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Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:669-677

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:669-677.)
© 1995 American Heart Association, Inc.

Articles

Hemostatic, Metabolic, and Androgenic Risk Factors for Coronary Heart Disease in Physically Active and Less Active Postmenopausal Women

Edith T. Stevenson; Kevin P. Davy; Douglas R. Seals

From the Departments of Kinesiology (E.T.S., K.P.D., D.R.S.) and Medicine (Cardiology) (D.R.S.), University of Colorado, Boulder.

Correspondence to Edith T. Stevenson, PhD, University of Colorado, Department of Kinesiology, Campus Box 354, Boulder, CO 80309.


*    Abstract
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 *Abstract
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Abstract Physically active postmenopausal women have a lower incidence of coronary heart disease (CHD) than their more sedentary peers, but little information is available concerning the responsible mechanisms. The primary aim of this study was to test the hypothesis that physically active postmenopausal women demonstrate more favorable levels of hemostatic, metabolic, and androgenic CHD risk factors than less active control subjects. If so, a secondary aim was to determine which of the characteristics associated with a physically active lifestyle, ie, low body fat, a high-carbohydrate/low-fat diet, high maximal aerobic capacity (aerobic fitness), and high levels of physical activity, are most closely related to this lower risk profile. To address these aims, we compared CHD risk factors in physically very active women (n=14; age, 55±2 years) with those in healthy, nonobese sedentary control subjects (n=17; age, 56±1 years). Maximal aerobic capacity (fitness) was 83% higher (P<.001) in the physically active women. Concentrations of plasminogen activator inhibitor type 1 activity and tissue plasminogen activator antigen were lower (more favorable) (P<.005) in the physically active women versus control subjects, whereas plasma fibrinogen levels did not differ. The physically active women had lower (P<.01) fasting plasma insulin and glucose concentrations as well as smaller responses to an oral glucose challenge. Both total-body and abdominal fat levels were lower (P<.001) and lipid and lipoprotein profiles were generally more favorable (P<.05) in the physically active women. Plasma sex hormone–binding globulin concentrations were higher (P<.01) in the physically active women, indicating a lower androgenicity-related CHD risk. In addition, the physically active women consumed a diet that was higher (P<.002) in carbohydrates and lower (P<.02) in fat and protein. Stepwise multiple regressions indicated that although a portion of the observed variability in these CHD risk factors can be explained by physical activity levels per se, the associated differences in total body and abdominal fat, dietary composition, and aerobic fitness also contribute in a significant but selective manner. Thirty percent to 40% of each group were on hormone replacement therapy, but its effects appeared to be minimal. These results demonstrate that physically active postmenopausal women exhibit favorable levels of hemostatic, metabolic, and androgenic CHD risk factors, which could contribute to their lower incidence of CHD.


Key Words: aging • coronary heart disease • exercise • risk factors


*    Introduction
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Cardiovascular diseases (CVD), especially coronary heart disease (CHD) and cerebrovascular disease, are the leading causes of death, as well as morbidity and disability, in middle-aged and older American women.1 2 Recent estimates indicate that 1 in 9 women 45 to 64 years old has some form of CVD; after age 65 this ratio increases to 1 in 3 women.1 The health care costs associated with CVD in postmenopausal women alone have been estimated to exceed $11 billion per year.2 With the number of women >=45 years old increasing annually, the societal impact of CVD in this population will be even greater in the future.

Epidemiological data indicate that physically active postmenopausal women are at a lower risk of developing CVD in general and CHD in particular than their more sedentary peers.3 The mechanisms responsible for the lower CHD risk in physically active middle-aged and older women, however, have not been determined. Lower levels of total body fat and more favorable plasma lipid and lipoprotein profiles have been reported in physically active versus inactive postmenopausal women.4 5 6 7 8 However, little or no information is available on other CHD risk factors. Hemostatic factors, such as high levels of plasma fibrinogen, plasminogen activator inhibitor type 1 (PAI-1) activity, and tissue-type plasminogen activator (TPA) antigen, are associated with thrombosis,9 whereas other metabolic factors, such as elevated fasting plasma levels of glucose and insulin, glucose intolerance,10 11 high levels of abdominal fat, and high androgenicity (as reflected by low levels of sex hormone–binding globulin [SHBG]),12 13 are associated primarily with atherosclerosis. Importantly, there are no data on all of these CHD risk factors in a single population of physically active and inactive postmenopausal women. This is critical in light of recent findings indicating that unfavorable levels of these factors tend to occur together and, as such, result in a substantially higher risk of CHD than when they occur individually.14 15 16

