumented
with electromagnetic flow probes on the aorta were studied when cardiac output was elevated by increasing preload to the maximum tolerated by the conscious dogs and
when cardiac output was reduced by diminishing preload.
CIRCULATION RESEARCH
558
To ascertain maximal increases in stroke volume, two
cardioactive sympathomimetic amines, isoproterenol, a
j8-adrenergic agent with positive inotropic and chronotropic properties and dobutamine, an inotropic agent with
a relatively weak positive chronotropic effect,'1 were infused in the presence of elevated preload. Finally, we
examined a physiological situation, in which both preload
and the inotropic state rise, i.e., maximal exercise. By
studying these interventions, we obtained a comprehensive picture of the regulation of cardiac output and stroke
volume under conditions of altered preload and inotropic
state in the normal, conscious dog.
Methods
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Twenty four mongrel dogs weighing 18-25 kg were
anesthetized with pentobarbital, Na, 30 mg/kg, iv.
Through a left thoracotomy in the 4th intercostal space,
an electromagnetic flow probe (Zepeda Instruments) was
implanted around the ascending aorta, and heparin-filled
Tygon catheters were implanted in the aorta and the left
atrium.
Arterial and atrial pressures were measured with the
catheters and Statham P23Db strain gauge manometers
(Statham Instruments). A square wave electromagnetic
flowmeter (Benton Instruments) was used to measure
cardiac output and stroke volume. A modification of the
Benton miniature electromagnetic flowmeter was used to
measure and radiotelemeter stroke volume and cardiac
output during severe exercise. Flow probes were calibrated in vitro with a gravity flow system and crosscalibrated in vivo by using the radioactive microsphere
technique to measure cardiac output.
The experiments were conducted 2-6 weeks postoperatively when the dogs had recovered from operation and
were fully accustomed to the laboratory and personnel.
Control records of cardiac output, heart rate, and arterial
and atrial pressures were obtained while the unsedated
dogs were lying quietly and during the various interventions. Experiments were discarded if the dogs showed
signs of arousal or excitement or if baseline heart rate was
VOL. 42, No. 4, APRIL
25% greater than that obtained prior to operation. Baseline heart rate prior to operation was 60 ± 3 beats/min.
After control recordings, 1.2 ± 0.2 liters of normal saline,
warmed to 37°C, were infused over 5-10 minutes to raise
left atrial pressure by 15 mm Hg. Data were averaged
over 10 to 15-second periods, which included several
respiratory cycles, for each 5 mm Hg increment in left
atrial pressure. This was important, because many of the
conscious dogs exhibited marked sinus arrhythmia. When
left atrial pressure rose by more than 15 mm Hg, some
dogs became restless and excited. Thus, the amount of
saline infusion used in this study can be considered the
maximum tolerated by the resting, conscious dog. When
left atrial pressure rose by 15 mm Hg, isoproterenol, 0.4
/ug/kg per min, was infused for 5 minutes. This protocol
was repeated several days later, substituting dobutamine
(20 jiig/kg per min) for isoproterenol. On separate days,
the inotropic agents were infused in the absence of volume
loading. The effects of volume loading also were studied
in four of the dogs with open chests after implantation of
the electromagnetic flow probe. In these experiments,
saline was infused at a rate similar to that used for the
conscious dogs. In six other conscious dogs, volume
loading was performed by infusing blood, maintained at
37°, over 5-10 minutes until 30 ml/kg had been infused
and left atrial pressure increased by 15 mm Hg. In these
dogs, on a different day, as well as in 10 other conscious
dogs, volume depletion was studied by withdrawing blood
at a rate of 0.5 ml/kg per min for 1 hour, until 30 ml of
blood per kg had been withdrawn. Finally, the effects of
severe exercise were examined with radiotelemetry of
aortic blood flow from the unrestrained conscious dogs
running spontaneously in the field at speeds of up to 25
mph behind a mobile recording unit.
