Download Gender-related differences in cardiac response to supine

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JACC Vol. 13, No. 3
March 1, 1989:6X-9
Gender-Related Differences in Cardiac Response to Supine Exercise
Assessed by Radionuclide Angiography
PETER
IAN
C. HANLEY,
P. CLEMENTS,
MANUEL
Rochester,
L. BROWN,
MD, FACC,
MD, FACC,
ALAN
ALFRED
MD, RAYMOND
R. ZINSMEISTER,
A. BOVE,
J. GIBBONS,
PHD,
MD, PHD, FACC,
MD, FACC
Minnesota
This study examines the recently reported gender differences in cardiac responses to exercise. The study group
consisted of 192 men and 67 women with a low probability
of coronary artery disease who underwent supine exercise
radionuclide angiography.
Men had a lower rest ejection fraction than that of
women (0.63 versus 0.66, p = 0.02) and greater increases in
ejection fraction with exercise (0.08 versus 0.02, p =
0.0001). The slope relating ejection fraction to metabolic
equivalents of exercise (METS)was greater (p = 0.004) for
men, even after adjustment for differences in rest ejection
fraction and end-diastolic volume index. Compared with
In recent years it has been reported that the cardiac response
to exercise of women may differ from that of men. Gibbons
et al. (1) observed that the ejection fraction response to
exercise measured by radionuclide angiography exhibited a
gender difference. The ejection fraction failed to increase
during exercise in approximately 30% of women, but in only
10% of men, who had chest pain and normal coronary
arteries. The relatively poor specificity for radionuclide
angiographic results in women has been confirmed by others
(2,3). On the basis of these results, in a small number of
normal volunteers, Higginbotham et al. (4) suggested that
these observations are due to a gender difference in the
response of the ejection fraction and end-diastolic volume to
upright exercise. The purpose of this study was to examine
gender differences during supine exercise in a much larger
series of patients with a low probability of coronary artery
disease.
From the Division of Cardiovascular Diseases and Internal Medicine and
the Sections of Medical Research Statistics and Diagnostic Nuclear Medicine,
Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
Manuscript received February 1, 1988; revised manuscript received
October 12, 1988, accepted October 20, 1988.
Address for reorints: Raymond J. Gibbons, MD, Mayo Clinic, 200 Second
Street Southwest, Rochester, Minnesota 55905.
01989 by the American College of Cardiology
men, women had a smaller rest end-diastolic volume index
(87 versus 97 ml/m’, p = 0.003) and a greater increase in
end-diastolic volume index with exercise (6 versus -2 ml/
m2, p = 0.002).
The slope relating end-diastolic volume to METS was
greater for women, even after adjustment for differences in
rest end-diastolic volume index and peak work load. There
are clear gender differences in the supine exercise response
of ejection fraction and end-diastolic volume that are not
explained by differences in exercise capacity.
(J Am Co11Cardiol1989;13:624-9)
Methods
Study subjects. The study group consisted of 192 men
and 67 women who underwent radionuclide angiography in
our laboratory between December 1983and September 1986
and satisfied the following criteria indicating a low probability of coronary artery disease: age ~50 years, no chest pain
or nonanginal chest pain (by history before exercise testing),
nonischemic exercise electrocardiographic (ECG) response,
no chest pain during exercise, a peak exercise heart rate
>120 beatslmin during exercise and a rest radionuclide
angiographic ejection fraction >50%. Patients underwent a
careful clinical evaluation; those with a cardiac pacemaker,
congenital heart disease, other valvular heart disease (including mitral valve prolapse with significant regurgitation),
hypertrophic cardiomyopathy, previous cardiac surgery,
congestive heart failure, hypertension, previous myocardial
infarction or left bundle branch block were excluded. The
major clinical indication for these studies was patient reassurance, in individuals who were asymptomatic or had
noncardiac chest pain. Patients taking a beta-receptor
blocker, calcium channel blocker or long-acting nitrate were
also excluded.
Exercise protocols and radionuclide angiography. Rest
and exercise radionuclide angiograms were obtained from all
0735-1097/89/$3.50
JACC Vol. 13, No. 3
March 1, 1989:624-9
GENDER-RELATED
625
HANLEY ET AL.
DIFFERENCES IN EXERCISE
patients in the supine position. The 12 standard ECG leads
were continuously monitored and recorded every minute.
Blood pressure was monitored indirectly in the right arm
with the use of a sphygmomanometer. The patients’ erythrocytes were labeled with the use of 30 mCi of technetium99m and the modified in vivo method of Callahan et al. (5).
