Download Sex-related dilferences in the normal cardiac response

PATHOPHYSIOLOGY AND NATURAL HISTORY
EXERCISE
Sex-related dilferences in the normal cardiac
response to upright exercise
MICHAEL B. HIGGINBOTHAM, M. B., KENNETH G. MORRIS, M. D., R. EDWARD COLEMAN, M. D.,
AND FREDERICK R. COBB, M.D.
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ABSTRACT In previous studies from this laboratory, we found that approximately 30% of women
with chest pain and normal coronary arteries demonstrated either a decrease in or a failure to increase
radionuclide ejection fraction during exercise. To examine the hypothesis that this apparent abnormality in left ventricular function represents a physiologic difference between men and women, we
prospectively studied central and peripheral cardiovascular responses to exercise in 31 age-matched
healthy volunteers (16 women and 15 men). A combination of quantitative radionuclide angiography
and expired-gas analysis was used to measure ejection fraction and relative changes in end-diastolic
counts, stroke counts, count output, and arteriovenous oxygen difference during symptom-limited
upright bicycle exercise. Normal male and female volunteers demonstrated comparable baseline left
ventricular function and similar aerobic capacity, as determined by weight-adjusted peak oxygen
consumption (22.1 ± 5.1 and 22.6 4.3 ml/kg/min, respectively). However, their cardiac responses
to exercise were significantly different. Ejection fraction increased from 0.62
0.09 at rest to 0.77
0.07 during exercise in men (p < .001), but was unchanged from 0.63 0.09 at rest to 0.64 0.10
during exercise in women. The ejection fraction increased by 5 points or more in 14 of 15 men, but in
only seven of the 16 women. End-diastolic counts increased by 30% in women (p < .001), but was
unchanged in men. Because decreases in ejection fraction were matched by increases in end-diastolic
counts, relative increases in stroke counts and count output were the same for men and women. These
data demonstrate a basic difference between men and women with respect to the mechanism by which
they achieve a normal response of stroke volume to exercise; these differences must be taken into
account when measurements of cardiac function during exercise stress are used for diagnostic purposes.
Circulation 70, No. 3, 357-366, 1984.
±
±
IN EARLIER STUDIES from this laboratory],2 we
observed that the radionuclide ejection fraction either
failed to increase or decreased during exercise in approximately 30% of women who presented for evaluation of chest pain and were found to have angiographically normal coronary arteries; similar responses were
seen in only 10% of comparable men. The poor specificity of results of exercise radionuclide angiographic
examination in women has also been noted by others.
While these observations are consistent with the suggestion by several investigators9 that such patients
may have abnormal cardiac function or myocardial
From the Department of Medicine, Division of Cardiology, and the
Department of Radiology, Duke University Medical Center and Durham Veterans Administration Medical Center, Durham.
Supported by grant HL17670 from the National Heart, Lung and
Blood Institute.
Dr. Higginbotham received support from the North Carolina affiliate
of the American Heart Association.
Address for correspondence: Frederick R. Cobb, M.D., Professor of
Medicine, Division of Cardiology ( 1 l A), Durham VA Medical Center, 508 Fulton St., Durham, NC 27705.
Received Nov. 28, 1983; revision accepted June 15, 1984.
Vol. 70, No. 3, September 1984
perfusion, they may also indicate a fundamental difference in the cardiac responses of men and women to
upright exercise; if the latter were true, one would also
expect to see a difference between normal healthy men
and women. Such a difference has not been described
previously, and if present would be an important consideration in the correct interpretation of tests in which
cardiac function is measured during upright exercise.
A prospective study was therefore undertaken to
examine the effect of sex on the cardiovascular response to exercise. The study was designed specifically to examine populations of age-matched healthy
male and female volunteers. Central and peripheral
cardiovascular variables were measured noninvasively
by a combination of radionuclide angiography and expired-gas analysis during staged symptom-limited upright bicycle exercise.
Methods
Subjects. Sixteen normal women from 32 to 68 years old
(mean 52 + 11 years) volunteered to participate in the study;
none had a history of hypertension or were suspected of having
357
HIGGINBOTHAM et al.
