Download Increased Myocardial Oxygen Consumption and Contractile State

Increased Myocardial Oxygen Consumption
and Contractile State Associated
with Increased Heart Rate in Dogs
By Robert C. Boerth, M.D., Ph.D., James W. Corel I, M.D.,
Peter E. Pool, M.D., and John Ross, Jr., M.D.
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ABSTRACT
The effects of increasing the frequency of contraction on myocardial oxygen
consumption per minute (MVo2) were examined in eight dogs using an
isovolumic left ventricular preparation. MVo2 was determined at two to four
levels of heart rate in each animal. Peak wall stress was maintained constant in
each animal so that changes in it would not influence the effects of heart rate
on oxygen consumption per beat. As heart rate was increased, there was a
highly significant linear increase in MVo2. Oxygen consumption per beat was
shown to be a negative linear function of the reciprocal of heart rate. Thus, as
heart rate increased there was a significant increase in oxygen consumption per
beat; when basal oxygen consumption was subtracted from total oxygen
consumption, there was a much larger increase in oxygen consumption per
beat. Myocardial contractile state, defined as the maximum observed contractile
element velocity at the lowest common level of wall stress, was significantly
increased by increasing heart rate. The data suggest that the increased M"v"o2
associated with augmented heart rate is secondary to augmentation of
contractile state, as well as to the increase in stress development per minute.
ADDITIONAL KEY WORDS
myocardial metabolism
inotropic state
stress-velocity relation
peak myocardial wall stress
isovolumic left ventricular contractions
• There is general agreement that increasing
the frequency of contraction augments the
inotropic or contractile state of the myocardium, as reflected by a shift of the force-velocity
relationship, both in isolated cardiac muscle
(1-3) and the intact heart (4, 5). Recently, it
has been shown that the contractile state of
the heart is an important determinant of
myocardial oxygen consumption (6-9), and
therefore, it might be expected that increasing
the frequency of cardiac contraction would be
From the Cardiology Branch, National Heart
Institute, Bethesda, Maryland 20014.
This work was presented in part at the Federation
of American Societies for Experimental Biology,
Atlantic City, New Jersey, April 17, 1968.
Dr. Boerth's present address is Cardiovascular
Laboratory, Baltimore Public Health Service Hospital,
Wyman Park Drive and 31st Street, Baltimore,
Maryland 21211.
Received October 23, 1968. Accepted for publication March 23, 1969.
Circulation Research, Vol. XXIV, May 1969
associated with increased myocardial oxygen
utilization. Since 1885, when Yeo showed that
a beating heart consumes more oxygen than a
nonbeating heart (10), a number of investigators have demonstrated that tachycardia
produces an augmentation of myocardial
oxygen consumption per minute (11-15).
However, the question whether oxygen consumption per beat is augmented has remained
unanswered because systolic pressure and the
level of myocardial wall stress are altered by
increasing the heart rate, and both of these
factors are now recognized to be important
determinants of myocardial energy utilization
(9, 14, 16-18). Thus, in previous experiments
a decrease (11, 15), no change (13), or an
increase (14) in oxygen consumption per beat
has been found to accompany increased heart
rate. To circumvent this problem in the
present investigation the effect of increased
contractile state, produced by increasing heart
725
726
BOERTH, COVELL, POOL, ROSS
rate, on the myocardial oxygen consumption
per beat was examined in the isovolumically
contracting canine left ventricle. The peak
wall stress was maintained constant as heart
rate was increased, so that the inotropic effect
of tachycardia alone on energy utilization per
beat could be determined.
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Methods
Mongrel dogs of either sex were anesthetized
with intravenous pentobarbital sodium (average
34 mg/kg). Respiration was maintained with a
positive-pressure respirator, and the heart and
great vessels were exposed through a midline
sternotomy. The preparation (Fig. 1) has been
presented in detail previously (9). In brief, the
animal was placed on total cardio-pulmonary
bypass, blood from the venae cavae being
oxygenated and pumped retrogradely into a
femoral artery. Aortic pressure remained constant
throughout each experiment (mean = 89 mm
Hg). A thin latex balloon attached to a wide-bore
metal cannula was placed within the left
ventricle; plastic discs were placed in the mitral
annulus and in the left ventricular outflow tract to
keep the balloon within the left ventricular cavity.