After rest blood pool imaging, supine exercise was performed on a bicycle ergometer table. The exercise protocol
began at a work load of 300 kpm/min; the work load was
increased every 3 min in increments of 300 kpmlmin. The
initial work load and incremental work load were occasionally modified by the monitoring cardiologist, depending on
the patient’s clinical status and performance at earlier exercise levels. An attempt was made to maintain the work load
constant throughout each 3-min stage. The usual exercise
end points used in our laboratory include 1) severe fatigue, 2)
moderate or severe chest pain, 3) severe arrhythmia, and 4)
marked ECG changes (horizontal or downsloping ST segment depression ~0.2 mV). However, no patient in this
study had exercise discontinued because of ischemic chest
pain, severe arrhythmia or ECG abnormalities; severe fatigue was their exercise end point.
Repeat blood pool imaging was obtained during the last 2
min of each exercise stage in the left anterior oblique view
that best separated the ventricles. Acquisitions were gated to
the patients’ ECG and collected at 16 frames/cardiac cycle
with the use of standard gamma cameras. A blood sample
was obtained immediately after exercise for cardiac volume
determinations. Heart rate and systolic and diastolic blood
pressure were obtained at rest and at maximal work load.
The peak rate-pressure product was calculated as the product of peak exercise heart rate and peak systolic blood
pressure.
Data processing. Radionuclide data were processed with
use of a commercially available dedicated computer system
and software (Medical Data Systems) and previously reported techniques (6,7). The left ventricular region of interest was identified in each frame with use of a second
derivative technique and a background region was defined 5
pixels lateral to the left ventricular systolic region. Ejection
fraction was calculated from the background-corrected left
ventricular counts versus time curve by use of a commercially available operator interactive program. The change in
ejection fraction was computed as peak exercise ejection
fraction minus rest ejection fraction. End-diastolic volume
was determined with a count-based method (8) and a previously reported regression equation from this laboratory (9).
The end-diastolic volume index was determined by dividing
end-diastolic volume by body surface area; the correlation
coefficient for end-diastolic volume determined by this
method compared with contrast ventriculography has been
previously reported as 0.85 (9). Previous studies from this
laboratory (10) have demonstrated that a single rest blood
sample may be employed for volume measurements be-
0.50
fi
1
2
3
4
METS
5
6
of
7
*
9
to
exercise
Figure 1. Data from an individual patient showing the relation
between ejection fraction and metabolic equivalents (METS) of
exercise at rest at four different levels of exercise. A linear model
was used to compute the slope and intercept of the ejection fraction
response in each patient.
cause, with this labeling method, plasma activity is unchanged with exercise. Oxygen consumption (‘?OJ at peak
exercise was estimated from the formula (I 1):
Q
= ‘* x work load (kpmimin)] t 300
weight (kg)
Estimated oxygen consumption is a measure of exercise
intensity and reflects the fact that subjects of different body
size are at different levels of exercise intensity at the same
bicycle work load. Metabolic equivalents of exercise
(METS) can be estimated by dividing VO, by 3.5.
Data analysis/statisticalmethods. Comparison of men and
women on single response values (for example, METS) was
based on the two-sample t test on the Wilcoxon rank sum,
whereas multivariate comparisons (for example, rest and
peak values, alone, of ejection fraction) were based on
Hotelling’s TZ statistic, a multivariate extension of the usual
two sample t test. Hemodynamic variables are presented in
terms of medians and percentiles, as preliminary analysis
suggested that several of these variables are not “normally”
distributed.
The data comprising ejection fraction response and enddiastolic volume response at rest and at each subsequent
exercise level were first summarized within subjects. A
linear model with METS as the independent variable was
used to compute the slope and intercept for ejection fraction
response in each subject (Fig. 1). The end-diastolic volume
values within a subject were first “normalized” by dividing
each exercise value by the rest volume. These ratios were
then transformed to log scale yielding a measure of “relative
change” in end-diastolic volume with exercise. A linear
model with METS as the independent variable was again
used to compute a slope and intercept term for each subject
by using just the (log) normalized values during exercise
(Fig. 2).
A plot of the resulting slopes for both ejection fraction
response and end-diastolic volume response against intercept values (which closely approximate the rest values)
626
JACC Vol. 13, No. 3
March 1, 1989:624-9
HANLEY ET AL.
GENDER-RELATED DIFFERENCES IN EXERCISE
0.3
0.2 -
4
(E-z,.,,)
0.1 -
O.O -0.1
-0.2
-0.3
.
.
.