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heart disease. Three of these women were medical center staff
who agreed to participate at the request of one of the investigators; each was sedentary and only two regularly exercised. The
remaining 13 participants were identified after enrollment in a
physical fitness program. They were starting the program with
the expectation of improved general health and fitness, and with
the intention of losing weight. No subject was extremely obese;
weight ranged from 61 to 88 kg (mean 67 -+ 11 kg). The two
subjects who were exercising regularly before enrollment had
been jogging.
Fifteen normal men from 31 to 67 years old (mean 46 + 13
years) also volunteered for the study. Six were medical center
staff, seven had enrolled in the training program described
above, and two had been evaluated for atypical chest pain and
results of treadmill testing and cardiac catheterization had been
completely normal. All male subjects were sedentary and only
three had been exercising regularly before the study. Body
weight ranged from 76 to 122 kg (mean 91 + 10 kg).
Once subjects had volunteered for the study, no further tests
were performed for the purpose of selection; the study population thus represents a consecutive series of normal volunteers.
Physical examinations were performed and electrocardiograms
obtained in all subjects and results were normal. Although status
of physical activity was not tested formally, the general condition of the normal volunteers appeared to be representative of
the general sedentary middle-aged population.
Exercise protocols. All subjects reported to the exercise
laboratory while in the postabsorptive state. After written informed consent was obtained, subjects exercised in the upright
position on an isokinetic bicycle ergometer (Fitron. Lumex,
Inc.) at a constant pedalling rate of 60 rpm.
After baseline measurements were obtained in resting subjects, they commenced exercise at a workload of 150 kilopondmeters (kpm)/min (25 W). every 3 min the workload was increased by the same amount. Exercise was continued until
limited by fatigue and/or shortness of breath. During exercise
the electrocardiogram was monitored continuously and standard
limb leads and leads V, and V6 were recorded at I min intervals.
Blood pressure was measured by cuff manometry and was recorded at rest and at the end of each exercise stage.
Measurement of oxygen consumption and end points of
exercise. Expired gases were analyzed continuously for calculation of oxygen consumption and production of carbon dioxide at
rest and during progressive exercise. The oxygen content of
expired air was measured with a Beckman OM- 14 analyzer, and
carbon dioxide content was measured with a Beckman LB-2
analyzer. Strip-chart recordings were made after instrument
calibration, in subjects at rest, and during the last minute of each
exercise stage. Minute volume was recorded continuously with
a Pneumoscan spirometer. Maximum oxygen consumption was
used as an objective index of aerobic work performance or
cardiovascular reserve. The respiratory gas exchange ratio, or
VCO,/V0., was calculated for each exercise stage and was used as
a measure of the extent of anaerobic metabolism, as described
by Whipp et al. '0 By making such measurements, it was possible to compare the two groups with respect to maximum aerobic
capacity and degree of exercise effort or motivation.
Radionuclide angiography. The use of 3 min stages of exercise permitted acquisitions of data in subjects at rest, during at
least two intermediate exercise stages, and at peak exercise.
Radionuclide angiograms were acquired during the last 2 min of
each exercise stage so that they corresponded with the other
noninvasive measurements.
After labeling of red blood cells in vivo with 30 mCi technetium-99m, gated equilibrium radionuclide studies were performed with a Searle L.E.M. mobile gamma camera with a
high-sensitivity 30 degree slant-hole collimator interfaced with
358
an A2 computer (Medical Data Systems). Gating was triggered
by the R wave of the electrocardiogram. All images were acquired in the left anterior oblique projection that allowed best
separation of left and right ventricles (approximately 40 degrees), and time of data acquisition ranged from 1.5 to 2 min for
each study. During the exercise studies particular care was taken
to minimize extraneous movement of the subject, to avoid firm
gripping of the camera, and to maintain a constant workload.