If physically active postmenopausal women demonstrate more favorable levels of some or all of these CHD risk factors, an important question concerning the role of physical activity levels per se remains unanswered. High levels of physical activity are associated with low levels of total body and abdominal fat, high aerobic fitness, and often a high-carbohydrate/low-fat diet. Each of these factors may affect risk factors independently of physical activity levels.

The primary aim of this study was to test the hypothesis that physically active postmenopausal women demonstrate more favorable levels of hemostatic, metabolic, and androgenic CHD risk factors than less active control subjects. If so, a secondary aim was to determine which of the characteristics associated with a physically active lifestyle, ie, low body fat, a high-carbohydrate/low-fat diet, high maximal aerobic capacity (aerobic fitness), and high levels of physical activity, are most closely related to this lower risk profile. To address these aims, we used a cross-sectional study design in which middle-aged and older (masters) female endurance athletes were compared with age-matched, healthy, nonobese control subjects, similar to the experimental approach we used previously in men.17 18


*    Methods
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 *Methods
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Subjects
Thirty-one healthy women participated in this study: 14 highly trained runners (55±2 years old, mean±SEM; range, 49 to 67 years) and 17 age-matched, minimally active control subjects (56±1 years old; range, 50 to 64 years). The runners were selected from age-group winners in a local, national-class road race. The control subjects were recruited from respondents to newspaper advertisements. The runners had been training for 18±2 years (range, 10 to 40 years); they ran 31±3 miles/wk (range, 20 to 46 miles/wk). Most of them (12 of the 14) supplemented their running with 1 to 4 weekly cross-training sessions (swimming, bicycling, pool running, tennis). The women in the control group did not follow any program of regular physical exercise.

All subjects were free of overt coronary artery disease, as assessed by medical history, physical examination and by resting and maximal exercise electrocardiograms. Of the 31 subjects, 30 were postmenopausal, as indicated by plasma follicle stimulating hormone (FSH) levels >40 IU/L.19 One of the runners was experiencing menopausal symptoms, but her plasma FSH levels indicated that she was not yet postmenopausal. However, because inclusion of her data did not affect the mean values of the dependent variables of interest, she was included in the study. Four of the 14 active women ({approx}30%) and 7 of the control subjects ({approx}40%) were on oral hormone replacement therapy consisting of conjugated estrogen (Premarin, 0.625 mg/d) in combination with medroxyprogesterone acetate (Provera, 2.5 mg/d). None of the subjects smoked or took medications that could affect any of the dependent variables. Group data on maximal oxygen uptake (O2max) and vascular volumes have been reported elsewhere.20

The nature, purpose, and risks of the study were explained to each subject before written informed consent was obtained. The experimental protocol was approved by the Human Research Committee at the University of Colorado at Boulder. Procedures followed were in accordance with institutional guidelines.

Measurements
O2max was determined with on-line computer-assisted open-circuit spirometry during incremental treadmill exercise, as described previously.20 All anthropometric measurements were made by a single investigator while the subject was in a standing position. Waist circumference was measured at the narrowest part of the torso, and hip circumference was measured at the maximal extension of the buttocks.21 Body fat was estimated from the sum of skin folds measured at five body sites.22 Estimated daily energy expenditure was assessed by the Stanford Physical Activity Questionnaire.23 Daily dietary intake and composition were assessed from analyses of 3-day dietary intake records (Food Processor Plus, ESHA Research).