Data were recorded on a multichannel tape recorder
and played back on a direct-writing oscillograph. A cardiotachometer, triggered by the signal from the pressure
pulse, provided instantaneous and continuous records of
heart rate. Mean arterial pressure and cardiac output were
obtained by electronic resistance-capacitance filters with
TABLE 1 Comparison of the Effects of Volume Loading in Conscious and Anesthetized
Dogs
Control
1978
+5
+ 10
+ 15
Cardiac output (ml/min)
Conscious (n = 1)
Anesthetized (n = 4)
2340 ± 80
2130 ± 170
3720 ± 150*
3450 ± 65*
4630 ± 180*
5050 ± 230*
5760 ±210*
6400 ± 73*
Heart rate (beats/min)
Conscious (n = 7)
Anesthetized (n = 4)
62 ± 2
163 ± 14
100 ± 4*
146 ± 13t
125 ± 5*
149 ± 13t
155 ± 6*
157 ± 13t
Stroke volume (ml)
Conscious (n = 1)
Anesthetized (n = 4)
37 ± 2
13 ± 2
38 ± 2
24 ± 2*t
37 ± 2
36 ± 5*t
38 ± 2
43 ± 9*t
Mean arterial pressure (mm Hg)
Conscious (n = 7)
Anesthetized (n = 4)
84 ± 6
77 ± 6
122 ± 8*
115 ± 14*
129 ± 5*
113 ± 14*
101 ± 8*
95 ± 8*
* Significantly different from control, P < 0.01.
t Anesthetized response significantly different from conscious, P < 0.01.
CONTROL OF CARDIAC OVTPVTIVatner and Boettcher
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FIGURE 1 Effects of volume loading in a conscious dog are shown
on responses of phasic and mean aortic blood flow (cardiac output), heart rate, calculated stroke volume, and mean arterial and
left atrial pressures. In the conscious dog, volume loading increased cardiac output and heart rate but not stroke volume.
2-second time constants. Stroke volume was calculated as
the quotient of cardiac output and heart rate and confirmed by means of an electronic integrator. Responses
were compared to control by paired Mest.5 Values are
reported as averages ± SEM.
Results
1. Effects of Volume Loading (Table 1)
In the conscious dogs, saline infusion elevated left atrial
pressure by 15 mm Hg, cardiac output from 2340 ± 80 to
559
5760 ±210 ml/min (147 ± 7%), heart rate from 62 ± 2
to 155 ± 6 beats/min (143 ± 7%), and mean arterial
pressure from 84 ± 6 to 129 ± 5 mm Hg, but failed to
alter stroke volume from a control of 37 ± 2 ml (Fig. 1).
Whereas stroke volume remained constant, there was a
graded increase in heart rate in response to graded increases in left atrial pressure and volume loading (Table
1). When blood was infused into six other conscious dogs,
cardiac output rose from 2460 ± 160 to 4900 ± 240 ml/
min (100 ± 5%), heart rate rose from 66 ± 5 to 133 ± 6
beats/min (108 ± 10%), and stroke volume fell, but not
significantly, from a control of 38 ± 2 ml (Fig. 2).
In four anesthetized dogs with the chest open, when
atrial pressure was elevated by an amount equivalent to
that induced in the conscious state, cardiac output rose
from 2130 ± 170 to 6400 + 730 ml/min (208 ± 47%). In
contrast to the results for conscious animals, the increases
in cardiac output were mediated entirely by increases in
stroke volume, which increased from 13 ± 2 to 43 ± 9 ml
(243 ± 89%), while heart rate did not change significantly
(Table 1; Fig. 3).
2. Effects of Inotropic Interventions
Isoproterenol infusion without prior volume loading
increased cardiac output by 102 ± 5% from a control of
2500 ± 230 ml/min and heart rate by 173 ± 16% from a
control of 72 ± 5 beats/min; it reduced mean arterial
pressure by 25 ± 2% from a control of 86 ± 8 mm Hg,
stroke volume by 25 ± 3% from a control of 35 ± 3 ml
(Fig. 4), and mean left atrial pressure by 4 ± 1 mm Hg.