Left ventricular ejection fraction was calculated with standard computer algorithms. Left ventricular borders were defined by a semiautomated edge detection method; background
was selected automatically by reference to the end-systolic
frame, and ejection fraction (EF) was computed from the enddiastolic (ED) and end-systolic (ES) counts, as follows:
EF
(ED counts-background)
(ES counts-background)
(ED counts-background)
In addition to measurement of ejection fraction, the background-corrected end-diastolic count rate, a relative measure of
end-diastolic volume, was recorded for each acquisition. Proportional changes in end-diastolic counts from rest to exercise
were computed (see Appendix). Each value for end-diastolic
counts (EDC) during exercise was back-corrected to the time of
the resting study to allow for isotope decay. The formula was
EDC =
EDC,
xe,t
where EDC0 back-corrected value. EDC, = value recorded
at time t; ?
0.693/isotope half-life.
As shown in the Appendix, proportional changes in stroke
counts and count output were derived from the measurements of
end-diastolic counts, ejection fraction, and heart rate.
Proportional changes in arteriovenous oxygen difference
from rest to exercise were measured indirectly from changes in
count output and oxygen consumption (VO). Thus, a measure of
oxygen utilization, or "peripheral" cardiovascular function,
was available in addition to the measures of 'central" function
made from radionuclide measurements alone.
The basic assumption necessary for use of these methods is
that count data derived from a left ventricular region of interest,
corrected for background activity, are proportional to left ventricular volume. This concept has been validated in studies from
several different laboratories, ''- and is the basis for measurement of ejection fraction. Absolute left ventricular volume was
not calculated in the present study. The preceding calculations
are dependent on the precision of measurements of ejection
fraction and end-diastolic counts, which was tested by performing duplicate radionuclide studies in 30 subjects at rest; the
variability between measurements was 0.02 + 0.017 for ejection fraction and 7.7 + 4.7% for end-diastolic counts. The
noninvasive measurement of changes in cardiovascular function
from rest to exercise was validated in a separate study involving
eight healthy male volunteers. Radionuclide and expired-gas
data were acquired as previously described; in addition, blood
samples were taken from the pulmonary artery (via a SwanGanz catheter) and the brachial artery of each subject while at
rest and during each exercise stage. Simultaneous direct and
indirect measurements of changes in arteriovenous oxygen difference and cardiac output were compared.
Figures 1 and 2 summarize the results of the validation study
in which proportional changes in arteriovenous oxygen difference and cardiac output from rest to exercise were compared
with corresponding noninvasively determined estimates; the estimates correlated well (figure 1) with direct measurements of
arteriovenous oxygen difference (r = .88) and cardiac output (r
- .89). In figure 2, changes occurring with progressively more
=
CIRCULATION
PATHOPHYSIOLOGY AND NATURAL HISTORY-EXERCISE
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EX/R A-V 02 (Direct)
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FIGURE 1. Validation study. Proportional increases in Fick cardiac output (A) and directly measured arteriovenous oxygen
difference (A-V02, B) during exercise are plotted against the corresponding noninvasive estimates derived from radionuclide
data in eight healthy male volunteers. The line of identity is shown.
hypokinetic by consensus of at least two of the authors. Wall
motion was analyzed without knowledge of the identity of the
subject or the ejection fraction.
Statistical analysis. Cardiovascular variables in the two
groups of subjects at rest and during peak exercise were compared with unpaired t tests. To compare the time course of
changes in a certain variable, individual response curves were
derived from linear regression analysis, and the slopes produced
were compared with unpaired t tests.16 The significance of
strenuous exercise are shown for individual patients. Mean val-
or
obtained in the validation study were estimated accurately
by noninvasive methods, which reproduces our findings in a
previous validation study of patients with abnormal left ventricular function.'5
Wall motion was assessed from a real-time endless-loop display of the unprocessed radionuclide data. The left anterior
oblique view was divided into three segments posterolateral,
inferoapical, and septal and each segment was judged normal
ues
NONINVASIVE
Ai
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NVASIVE
4.0.~~~~~~~~~~~~~~~~~
0 30z
0O
750
900
1050
1200
WORK LOAD
0
150
300
450
(KPM/MIN)
FIGURE 2. Validation study. Invasive (direct) measurements of proportional changes in arteriovenous oxygen difference and
cardiac output during progressive exercise are compared with noninvasive estimates of these variables. The heavy line represents
mean data for the group.