The ventricle contracted isovolumically, and
ventricular volume and pressure were regulated
by introducing known amounts of saline into the
balloon through the metal cannula using a
calibrated syringe. The sinoatrial node was
crushed, and the heart was electrically paced
from the right atrium. A drainage tube in the
right ventricle collected coronary venous blood,
and this effluence was used to measure coronary
blood flow and to collect coronary venous blood
samples; it has recently been shown that this
effluence represents 95% of the total coronary
blood flow (19). Oxygen content of the blood
was determined manometrically by the method of
Van Slyke and Neill (20). The weight of the left
ventricle including the septum was obtained by
removing the atria and free wall of the right
ventricle. Myocardial oxygen consumption in
ml/min/100 g left ventricle (MVo2) was calculated as the product of coronary blood flow and
the coronary arteriovenous oxygen difference.
Systemic arterial and left ventricular pressures
were measured using Statham P23Db transducers. The first derivative of left ventricular pressure
with respect to time (LV dP/dt) was measured
using an electronic differentiator,1 the dynamic
characteristics of which have been previously
described (21). Myocardial wall stress, expressed
as the tangential force per unit cross-sectional
area of the left ventricular wall, was continuously
calculated by an analog computer,2 and maintained constant by altering internal ventricular
volume. Stress in g/cm2 was calculated as Pr/2h
assuming a thick-walled spherical model, where
P = intraventricular pressure in g/cm2, r = internal radius in centimeters, and h = wall thickness
in centimeters derived from internal volume and
muscle volume (obtained from a previously
determined curve of left ventricular muscle
volume vs. body weight). Myocardial wall stress,
the electrocardiogram, and pressures were recorded on a direct-writing oscillograph at paper
speeds of 100 mm/sec.
After completion of each experiment, the heart
was weighed and this actual value used for
electronic Gear, Inc., Elmont, New York, Model
No. 5602.
2
Electronic Associates, Inc., West Long Branch,
New Jersey, Model TR-20.
FIGURE 1
Isovolumic left ventricular preparation used. ST1M.
=z stimulator with electrodes on the right atrium; SG
= strain gauge; cannula from plug in the mitral
annulus drains coronary flow from the left ventricle;
P.A. = pulmonary artery; RV = right ventricle; LV =
left ventricle.
Circulation Research, Vol. XXIV, May 1969
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c\
|
53
128
160
137
202
134
5.7
7.3
5.42
8.68
56.5
61.0
62.0
48.5
49.0
744
1158
1241
1327
1637
360
290
300
255
250
150
125
130
130
105
72
85
88
92
90
22.5
19.5
19.0
12.0
12.0
55.9
69.8
41.4
49.8
45.4
4.51
8.87
8.75
8.4
10.2
10.4
68
110
106
98
179
181
124
29.1
33.8
44.8
43.5
42.5
46.5
822
995
1212
340
290
270
160
135
130
74
74
83
10.5
10.0
9.5
5.44
6.95
10.19
2.4
3.0
4.4
220
220
220
113
155
197
95
49.8
49.5
57.3
57.0
54.5
55.0
953
1104
1305
370
320
280
165
150
125
98
95
94
140
120
11.5
11.0
11.5
97
100
4.82
6.34
9.49
14.0
13.0
82
79
82
86
5.2
6.9
7.8
96
96
128
101
141
200
104
6.46
8.72
22.0
21.5
20.0
19.0
45.9
54.6
53.0
53.0
5.0
6.8
4.58
5.24
7.20
9.46
290
260
1524
2032
184
184
121
160
142
22.6
23.4
29.8
33.4
62.0
59.0
59.0
59.0
916
958
1166
1332
350
330
300
250
8.2
8.0
10.1
11.3
150
140
120
115
72
84
92
108
100
124
164
200
129
180
170
155
34.6
43.7
47.6
101
104
108
65.5
66.5
66.0
14.5
14.0
13.0
918
1052
1224
4.15
5.80
7.74
1.9
2.4
3.2
240
255
262
101
122
162
110
25.9
32.9
36.7
41.0
42.0
42.5
680
742
865
340
310
270
430
405
360
150
130
120
66
69
72
25.0
24.0
23.0
4.13
5.25
6.20
5.5
6.4
6.5
154
167
194
128
164
200
205
Max V
(cm/sec)
Po
(g/cm=)
LV dP/dt
(mm Hg/sec)
Dur.
(msec)
TTP
(msec)
LVP
(mm Hg)
LV vol.