36
AORTIC
FLOW
(L/min)
SALINE INRISION
0
10
CARDIAC
OUTPUT
(L/min)
20C
HEART
RATE
(beats/min)
0100
STROKE
VOLUME
(ml)
0200-
MEAN
ARTERIAL
PRESSURE
(mmHg)
MEAN
ATRIAL
PRESSURE
(mmHg)
FIGURE 2 Effects of volume loading with blood (right of center)
are compared with volume depletion (left of center) on responses
of cardiac output (circles and solid lines), heart rate (triangles and
dotted lines), and stroke volume (squares and dashed lines). Heart
rate rose almost equally with volume loading and depletion. In
contrast, stroke volume fell strikingly with hemorrhage and remained essentially constant with infusion of blood.
025-
0-
FIGURE 3 Effects of volume loading in an anesthetized, openchest dog are shown on responses of aortic flow, cardiac output,
heart rate, calculated stroke volume, and mean arterial and left
atrial pressures. In contrast to the response in Figure I, in the
anesthetized open-chest dog, volume loading increased cardiac
output and stroke volume but not heart rate.
CIRCULATION RESEARCH
560
-r
FROM
CONTROL
-Wt-
CARDIAC
OUTPUT
HEART
RATE
•
[S3
O
•
SALINE
BLOOD
HEMORRHAGE
ISOPROTERENOL
^
ISOPROTERENOL & S A L M
•
EXERCISE
STROKE
VOLUME
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FIGURE 4 Comparison of the effects of volume loading with
saline (solid bars) and with blood (lined bars), volume depletion
by hemorrhage (checked bars), isoproterenol infusion (stippled
bars), isoproterenol plus volume loading (cross-hatched bars), and
exercise (clear bars) on cardiac output, heart rate, and stroke
volume. Note that only isoproterenol plus volume loading or
exercise increased stroke volume, and in both cases by approximately 25%.
Dobutamine infusion without prior volume loading increased cardiac output by 101 ± 7% from a control of
2270 ± 200 ml/min, heart rate by 61 ± 3 % from a control
of 66 ± 2 beats/min, mean arterial pressure by 13 ± 6%
from a control of 86 ± 5 mm Hg, and stroke volume by
25 ± 3% from a control of 36 ± 4 ml; it did not affect left
atrial pressure significantly.
3. Effects of Combined Volume Loading and Inotropic
Stimulation (Fig. 4)
The superimposition of isoproterenol infusion in the
volume-loaded state increased (from control) cardiac output by 355 ± 27%, heart rate by 191 ± 19%, mean
arterial pressure by 61 ± 8 % , and stroke volume by 42 ±
2%, while left atrial pressure rose by an identical amount,
15 ± 1 mm Hg, as occurred with volume loading above.
4. Effects of Severe Exercise (Fig. 4)
From reclining control values equivalent to those reported above under sections 1 and 2, exercise increased
cardiac output by 402 ± 24%, heart rate by 312 ± 16%,
and stroke volume by 27 ± 2%. A prior study from this
laboratory has shown that increases in stroke volume are
greater and increases in heart rate are less during exercise
when control values are taken in the standing, as opposed
to reclining, position.6
5. Effects of Volume Depletion (Fig. 2)
After a hemorrhage of 30 ml/kg in 16 conscious dogs,
there was a progressive fall in cardiac output from 2420
± 90 ml/min to 1180 ± 90 ml/min (-49 ± 4%) and in
stroke volume from 37 ± 2 to 8 ± 1 ml (-75 ± 2%),
while heart rate rose from 70 ± 3 to 144 ± 8 beats/min
(113 ± 15%).