Vol. 70, No. 3, September 1984
359
HIGGINBOTHAM et al.
changes in values from rest to maximal exercise was assessed by
paired t tests. For each comparison, a p value of <.05 was
considered indicative of significance.
Results
200k
1 60-
E-
Exercise performance. All 31 normal volunteers exer-
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cised to exhaustion; none had chest pain or ST segment
depression. Women achieved a lower maximal external workload (600 + 77 kpm/min) than did men (740
+ 144 kpm/min), and this corresponded to a 27%
lower total oxygen consumption (1.5 ± 0.3 vs 2.1 +±
0.6 liter/min). However, as shown in figure 3, women
(group A) and men (group B) had the same level of
aerobic capacity as measured by oxygen consumption
indexed for body weight (22.6 + 4.3 and 22.1 ± 5.1
ml/kg/min, respectively), suggesting that these groups
did not differ greatly in terms of relative physical fitness. Men had a slightly lower oxygen consumption
(expressed as ml/kg/min; figure 3) during intermediate
exercise stages, as shown by a more gradually rising
response curve compared with that for women (p =
.002). However, when oxygen consumption was expressed in milliliters per minute, values for women
were approximately 10% less than those for men at
each intermediate workload.
The respiratory gas exchange ratio, an index of the
degree of anaerobic metabolism, also is illustrated in
figure 3. Maximum values were the same for women
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15o
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,
300
450
600
WORK LOAD (Kpm/min)
750
900
FIGURE 3. Progressive changes in VO and respiratory gas exchange
ratio during submaximal and maximal exercise, plotted as mean data +
SD for normal female (F) and male (M) volunteers. Significant intergroup differences are shown for the slope of the response. as well as for
data from subjects at rest and during maximal exercise.
360
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80F
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450
600
750
900
WORK LOAD (Kpm/min)
FIGURE 4. Heart rate and systolic blood pressure response to progressive exercise, represented as in figure 3.
(1.16 + 0.10) and men (1.14 ± 0.10). Each subject
achieved a maximum ratio of at least 1.0, and values
equal to or more than l. 1 were recorded for 11 of the
16 women and 1 1 of the 15 men. These findings suggest that exercise effort was similar for the two groups.
Central and peripheral cardiovascular responses to exercise. Heart rate and systolic blood pressure responses,
as illustrated in figure 4, were comparable at rest and
during exercise in the female and male subjects. Maximum values for heart rate were 156 + 1 1 beats/min for
women and 155 ± 17 beats/min for men; respective
values for systolic blood pressure were 202 ± 25 and
216 ± 29 mm Hg. Although heart rate appeared to
increase slightly more rapidly in women than in men,
there was no significant difference between the response slopes.
Figure 5 illustrates the ejection fraction responses to
graded upright bicycle exercise. In normal women and
men, the mean resting ejection fraction and the distribution of individual resting measurements were similar. The ejection fraction responses during submaximal exercise also were similar (for example, at 300
kpm/min ejection fraction was 0.71 ± 0. 1 1 for women
and 0.71 ± 0.08 for men); however, at maximum
exercise there was an almost uniform decrease in ejection fraction in women, while in men it either remained
CIRCULATION
PATHOPHYSIOLOGY AND NATURAL HISTORY-EXERCISE
FEMALE VOLUNTEERS 32-68 YRS
l O°r
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40k
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MALE VOLUNTEERS 31- 67 YRS.
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.40
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6
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(p<O.OOl0
1
5o
300
450
600
750
900
0
150
300
450
6500
750
900
WORK LOAD (Kpm/min)
FIGURE 5. Ejection fraction responses during exercise in which the workload was increased every 3 min. Progressive individual
data are shown for the two study groups. Mean submaximal and maximal group data are plotted on the right, and are compared as
in figures 3 and 4.
the same or continued to increase, except in one subject whose resting ejection fraction was 0.83. Ejection
fraction changed significantly from 0.62 0.09 at rest
to 0.77 + 0.07 at maximal exercise in men, but there
was no increase in women: in this group, resting ejection fraction was 0.63 + 0.09 and that at maximum
0.10. The ejection fraction inexercise was 0.64
creased by 0.05 in 14 of 15 men but in only seven of 16
women.