All measurements of blood-derived risk factors were performed in the clinical laboratory affiliated with the Clinical Research Center at the University of Colorado Health Sciences Center. Subjects reported to the Center between 7:30 and 9 AM after a 12-hour overnight fast and a 24-hour period with no strenuous physical activity. Upon arrival, each subject rested in a supine position while a catheter was inserted into an antecubital vein. After 20 minutes of supine rest in a quiet, semidarkened room (the typical procedure for basal measurements of these variables), 12 mL of blood was drawn for subsequent analysis of plasma levels of norepinephrine, fibrinogen, PAI-1 activity, TPA antigen, and FSH. Plasma norepinephrine concentrations were determined because of the postulated role of elevated sympathetic nervous system activity in syndromes associated with multiple risk factors.14 24 Plasma levels of PAI-1 activity were measured because it is known to inhibit fibrinolysis.9 Plasma concentrations of TPA antigen have been shown to be a risk factor for myocardial infarction and are associated with mortality in patients with CHD.25 26 Both of these factors are known to increase with age.27 Measurements of plasma TPA activity could not be obtained from the clinical laboratory. After 10 minutes in an upright sitting position (typically used for these measurements), 27 mL of blood was drawn to be analyzed for plasma lipids (total cholesterol [TC], HDL cholesterol [HDL-C], HDL3-C, and triglyceride [TG] levels), plasma SHBG concentrations, and fasting levels of plasma glucose and insulin. SHBG was determined to assess the level of androgenicity, which has been linked to syndromes associated with multiple risk factors14 24 28 ; low levels of SHBG reflect high androgenicity and vice versa.28 Because of the influence of estrogen on plasma SHBG levels, it was assessed only in those women who were not on hormone replacement. Immediately afterward, an oral glucose tolerance test was administered, as described in detail previously.17 Subjects ingested a standard glucose drink that contained 40 g glucose/m2 body surface area. Venous blood samples (5 mL each) were obtained 30, 60, 90, 120, and 180 minutes after glucose ingestion. Total areas under the concentration-time curves for plasma glucose and insulin were calculated by the trapezoid rule, in which only positive areas above fasting baseline levels were included, as described previously.17

Analyses
Conventional enzymatic methods were used to determine plasma TC and TG.29 30 Plasma HDL-C and HDL3-C levels were determined by the dextran precipitation technique31 ; plasma HDL2-C was calculated as the arithmetic difference between plasma HDL-C and HDL3-C. Plasma LDL-C levels were computed by the Friedewald equation32 as TC-HDL-TG/5. Plasma glucose levels were determined enzymatically33 and plasma insulin concentrations by radioimmunoassay with polyethylene gel.34 The Clauss method for clottable fibrinogen was used to determine plasma fibrinogen levels.27 Plasma PAI-1 activity27 and TPA antigen35 were determined by commercially available enzyme immunoassay kits (Instrumentation Laboratories). A competitive radioimmunoassay kit (Techland Sex Hormone Binding Globulin Kit, Wien Labs Inc) was used to measure plasma levels of SHBG.36 Plasma norepinephrine levels were determined with a radioenzymatic assay.37 A chemiluminescence immunometric assay kit was used to measure plasma FSH levels (Nichols Institute Diagnostics).38

Data Analysis
Differences in the dependent variables between the physically active women and control subjects were assessed by a multivariate analysis of variance (ANOVA). If a significant overall F (Wilks' lambda) was found, a one-way ANOVA was then used to locate group differences in each dependent variable. The significance level was set at P<.05. Simple linear regression analysis was used to assess relations between body fat and its distribution, diet, O2max, physical activity levels, hormone replacement, and the other dependent variables of the study. In addition, stepwise multiple regressions were used to assess the relative contributions of the physical activity–associated characteristics to each of the CHD risk factors.


*    Results
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Physical Characteristics
The physically active women and control subjects were similar in age, height, casual blood pressure at rest, and estimated fat-free mass, but body weight, body mass index, and resting heart rate were lower (P<.001) in the active women (Table 1Down). In addition, estimated daily energy expenditure and O2max, both relative to body weight, were higher (P<.001) in the active women.


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  		Table 1. Subject Characteristics

Hemostatic Factors
Plasma fibrinogen levels were similar in the two groups (P=.41) (Table 2Down). However, plasma concentrations of PAI-1 activity and TPA antigen were 67% and 44% lower (P<.005), respectively, in the physically active women relative to the control subjects.