II
1
2
3
I
I
I
I
I
I
4
5
6
7
8
9
10
METS of exercise
Figure2. Data from an individual patient showing the relation
between end-diastolic volume (EDV) and metabolic equivalents
(METS) of exercise at four different levels of exercise. End-diastolic
volume at each level of exercise was divided by the rest enddiastolic volume, thereby presenting a measure of “relative change”
with exercise. These ratios were transformedinto a log scale; with
use of a linear model, a slope and intercept were computedfor each
subject.
indicated that higher intercepts corresponded to smaller
slope values. The comparison of men and women was based
on linear regression analysis with the individual subject
estimated slope values as the dependent variables. In the
comparison of ejection fraction response, the intercept and
(log) rest end-diastolic volume index along with gender (as a
dummy regression variable) were the independent variables.
For the comparison of normalized end-diastolic volume
index response, the intercept, peak metabolic equivalents
and gender were the independent variables.
To summarize and display the group slope values (men,
women), the least squares estimated mean slopes (?2 SE)
were computed for the ejection fraction response adjusting
for the intercept and the rest end-diastolic volume index.
The least squares estimated mean slopes were also computed for the normalized end-diastolic volume response
adjusting for peak work load and the intercept.
Results
Patient group characteristics(Table 1). The average age
of both groups was similar. The men were significantly taller
and heavier than the women. Thirty-eight percent of the men
and 45% of the women exceeded their ideal body weight (12)
by 25%; this difference was not significant.
Exercise and ECG test response variables (Table 2). The
heart rate at rest was lower in men (median 69) than in
women (median 77). Systolic blood pressure was slightly
higher at rest in men, but no difference was detected in the
rate-pressure product at rest between men and women. At
peak exercise, both men and women achieved similar peak
heart rates. However, peak systolic blood pressure was
higher in men (median 200 mm Hg) than in women (median
170 mm Hg), as was the rate-pressure product (median
30,752 for men compared with 26,180 for women). The
median peak work load level achieved by men was almost
twice as high as that for women (1,100 versus 600 kprn/min).
There was also a highly significant (p < 0.0001) difference in
estimated metabolic equivalents of exercise (METS) between men (7.0 METS) and women (5.4 METS).
Radionuclide angiographic test response variables (Table
3). The rest ejection fraction for men (median 0.63) was
significantly lower than that for women (median 0.66). Both
change in ejection fraction (0.02 for women versus 0.08 for
men) and peak exercise ejection fraction (0.68 for women
versus 0.71 for men) were significantly lower for women than
for men. Thirty percent of the women and 16% of the men
decreased their ejection fraction with exercise (change in
ejection fraction CO). The end-diastolic volume index in
women was smaller at rest (87 versus 97 ml/m*, p < 0.005).
With exercise, women had a slight increase (6 ml/m*) in
end-diastolic volume index, whereas men had a slight decrease (-2 ml/m*); this difference was highly significant (p <
0.005).
Radionuclide angiograpbic test response by statistical
model (Fig. 3 and 4). The slope of ejection fraction versus
estimated METS was significantly (p < 0.005) greater for
men than for women (Fig. 3), even after adjustment for
gender differences in rest ejection fraction and rest enddiastolic volume index. The slope of normalized enddiastolic volume versus estimated METS was significantly (p
< 0.05) greater for women than for men (Fig. 4) even after
adjustment for gender differences in rest end-diastolic volume index and peak work load.
Discussion
This study was designed to evaluate possible gender
differences in exercise ventricular performance in a clinical
patient group without coronary artery disease. The study
group was entirely composed of patients who, on the basis of
Table1. Patient Characteristics
Age (median; 25th, 75th percentile) (yr)
Weight (median; 25th, 7Sth percentile) (kg)
Height (median; 25th, 75th percentile) (cm)
% in excess of 1.25 x ideal weight
Men
(n = 192)
Women
(n = 67)
p Value
41;36,45
84;76,92
178;174,183
38%
40;34,43
65;58,77
165;16,168
45%
NS
<O.oool
<O.oool
NS
JACC Vol. 13, No. :i
March I. 1989:62&Y
GENDER-RELATED
HANLEY ET AL.