The previously demonstrated negative correlation
between the change in ejection fraction from rest to
exercise and resting ejection fraction17 and age'8 were
also found in the present study. Linear regression analyses in which change in ejection fraction was related to
resting ejection fraction and to age yielded r values of
-.46 and -.40, respectively. These overall relationships applied in both the female and male groups
(change in ejection fraction vs resting ejection fraction
r =
.67 for men, .34 for women; change in ejec-.38 for men, -.17 for
tion fraction vs age r
women), and therefore did not affect the intergroup
comparisons. Changes in ejection fraction did not correlate with peak V02 (r = .03) or the ratio of respi.17), confirming that
ratory gas exchange (r =
unrelated to physwere
differences in ejection fraction
ical fitness and were not an artifact caused by variable
exercise effort during the test.
-
-
-
-
Vol. 70, No. 3, September 1984
Proportional increases in end-diastolic counts are
shown in figure 6. There were clear differences between normal male and female volunteers. In women
end-diastolic counts increased at low exercise levels by
20% to 30%, and this increase was maintained at maximum exercise (p < .001). In men, there was an early
increase of approximately 10%, but no net change at
maximal exercise. The overall response curves and
maximal values for end-diastolic counts were clearly
different for the two groups (p < .001). Despite differences between cardiac volume responses in men and
women, changes in stroke counts were similar, increasing to a plateau during the early stages of exercise
(figure 6); stroke counts increased 33% in women and
23% in men at peak exercise.
Count output increased progressively in each group
and responses in normal male and female subjects were
very similar (figure 6): count output increased approximately 2.5-fold and the relationship between the ratio
of exercise to resting count output and workload was
essentially the same in each group. Peripheral utilization of 02, expressed as the relative change from rest to
peak exercise, appeared comparable in the normal men
and women. The ratio of exercise to resting arteriovenous 02 difference increased progressively to a maximum of 2.33 + 0.45 in women and 2.34 + 0.51 in
men.
361
HIGGINBOTHAM et al.
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O
150
300
450
MAX
600
150
900
0
WORK LOAD (Kpm/min)
750
300
450
-
600
750
900
FIGURE 6. Cardiovascular responses to progressive exercise. Proportional changes from rest to exercise (Ex/R) are shown for
end-diastolic counts (EDC), stroke counts (SC), count output (CO), and arteriovenous 0 difference (A-VO). Data are displayed
as in the previous figures.
Wall motion analysis showed no asynergy induced
by exercise in any subject, despite the global decrease
in function in many women.
Cardiovascular variables also were expressed in relation to percent maximum VO0 to correct for the possible effect of variations in peak VO. between subjects.
When the results were analyzed as described earlier,
the findings were unchanged; women and men remained significantly different with respect to ejection
fraction (p .0006) and the ratio of exercise to resting
end-diastolic counts (p = .0002), but not with respect
to this ratio for stroke counts (p = .20) or count
output (p
.87).
Discussion
Our results confirm that normal middle-aged men
and women achieve increases in stroke volume during
upright exercise by different mechanisms. In men, a
23% increase in stroke counts resulted from an increase in ejection fraction with little or no change in
end-diastolic counts, while in women a similar increase in stroke counts (33%) was achieved through an
increase in end-diastolic counts without an increase in
ejection fraction from rest to maximal exercise. These
differences were demonstrated in normal sedentary
male and female volunteers who were unselected and
well-matched for age, resting left ventricular function,
heart rate, and blood pressure. The absence of a rela362
tionship between the change in ejection fraction and
such exercise variables as maximum VO0 and respiratory gas exchange ratio further supports the conclusion
that the observed differences were related to sex rather
than to variations in physical condition or motivation
to exercise.