(ml)
MVO:
(ml/min/100 g)
A-VOa
(ml/100 ml)
CBF
(ml/min)
HR
(beats/min)
LV wt.
(g)
LV wt. = left ventricular weight; HR = heart rate; CBF = coronary blood flow; A-Von = coronary arteriovenous oxygen difFerence; MVoL, = myocardial
oxygen consumption; LV vol. = left ventricular volume; LVP = peak left ventricular pressure; TTP = time from onset of LV contraction to peak wall stress;
Dur. = duration of contraction; LV dP/dt = maximum rate of rise of left ventricular pressure; P o =: peak wall stress; Max V = maximum contractile element
velocity observed at lowest common levels of stress.
Dog
no.
Effects of Changing Heart Rate on Myocardial Oxygen Consumption and Left Ventricular Dynamics
TABLE 1
5:
o
z
z
o
o
s
a
>
73
o
o
>
BOERTH, COVELL, POOL, ROSS
728
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muscle volume (assuming a sp. gr. of 1.0), and
values for left ventricular pressure and left
ventricular dP/dt were determined at 10-msec
intervals from two successive beats for every level
of heart rate and utilized for calculation of the
reported values for wall stress and contractile
element velocity (V CE ). The duration of
contraction was measured as the interval from
end diastole to the time when left ventricular
pressure returned to end-diastolic pressure. The
derivations of the equations for stress and for
contractile element velocity have been presented
in detail previously (9). In an isovolumic
contraction, VCE is equal to the rate of
lengthening of the series elastic component
(SEC) of the myocardium. The rate of series
elastic lengthening (V SE ) is directly proportional
to the rate of stress development (dS/dt) and
inversely related to the stiffness of the series
elastic component (dS/dl). This relationship then
can be written as: VCE = VSB = (dS/dt)/(dS/
dl), where dS/dl = 28S (5). VCE is expressed in
muscle lengths (or circumferences) per second
and was converted to cm/sec by multiplying by
the instantaneous circumference. Since the extrapolation of contractile element velocity to zero
stress (Vmnx) may be difficult and subject to
error, the inotropic state of the heart was
characterized by determining the maximum
observed contractile element velocity (max V) at
the lowest common level of wall stress in any
experiment (21).
In each of eight dogs, from two to four different
levels of heart rate were studied, ranging between
98 and 202 beats/min. The sequence of heart rate
variations in each experiment was selected at
random. Systemic arterial and coronary venous
blood samples were drawn simultaneously during
steady state conditions. As the heart rate was
increased or reduced, the volume of saline within
the left ventricular balloon was usually diminished or increased, respectively, to maintain peak
myocardial wall stress constant.
Linear regression lines were calculated for the
data using the method of least squares (22).
Significance of the slopes of the regression lines
was calculated using paired t-tests (23), and the
criterion of significance chosen was P < 0.05.
Results
The effects of heart rate on the characteristics of left ventricular isovolumic contractions
and MVoo are given in Table 1. In all
STRESS
g/cm*
202
8.68
43.0
HR tedte/min
MVO, ml/min/IOOg
MV0» jjl/beoi/IOOg
FIGURE 1
Oscillographic tracings obtained at two different heart rates. ECG = electrocardiogram; LV
dP/dt = first derivative of left ventricular pressure; LVP = left ventricular pressure; LVEDP =
left ventricular end-diastolic pressure; AP = aortic pressure.
Circulation Research, Vol. XXIV, May 1969
MYOCARDIAL OXYGEN CONSUMPTION AND HEART RATE
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experiments there was a marked increase in
left ventricular dP/dt as heart rate was
increased, and the time to peak wall stress and
the duration of contraction were significantly
decreased. In 6 of the 8 experiments, as heart
rate was increased it was necessary to reduce
left ventricular volume (range 0 to 3.5 ml) in
order to maintain peak wall stress constant.
Figure 2 shows the oscillographic tracings
from dog no. 8: the tracings in panel A were
taken at a heart rate of 137 beats/min and
those in panel B at a rate of 202 beats/min.
Peak wall stress was maintained constant
without a change in ventricular volume in this
experiment. At the higher heart rate, left
ventricular dP/dt was increased from 1327
mm Hg/sec to 1637 mm Hg/sec; oxygen
consumption was increased when expressed
both as ml/min and as ^liters/beat. As heart
rate increased, coronary blood flow usually
increased as did the coronary arteriovenous
oxygen difference (Table 1).