Discussion
It is generally held that "an increased flow of blood
from the veins into the heart automatically forces an
VOL. 42, No. 4, APRIL
1978
equivalent increase in cardiac output by distending the
ventricle and increasing stroke volume."7 Indeed, in the
present study, in dogs anesthetized and with an open
chest, the increased cardiac output observed with volume
loading occurred entirely through increases in stroke
volume (Fig. 3). This is consistent with findings of other
investigators who used a similar preparaton.'- 8 " It would
not have been surprising to find that volume loading
increased cardiac output in the conscious dog as a result of
increased in both heart rate and stroke volume, as has
been observed previously.l0~12 However, we did not expect
to find, in the conscious dog, that the maximum tolerable
saline infusion did not result in any significant increase in
stroke volume (Table 1); the rise in cardiac output was
mediated entirely by tachycardia, which presumably was
due to the Bainbridge reflex.l3~15
It is of interest that, while stroke volume remained
constant, graded increases in volume loading and left
atrial pressure induced graded reflex increases in heart
rate in the conscious dog. It is important to point out that
the reflex effects of volume loading are complex and are
not due simply to effects on atrial stretch; they include
activation of baroreceptor afferents15 and also may involve
chemoreceptor afferents due to reductions in hematocrit
induced by the saline infusion. However, similar results
were observed with infusion of blood (Fig. 2), which
indicates that chemoreceptor afferents stimulated by hemodilution with saline did not significantly modify the
stroke volume response, i.e., stroke volume remained
constant in the conscious dog despite a massive increase in
preload.
The finding that stroke volume remains constant under
these conditions differs from those of previous studies in
this field,8"12 including those conducted in conscious
dogs.10"12 Since afterload rose with volume loading, it is
possible that this was responsible, in part, for preventing
a rise in stroke volume. However, this aspect of the
response to volume loading was not unique to the present
experiments in conscious dogs (Table 1) and. thus, cannot
reconcile the differences between the results in this study
in conscious and anesthetized dogs, or the differences
between the results in the present and prior studies.""12 It
is more likely that the differences can be reconciled on the
basis of differences in baseline heart rate. In the present
study, particular attention was paid to studying trained
dogs with physiologically low heart rates, whereas previous studies on anesthetized preparations8' " or conscious
dogs,10"12 all were conducted on animals with higher than
normal heart rates. The average resting cardiac rate in the
present study in conscious, instrumented dogs was 62 ± 2
beats/min, and this value is close to that of the resting
normal dog without prior operation and instrumentation.
Under these conditions, i.e., reclining conscious dogs with
normal spontaneous rhythm and low physiological heart
rates, stroke volume is relatively large at rest and cannot
be elevated further by maximally tolerable volume loading. In another study from our laboratory"' it was observed
that this amount of volume loading resulted in only a
slight increase in end-diastolic ventricular dimensions,1"
indicating that end-diastolic cardiac size is near maximal
in the reclining conscious dog with a physiological heart
CONTROL OF CARDIAC OUTPUT'/Vatner and Boettcher
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rate. Cowley and Guyton" also observed the importance
of cardiac rate in achieving an increase in cardiac output
when venous return was elevated by opening an arteriovenous fistula. Although the dogs in that study were
anesthetized, their initial heart rates were low, due to
surgically induced heart block.17
The experiments with hemorrhage indicate the extent
to which stroke volume can be reduced in the conscious
dog when preload is reduced. The magnitude of the
reduction in stroke volume with hemorrhage further illustrates the relatively large baseline stroke volume in the
resting, conscious, reclining animal (Fig. 2). To a great
extent, the reduction in stroke volume is due to the reflex
tachcardia induced by hemorrhage. It is of interest that
similar amounts of volume depletion and loading (30 ml/
kg) induced comparable increases in cardiac rate (Fig. 2).
Elevating the inotropic state by infusing isoproterenol
also failed to elevate stroke volume in the present study.
However, dobutamine, a sympathomimetic amine with a
less positive chronotropic effect than isoproterenol, elevated stroke volume slightly, by approximately 25%.
Thus, stroke volume can be increased slightly by administration of a positive inotropic agent, even when baseline
heart rate is low.