Comparison with previous studies. Although there have
been numerous studies describing the changes in heart
rate, stroke volume, cardiac output, and arteriovenous
0, difference that accompany exercise in normal subjects,'9-11 few have examined changes in cardiac volume and ejection fraction in healthy female and male
volunteers. The demonstration in the present study of a
physiologic difference in the ejection fraction response
to exercise in normal men and women is consistent
with preliminary observations in our laboratory and in
others. Previous reports from our laboratory' showed
that approximately 30% of women with chest pain and
angiographically proven normal coronary arteries either failed to increase or decreased their ejection fraction, compared with only 10% of comparable men.
Greenberg et al.3 also confirmed the poor specificity of
the ejection fraction response to exercise in the diagnosis of coronary artery disease in women. In their study,
five of 11 normal women (three of five asymptomatic
volunteers and two of six with normal coronary arteries) failed to increase their ejection fraction by 0.05, a
level found by many investigators to distinguish accurately between normality and abnormality in men.9. 32
CIRCULATION
PATHOPHYSIOLOGY AND NATURAL HISTORY-EXERCISE
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In a recent study, Rodeheffer et al.33 examined the
cardiac responses in groups of 15 female and 46 male
normal volunteers carefully selected to include only
subjects with a very low likelihood of coronary artery
disease; this study was mainly concerned with describing age-related differences, but also demonstrated a
possible sex difference in the ejection fraction response
to exercise. Ejection fraction failed to increase by 0.05
in five of 15 women (33%) compared with only seven
of 46 men (15%). The fact that these differences are
not as marked as those seen in the present study may be
explained by the high proportion of men in whom
findings were atypical in the previous study, and by the
possibility that the screening procedures used (which
included stress thallium scintigraphy in all subjects
over 40 years of age) may have excluded some normal
women with atypical responses.
Peak VO, for both the male and female volunteers in
the present study was considerably lower than that
described in most of the published literature, both
when values were corrected and uncorrected for body
weight.22"-' This difference becomes more understandable when the characteristics of the study populations
are considered. With few exceptions, previous studies
have described very well conditioned subjects, whereas the present study involved sedentary subjects, many
of whom were enrolling in an exercise training program. Our results do not differ greatly from those described by DeBusk et al.,11 who studied a group of
"moderately fit" middle-aged men being entered into
a study of the effects of bed rest and training. The
initial maximal VO at a heart rate of 170 + 3 beats/min
in these men was 25.4 + 6.2 ml/kg/min, compared
with a value of 22.1 ± 5.1 ml/kg/min in our male
subjects. The discrepancy between peak V'0. levels in
the present study and those in the large study of Hossack and Bruce32 may be partially explained by the
well-described 6% to 11% difference in peak V., in
subjects performing bicycle and those performing
treadmill exercise. 19
Further contribution to the low values for VO, found
in the present study was made by the fact that many of
our participants almost certainly did not attain truly
maximal VO despite symptom-limited exercise; this is
shown by the absence of a plateau in the VO, response
and by maximum heart rate of 156 + 1 1 and 155 + 17
beats/min in women and men, respectively. It should
be emphasized that the purpose of the present study
was not to characterize maximum VO, in middle-aged
subjects, but to obtain several measurements of central
and peripheral cardiovascular function during exercise. For the comparison between the sexes to be valid
Vol. 70, No. 3, September 1984
at maximal exercise, it was not necessary that the subjects achieve maximal V?,, but only that male and
female subjects achieve equivalent levels of peak exercise in relation to maximal V1O,. There is strong evidence that this was achieved; maximal values for respiratory gas exchange ratio were greater than 1.0 in all
subjects and greater than 1. 1 in 1 1 of 16 women and 1 1
of 15 men. Thus, the differences in cardiovascular
variables observed in the present study at peak exercise
were observed during closely matched levels of stress.
Furthermore, differences were seen at submaximal
levels of exercise expressed as absolute workload or
percent of maximal Vs1.