In each experiment, the relationship be-
729
tween heart rate in beats/min and MVo2 was
examined by linear regression analysis (Fig.
3). The values for the slopes and the Y
intercepts in the eight experiments were then
averaged, and a mean regression line of MVo2
vs. heart rate was computed. The positive
slope for this regression was 0.05 ± 0.003
ml/beat/100 g left ventricular weight (mean
± S E M ) , and this slope was highly significant
(P<0.001).
Using analysis of variance, the function was
shown statistically not to deviate from linearity (F<0.03). However, as heart rate was
increased, the total peak wall stress generated
during 1 minute also increased; for example,
in experiment no. 8, the product of peak wall
stress (Po) and heart rate increased from 6644
g/cm2/min to 9898 g/cm2/min. Since peak
stress is a major determinant of energy
utilization (9, 14, 16-18), it might be predicted that the MVoo also would be increased.
Therefore, to determine whether the oxygen
consumption at higher heart rates was aug-
10
cn
O
O
8
1
O
•>
100
120
140
160
180
200
HEART RATE
FIGURE 3
the effect of increasing heart rate on myocardial oxygen consumption per minute per 100 g
left ventricular weight. Each symbol represents the value obtained in a single experiment, wall
stress being maintained constant within the experiment.
Circulation Research, Vol. XXIV, May 1969
730
BOERTH, COVELL, POOL, ROSS
50
-TOTAL MVO2
Slope = - 6 8 6 /i.1 /min/IOOg
P<O.O2
45
O
O
40
_y TOTAL MINUS BASAL MV0 2
(1.43ml/min/IOOg)
Slope = - 2 l l 6 / i l / m i n / 100 g
35
O
>
P< 0.001
30
Colculoted Mean Regression Lines
N=8
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25
5
(200)
6
7
1
HR
8
x
I0
3
9
10
(100)
FIGURE 4
Calculated mean regression lines of oxygen consumption per beat on the reciprocal of heart
rate times 103. See text for derivation of mean regression lines; MVoo = myocardial oxygen consumption per beat per 100 grams left ventricular weight; N = number of dogs; numbers in
parentheses on the abscissa are locations of heart rates of 100 and 200 beats/min.
mented above that demanded by increased
stress generation per minute, the oxygen
consumption per contraction was examined.
Since oxygen consumption per minute was a
linear function of heart rate, it was evident
that oxygen consumption per beat could not
be a linear function of heart rate. The linear
relationship between myocardial oxygen consumption per minute (MVo2) and heart rate
can be described by the equation MVo2 = m
(HR) + b, where m = slope, HR = heart rate
in beats per minute, and b = MVo2 intercept.
When both sides of the above equation are
divided by heart rate, it becomes MVo2/HR
= m+b (1/HR), since oxygen consumption
per beat is calculated as MVo2 divided by
heart rate. From the latter equation it is
apparent that MVo2/HR (i.e., oxygen consumption per beat) is a linear function of the
reciprocal of heart rate, and this linear
function can be statistically examined by
regression analysis. For each of the eight dogs,
we calculated the regression line of myocardial
oxygen consumption per beat on the reciprocal of heart rate. The values for the slopes and
Y intercepts for these eight regression lines
were averaged to calculate a mean regression
line (top line of Fig. 4). The negative slope of
the calculated mean regression line (— 686 ±
231 jiiliters/min/100 g left ventricular weight)
was significant at P < 0.02, indicating that as
heart rate increased there was a significant
increase in oxygen consumption per beat.
Changes in inotropic or contractile state
were characterized by changes in VCE at the
lowest common stress (max V) within each
experiment. The values for max V were
obtained from the force-velocity relations as
determined from isovolumic contractions (21,
24). These relations at heart rates of 100 and
200 beats/min in a representative experiment
are shown in Figure 5. The augmentation of
VCE at the higher rate is evident, indicating
that inotropic state was enhanced. With only
two exceptions (dogs 5 and 7; Table 1), max
V increased whenever heart rate was increased, and this augmentation of max V was
statistically significant (P<0.001). To determine whether the increased oxygen consumption per beat at higher heart rates was related
Circulation Research, Vol. XXIV, May 1969
731
MYOCARDIAL OXYGEN CONSUMPTION AND HEART RATE
60
H.R.