To achieve a greater effect on stroke volume, myocardial contractility was stimulated by isoproterenol and
dobutamine infusions after volume loading. Even under
these extreme circumstances, stroke volume rose only by
26% with isoproterenol and by 42% with dobutamine.
This response approximated that observed during maximal
exercise in dogs running at speeds over 20 mph in the
field, when stroke volume rose by 27%. However, a
greater increase in stroke volume is observed when the
maximal response during exercise is compared to a control
value in the upright posture rather than in the reclining
state,6 since stroke volume falls and heart rate rises upon
assuming the upright posture.
These findings indicate that in the normal, conscious,
reclining dog with all control mechanisms intact, reduction
of cardiac output by volume depletion is mediated entirely
by a reduction in stroke volume, but augmentation of
cardiac output in response to an elevation in preload is
not mediated by increases in stroke volume, as long as
heart rate can increase, because stroke volume is relatively
large at rest. However, when an increase in preload is
561
combined with inotropic stimulation, as occurs during
exercise, there is a modest increase in stroke volume. In
contrast, in the aroused or anesthetized dog, stroke volume is diminished under baseline conditions and then can
increase in response to a variety of stimuli, even with a
simple increase in preload. Thus, the baseline values for
heart rate and stroke volume prior to experimentation, as
well as the strikingly different responses of the conscious
and anesthetized, open-chest animal to volume loading,
must be considered in the interpretation of data from
experiments designed to assess the effects of interventions
on stroke volume and heart rate.
References
1. Starling EH: The Linacre lecture on the law of the heart. Given at
Cambridge, 1915. London, Longmans, Green, 1918
2. Rushmer RF: Constancy of stroke volume in ventricular responses to
exertion. Am J Physiol 196: 745-750, 1959
3. Rushmer SF, Smith O, Franklin D: Mechanisms of cardiac control in
exercise. Circ Res 7: 602-627, 1959
4. Vatner SF, McRitchie RJ, Braunwald E: Effects of dobutamine on
left ventricular performance, coronary dynamics and distribution of
cardiac output in conscious dogs. J Clin Invest 53: 1265-1273, 1974
5. Snedecor GW, Cochran, WG: Statistical Methods. Ames, Iowa, Iowa
State University Press, ed 6. pp 1967, 91-98
6. Vatner SF, Franklin D, Higgins CB, Patrick T, Braunwald E: Left
ventricular response to severe exertion in untethered dogs. J Clin
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7. Vander AJ, Sherman JH, Luciano DS: Human Physiology. The
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9. Weber KT, Janicki JS, Reeves RC, Hefner LT, Reeves, TJ: Determinants of stroke volume in the isolated canine heart. J Appl Physiol
37: 742-747, 1974
10. Bishop VS, Stone HL, Horwitz LD: Effects of tachycardia and
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Physiol 220: 436-439, 1971
11. Bishop VS, Stone HL, Guyton AC: Cardiac function curves in
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1976
13. Bainbridge FA: Influence of venous filling upon the rate of the heart.
J Physiol (Lond) 50: 65-84, 1915
14. Horwitz LD, Bishop VS: Effect of acute volume loading on heart rate
in the conscious dog. Circ Res 30: 316-321, 1972
15. Vatner SF, Boettcher DH, Heyndrickx GR, McRitchie RJ: Reduced
baroreflex sensitivity with volume loading in conscious dogs. Circ Res
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16. Boettcher DH, Vatner SF, Heyndrickx GR, Braunwald E: Extent of
utilization of the Frank-Starling mechanism in control of cardiac
performance in the conscious dog. Am J Physiol, Heart Circulatory
Physiol (in press)
17. Cowley AW, Guyton AC: Heart rate as a determinant of cardiac
output in dogs with arteriovenous fistula. Am J Cardiol 28: 321-325,
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Regulation of cardiac output by stroke volume and heart rate in conscious dogs.
S F Vatner and D H Boettcher
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Circ Res. 1978;42:557-561
doi: 10.1161/01.RES.42.4.557
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1978 American Heart Association, Inc. All rights reserved.
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