Although peak VO, expressed in liters per minute was
27% lower in women than in men, in contrast to what
has been reported in several previous studies, weightcorrected values were not greater in men.22 23. 30 This
may be explained partially by the fact that average
weight of the male subjects (91 ± 10 kg) was considerably higher than that of the females (67 ± 11 kg).
The weight difference between the sexes was exaggerated by the fact that three of the males were obese,
weighing over 100 kg. Also, previous studies described male and female populations well matched for
level of physical activity either by careful selection or
by the use of large numbers of subjects. Sex-related
differences would be expected to be less apparent in
sedentary middle-aged populations in whom there is
wide variability in aerobic capacity.
Most previous studies in fit subjects have shown that
stroke volume increases by approximately 50% during
upright exercise.- 24. 29 However, it is well known that
exercise stroke volume is higher in trained populations.20 29 The increase in stroke counts of 30% seen in
the present study is considerably less than the abovementioned values, but is not inconsistent with the 30%
increase described by Ekblom et al.28 in studies performed in subjects before exercise training. Our demonstration of a gradual increase in stroke counts during
early workloads, with the plateau at approximately
50% of maxmum, is similar to observations on stroke
volume made in several other studies.22 26. 31 Stroke
volume was measured as a proportional change in
stroke counts from rest to exercise in our study so that
we were unable to compare absolute values for maximum exercise in men and women. Most previous investigators have observed greater values for stroke volume in men than in women both at rest and during
maximal exercise. The demonstration of a comparable
relative increase in stroke counts with exercise is consistent with these findings.24
Cardiac output, measured as count output in our
363
HIGGINBOTHAM et al.
study, increased approximately 2.5-fold in the present
study; this is low when compared with results of previous studies, but compatible with the lower values for
VO, obtained.
Our study confirmed a previously described linear
increase in arteriovenous O difference to a maximum
of 2½/2-fold in normal subjects.24 30 Arteriovenous 02
difference has been shown to be higher in men as a
result of their higher hemoglobin content. 19 However,
consistent with the findings in our study, this difference has been observed in subjects both at rest and
during exercise, leading to the conclusion that proportional increases do not differ between the sexes. 19- 24. 30
Mechanism of the different cardiac responses in men and
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women. While our data confirm that the ejection fraction decreases during upright exercise in a large proportion of normal women, the mechanism of this response is unclear and cannot be explained by the
findings in this study. One possible explanation is that
variations in the ejection fraction, which is not a specific index of left ventricular contractility, represent
the normal response of the left ventricle to different
loading conditions in women and men during exercise.
This possibility is supported by the observation in
hemodynamic studies that a decrease in stroke volume
follows an increase in arterial blood pressure (a major
component of afterload) or a reduction in left ventricular filling pressure (preload), as expected from the
Starling principle. 45 Recently, Peter and Jones36
demonstrated that isometric exercise results in a decrease in radionuclide ejection fraction, in association
with an increase in blood pressure. Since blood pressure increased a little more rapidly in women than in
men in the present study, it is possible that this relatively rapid increase in afterload could be an important
determinant of the ejection fraction response. However, the presence of this mechanism is not supported by
results of studies in experimental animals,37 which
have demonstrated that acute increases in afterload
result in only very transient subendocardial ischemia
and brief rather than sustained alterations in ventricular
performance. Furthermore, failure of the ejection fraction to increase in the present study was not associated
with a greater elevation in systolic blood pressure at
peak exercise.
A further possible explanation for the different ejection fraction responses in men and women is related to
the observation that in women, left ventricular enddiastolic counts increased by 20% to 30% during exercise, whereas no change was observed in men. The
increase in chamber size in women would be expected
to increase wall tension to a greater extent than in men,
364
assuming that changes in wall thickness were similar.
This increase may have caused an increase in afterload
with a resultant decrease in fiber shortening. It is unlikely that the ejection fraction decreased because of
inadequate left ventricular filling (preload), since enddiastolic counts increased to a greater extent during
exercise in women than in men.