MV0 2
ml/min
/^I/beat
50
a>
v>
40
30
o
o
20
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10
10
20
30
40
STRESS (g/cm 2 )
50
60
FIGURE 5
Stress-velocity relations in dog no. 3 at heart rates of 100 and 200 beats/min. Velocity =
contractile element velocity; stress — force/unit area (see Methods); myocardial oxygen
consumption per 100 g left ventricular weight expressed both as ml/min and as /iliters/beat.
to the increase in inotropic state (as reflected
in max V), these two variables were statistically analyzed by regression analysis. This
calculated mean regression line had a positive
slope of 0.24 + 0.07 (/^liters/beat/100 g left
ventricle)/(cm/sec), and this slope was highly significant (P<0.02).
Discussion
In 1871, Bowditch reported that increasing
the frequency of contraction augmented the
force of contraction of the heart (25). More
recently, it has been shown that there also is
an augmentation of the velocity of contraction
with increasing heart rate (1-5), an effect
confirmed in the present investigation. In the
present study, augmentation of the force of
contraction was usually but not invariably
observed when heart rate was increased, a
finding in agreement with studies in isolated
cardiac muscle (3). The maximum observed
contractile element velocity at the lowest
Circulation Research, Vol. XXIV, May 1969
common wall stress (max V) was used to
define the contractile or inotropic state of the
left ventricle, and using this index the
inotropic state was enhanced by increased
heart rate in 21 of 23 observations. Although it
is possible that the values for max V were
influenced by changes in muscle length,
ventricular volume was usually decreased as
heart rate was increased, and this would tend
to lower the values for max V at the high heart
rates (9). Thus it is probable that the increase
in contractile element velocity at zero stress
(Vmax) was even greater than the observed
augmentation of max V.
A number of investigators have examined
the influence of heart rate upon the heart's
oxygen requirements (11-15), and some of
these studies have indicated that a linear
relationship exists between heart rate and
myocardial oxygen consumption per minute
(11, 14, 15). The findings in the present
732
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investigation (Fig. 3) were in agreement with
this conclusion, and using analysis of variance
the regression of MVo2 on heart rate was
shown statistically not to deviate from linearity. However, as mentioned earlier, to determine whether the amount of oxygen consumed at the higher heart rates was in excess
of that necessary for stress production per
minute, it was necessary to determine the
effects of increasing heart rate upon the
myocardial oxygen consumption per beat. In
this connection, Laurent et al. (11) and Van
der Veen and Willebrands (15) have reported
that myocardial oxygen consumption per beat
decreased with increasing heart rate, and
Maxwell et al. (13), studying intact dogs,
have reported that increasing heart rate from
an average of 92 to 193 beats/min resulted in
no change in oxygen consumption per beat.
On the other hand, Monroe and French (14)
found an increase in oxygen consumption per
beat with increasing heart rate, although this
occurred when there was a marked increase in
the force of contraction. In the present study,
oxygen consumption per beat was shown to be
a linear function of the reciprocal of heart
rate. The negative slope of the regression of
oxygen consumption per beat on the reciprocal of heart rate (top line of Fig. 4) indicated
that as heart rate increased there was a
significant increase in oxygen consumption per
beat.
In examining the effects of heart rate upon
myocardial oxygen consumption, it is important to consider the various factors which
determine the total oxygen consumption of the
heart. It has been suggested that there are at
least five such factors (9): stress development,
external work, contractile or inotropic state,
activation, and basal requirements. Since both
wall stress and the contractile state of the
myocardium have been postulated to be
important determinants of myocardial oxygen
consumption (6, 9), comparisons of oxygen
consumption at different heart rates were
made at matched levels of peak wall stress to
minimize the effects of wall stress on oxygen
consumption. Since Monroe (26) and others
(27, 28) have found that peak tension rather
BOERTH, COVELL, POOL, ROSS
than the integrated tension is most closely
related to MVo2, peak wall stress levels were
matched in this study. This resulted in a
marked reduction in integrated wall stress per
beat at the higher heart rates, and it is
possible that this reduction may have minimized the augmentation of oxygen consumption per beat observed at higher heart rates.
The amount of shortening of myocardial fibers
against load (external work) is a determinant
of total energy utilization in isolated muscle
(29). In an isovolumically contracting ventricle there is little shortening of the myocardial
fibers. Although a small amount of shortening
could be associated with changes in the shape
of the ventricle (30), this contribution should
be similar at all heart rates and therefore
probably did not influence the present results.