DIFFERENCES IN EXERCISE
627
Table 2. Exercise and Electrocardiographic Response Variables
Men (n = 192)
(median; 25th. 75th
percentile)
Women (n = 67)
(median; 25th, 75th
percentile)
p Value
Heart rate
Rest
69; 60, 79
77; 69, 85
10.0001
156; 142, 170
151; 137. 169
NS
Rest
122; 118. 132
120; 110. 130
CO.05
Peak exercise
200: 180. 215
170: 150. 180
<0.0001
Peak exercise
Systolic blood pressure
Heart rate )i blood pressure
8,665; 7,285, 10,170
9,240; 8.120, 10,148
NS
30,752; 27.930. 34,219
26,180; 22,500, 29,070
600; 600, 700
<O.OOOl
Rest
Peak exercise
Work load (kpm per min)
1,050: 900. 1,200
Estimated METS
7; 6. 8.5
5.4: 4.3. 6.1
<0.0001
<O.OOOl
METS = metabolic equivalents of exercise
Bayes’ theorem. would be predicted to have a low probability of coronary artery disease. The groups were well
matched for age and no patient was >50 years old; hence,
differences in exercise response between men and women
should not be related to age.
Gender differences in work load, exercise intensity and
blood pressure response. The men were found to have sig-
nificantly higher values for exercise work load, exercise
intensity (estimated metabolic equivalents [METS]), exercise systolic blood pressure and exercise rate-pressure product. We do not believe that this difference reflects a lack of
motivation on the part of the women in the study to exercise,
because the values achieved are equivalent to those
achieved by normal volunteer women in the study by Higginbotham et al. (4) and because all our patients were
exercised to an end point of severe fatigue. Although the
physical activity levels and general level of conditioning of
Table 3. Radionuclide Angiographic Variables at Rest and
During Exercise
Men (n = 192)
(mean ? SEM)
Women (n = 67)
(mean +- SEM)
Rest
0.63 (kO.01)
0.66 (?O.Ol)
CO.05
Peak exercise
0.71 (?O.Ol)
0.68 (ZO.01)
<0.05
0.02 (?O.Ol)
<O.OOOl
p Value
EF
AEF
Mean
25th percentile
75th percentile
EDVI
Rest (ml/m’)
Peak exercise (mum’)
AEDVI (ml/m’)
0.08 (+O.Ol)
0.03
0.13
-0.02
0.09
97 (22)
87 (%3)
<0.005
95 (22)
-2 (?I)
93 (24)
6 Ii-?)
NS
10.005
EDVI = end-diastolic volume index; EF = ejection fraction: AEDVI =
exercise end-diastolic volume index - rest end-diastolic volume index: AEF
= exercise ejection fraction - rest ejection fraction.
our subjects are not known, their obesity and exercise
intensity achieved suggest a sedentary lifestyle. Peak estimated METS were lower in this study than described in most
of the exercise studies in which well conditioned subjects
have been evaluated. However, our estimates of METS do
not differ significantly from those actually measured by
DeBusk et al. (13) and Higginbotham et al. (4) in untrained or
sedentary subjects.
Ejection fraction response: comparison with previous studies. The gender difference in ejection fraction response in
the current study is similar to that described by others in
clinical patient groups. In the current study, the ejection
fraction decreased with exercise in 30% of the women and
only 16% of the men. These values should be compared with
the 30% for women and 10% for men reported by Gibbons et
al. (1) in patients with normal coronary arteries. These latter
results (I) have been attributed to “post-test referral bias”
(14), because only patients referred for coronary angiography were included. Clearly, this explanation cannot apply to
the current study population, in which coronary angiography
was not required. The gender difference in change in ejection
fraction in this clinical patient population is not as striking as
that reported by Higginbotham et al. (4) in normal volunteers. Change in ejection fraction was 50.05 in 60% of the
women and 43% of the men in our study compared with 56%
and 7% reported by Higginbotham et al. (4) for women and
men, respectively.
The only previous investigation to explore the mechanism
of the disparity in change in ejection fraction between men
and women has been that of Higginbotham et al. (4). There
were several key differences in methodology between their
study and the current study. We employed supine rather
than upright exercise and utilized a large study group selected from a clinical patient population rather than from
normal volunteers. In addition, we examined changes in
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JACC Vol. 13. No. 3
March I, 1989:6249
HANLEY ET AL.
GENDER-RELATED DIFFERENCES IN EXERCISE
determined, because echocardiography was not performed
routinely. However, it is possible that this finding was more
common in women. Previous studies (20,21) on the effect of
mitral valve prolapse on exercise left ventricular function
have yielded conflicting results.
Conclusions. Our data and those of Higginbotham et al.
(4) suggest a gender difference in the response of ejection
fraction and end-diastolic volume index to both upright and
supine exercise. The gender difference in exercise capacity
observed in our clinical patient population does not appear
to explain the observed differences in the response of
ejection fraction and end-diastolic volume index.
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629
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