Previous observations by Foster et al.38 and Barnard
et al.39 that the ejection fraction may decrease during
sudden strenuous exercise even in healthy young men
suggested to us that the apparently abnormal ejection
fraction response in women may in some way be related to the rapidity of the exercise protocol or to physical
deconditioning; we considered the possibility that in
previous studies' increasing the workload at 1 min
intervals may have represented sudden strenuous exercise in deconditioned women. However, the use of a
gradual (3 min) protocol did not abolish the tendency
for the ejection fraction to decrease in women. Further
evidence that the decrease in ejection fraction was unrelated to exercise conditioning was the lack of correlation between exercise performance and the ejection
fraction change: the ejection fraction decreased in
many women despite an exercise capacity equal to that
of men.
A further possibility to be considered is that middleaged women have a relatively reduced ability to increase left ventricular contractility in response to exercise stress compared with men of a similar age.
Decreases in ejection fraction were accompanied by
increases in end-diastolic counts, which is consistent
with a compensatory increase in cardiac size that
would be required to maintain stroke volume despite
reduced systolic function. Although this cannot be
proven, it raises the possibility that female sex may
have an influence on the contractile reserve of the
left ventricle. While a decrease in ejection fraction is
also consistent with myocardial ischemia, it seems unlikely that a large proportion of healthy female volunteers would experience myocardial ischemia during
exercise.
Clinical implications. The finding of
a uniform inin ejection fraction during exercise in asymptomatic men appears to confirm that a decrease in left
ventricular ejection fraction is highly specific for the
diagnosis of cardiac disease in male patients. It should
be remembered, however, that the specificity of a test
is influenced strongly by the patient population in
which it is employed. This point has been emphasized
recently by Rozanski et al. ,0 who noted that the specificity of radionuclide angiography decreased markedly
at their institution over a 5 year period during which
crease
CIRCULATION
PATHOPHYSIOLOGY AND NATURAL HISTORY-EXERCISE
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the study population dramatically changed through the
selection of patients with a higher pretest probability of
disease and the exclusion of many patients from cardiac catheterization. For this reason, ejection fraction
responses may be less uniform in men presenting for
investigation of chest pain than in normal male volunteers.
Berger et al.9 concluded, from a study of patients
with chest pain and normal coronary arteries, that failure of the ejection fraction to increase by 0.05 indicated "abnormal left ventricular reserve"; these investigators did not test an asymptomatic control group.
While our results do not exclude the possibility that
ischemia is responsible for failure of the ejection fraction to increase in some women with chest pain and
normal coronary arteries, the demonstration of a similar response in a large population of healthy women,
who had a very low probability of developing myocardial ischemia, implies that failure of the ejection
fraction to increase is nonspecific and cannot be interpreted as an indication of ischemia or myocardial dysfunction in women.
We thank Ms. Margaret Wilson and Ms. Cindy Baker for
their technical support, Dr. Kerry Lee for his assistance with
analysis, Medical Media Production Service at the VA Medical
Center for preparation of the illustrations, and Cathie Collins for
her excellent work in preparing the manuscript.
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Appendix
The following equations were used to calculate relative
changes in end-diastolic counts, stroke counts, count output,
and arteriovenous 02 difference from rest to exercise.
366
EX/R EDC
=ECEX
EDCR
EX/R SC
SCX
EDCEX X EFEX
SCR
EDCR
x
EFR
SCEX
X
HREX
Ex/R CO = CEX
COR
EX/R A- V02
SCR X HRR
A-VO2EEX-
VO0E
A VO2R
COEX X VO2R
X
COR
EX/R VO, X R/EX CO
where Ex = exercise; R rest; EDC = end-diastolic counts;
SC = stroke counts; CO = count output; A-V02 = arteriovenOUS 02 difference. EX/R represents the ratio of the exercise to the
resting value, and thus expresses the proportional change from
rest to exercise.
CIRCULATION
Sex-related differences in the normal cardiac response to upright exercise.
M B Higginbotham, K G Morris, R E Coleman and F R Cobb
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Circulation. 1984;70:357-366
doi: 10.1161/01.CIR.70.3.357
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