It has been shown recently that the oxygen
cost of electrical activation of the intact heart
is less than 1% of the total oxygen consumption
(31). The remainder of the activation energy
(i.e., that required for activation of the
contractile sites of the myocardium) probably
represents only a small percentage of the total
MVo2 (32, 33). It is not known, however,
whether changing heart rate affects the per
beat expenditure of oxygen for activation.
In the isovolumic preparation used in this
study, the basal oxygen consumption determined during arrest with 15% KG was found
to be 1.43 ml/min/100 g left ventricle. This
value represented a considerable portion of
the total myocardial oxygen consumption
(Table 1). If it is assumed that the basal
oxygen consumption is not affected by changing heart rate, then the amount of basal
oxygen consumption per beat must decrease
with increasing heart rate, since the basal
oxygen consumption per minute is divided
among more contractions per minute. The
lower line in Figure 4 shows that when basal
oxygen consumption per beat is subtracted
from the total oxygen consumption per beat,
there is a much larger increase in oxygen
consumption per beat with increasing heart
rate than when total oxygen consumption alone
is utilized.
Since the increased oxygen consumption per
Circulation Research, Vol. XXIV, May 1969
MYOCARDIAL OXYGEN CONSUMPTION AND HEART RATE
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beat seen at the higher heart rates does not
appear to be explained by changes in stress
development, external work, activation energy, or basal energy requirements, it seems
reasonable to associate the increased oxygen
consumption with the increased contractile
state produced by the increasing heart rate.
However, this observed increase in oxygen
consumption is of a smaller magnitude than
that reported in a study by Graham et al. from
this laboratory (9) in which inotropic state
was increased by the administration of norepinephrine. It is possible that a fundamental
difference exists in the relation between
contractile state and energy utilization during
these two procedures; on the other hand, if
basal oxygen consumption was subtracted
from the total oxygen consumption (lower
line of Fig. 4), the increased oxygen consumption associated with the increased contractile
state in the present study would more closely
approach that reported by Graham et al.
(9).
It is concluded that a positive, linear
relation exists between myocardial oxygen
consumption per minute and heart rate. In
addition, when peak wall stress is constant,
contractile state (as reflected by max V) is
increased by increasing heart rate and this
enhanced contractility is associated with an
increase in myocardial oxygen consumption
per beat.
Acknowledgments
The authors wish to express their appreciation to
Mr. Robert M. Lewis, Mr. Richard D. McCill, and
Mr. Noel Roane for their technical assistance, and to
Mrs. Hope Cook for the manometric determinations of
blood oxygen content.
N. S., JR.: Intrinsic effects of heart rate on left
ventricular performance. Am. J. Physiol. 205:
41, 1963.
5.
4.
Circulation Research, Vol. XXIV, May 1969
Ross, J.,
E.
JR., TAYLOR,
R.,
H . , AND B R A U N W A L D ,
E.:
ity of contraction as a determinant of myocardial oxygen consumption. Am. J. Physiol.
209: 919, 1965.
7. GRAHAM, T. P., JR., ROSS, J., JR., COVELL, J. W.,
SONNENBLICK, E. H., AND CLANCY, R. L.:
Myocardial oxygen consumption in acute
experimental cardiac depression. Circulation
Res. 21: 123, 1967.
8. COLEMAN, H. N., III.: Role of acetylstrophanthidin in augmenting myocardial oxygen consumption. Circulation Res. 21: 487, 1967.
9. GRAHAM, T. P., JR., COVELL, J. W., SONNENBLICK,
E. H., Ross, J., JR., AND BRAUNWALD, E.: Con-
trol of myocardial oxygen consumption: Relative
influence of contractile state and tension
development. J. Clin. Invest. 47: 375, 1968.
10. YEO, G. F.: An attempt to estimate the gaseous
interchange of the frog's heart by means of the
spectroscope. J. Physiol. 6: 93, 1885.
11.
LAURENT, D., BOLENE-WILLIAMS, C , WILLIAMS,
F. L., AND KATZ, L. N.: Effects of heart rate
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Circulation Research, Vol. XXIV, May 1969
Increased Myocardial Oxygen Consumption and Contractile State Associated with
Increased Heart Rate in Dogs
ROBERT C. BOERTH, JAMES W. COVELL, PETER E. POOL and JOHN ROSS, Jr.
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Circ Res. 1969;24:725-734
doi: 10.1161/01.RES.24.5.725
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