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  		Table 2. Hemostatic Factors

Plasma Glucose and Insulin
Fasting plasma glucose (4.5±0.1 versus 5.2±0.1 mmol/L) and insulin (39±1 versus 49±4 pmol/L) levels were lower (P<.01) in the active women relative to the control subjects (Figs 1Down and 2Down). The increases in plasma glucose and insulin concentrations were smaller in the active women (P<.001) at each measurement point in response to the oral glucose challenge, and both the attainment of peak concentrations and the return to or below fasting levels were more rapid. Moreover, the areas under both the glucose and insulin concentration-time curves were smaller (P<.001) for the active women.



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  		Figure 1. Graph showing plasma glucose levels after a 12-hour fast (time 0) and during a 3-hour oral glucose tolerance test in the active women and controls (top). Bar graph showing total areas under the respective glucose curves (bottom). *P<.01.



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  		Figure 2. Graph showing plasma insulin levels after a 12-hour fast (time 0) and during a 3-hour oral glucose tolerance test in the active women and control subjects (top). Bar graph showing total areas under the respective insulin curves (bottom). *P<.01.

Body Composition and SHBG
Sum of skin folds and estimated percent body fat were 59% and 49% lower (P<.001), respectively, in the physically active women relative to the control subjects (Table 3Down). In addition, the active women had smaller (P<.001) waist circumferences, although there was no difference in waist-to-hip ratios between the two groups. Plasma SHBG levels were 83% higher (P<.01) in the active women.


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  		Table 3. Body Fat, Regional Fat Distribution, and SHBG

Plasma Lipids
There were no significant intergroup differences in plasma TC, although the physically active women tended to have lower (P=.13) levels (Table 4Down). Plasma total HDL-C tended to be higher (P=.09) and LDL-C levels lower (P=.10) in the active women versus control subjects. The active women had {approx}150% higher (P<.002) levels of plasma HDL2-C and lower (P<.004) levels of plasma TG. The atherogenic indexes TC/HDL-C and TC/HDL2-C were lower and HDL-C/LDL-C higher for the active women (all P<.05).


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  		Table 4. Plasma Lipid and Lipoprotein Levels

Dietary Intake
Total estimated daily caloric intake was similar for the two groups (1926±101 versus 1856±115 kcal, physically active women versus control subjects), but dietary composition differed. The percentages of protein and fat in the diets of the active women were significantly lower (P=.02) than those for the control subjects (13±1% versus 16±1% for protein; 23±2% versus 30±2% for fat), whereas carbohydrate intake was significantly higher (P=.002) for the active women (63±2% versus 54±1%). Dietary sodium intake was marginally lower (P=.07) for the active women relative to the control subjects (2165±163 versus 2660±192 mg/d), whereas sodium excretion and urinary sodium concentrations did not differ. In addition, alcohol and caffeine consumption was similar for the two groups.

Plasma Norepinephrine Level
Supine levels of plasma norepinephrine were similar in the two groups at rest (2.07±0.15 nmol/L for the physically active women versus 2.28±0.17 nmol/L for the control subjects; P=.39).

Influence of Hormone Replacement Therapy
To determine whether hormone replacement confounded the interpretation of differences between the physically active women and control subjects, the two subject groups were reanalyzed with the data from the 11 hormone replacement users (4 active women and 7 control subjects) excluded. The group differences discussed above were unchanged when only the non–hormone replacement data were examined. To test for a possible interaction between training status and hormone replacement, a multivariate ANOVA was performed on the dependent variables of the study; no significant interactions were found. To further examine the influence of hormone replacement independent of training status, the dependent variables were compared for the group of hormone replacement users (n=11; 4 active women and 7 control subjects) versus the group of nonusers (n=20; 10 active women and 10 control subjects). The only significant difference between the two groups was a lower level of TPA antigen in the users of hormone replacement (3.0±0.4 versus 5.0±0.6 ng/mL, P<.02). In addition, levels of fasting plasma insulin (3.9±0.4 versus 4.7±0.3 pmol/L, P=.06) and PAI-1 activity (3.7±1.1 versus 7.8±1.6 arbitrary units/mL, P=.08) were marginally lower with hormone replacement therapy.

Influence of Body Composition, Dietary Intake, Aerobic Fitness, and Level of Physical Activity on CHD Risk Factors
Differences between CHD risk factors in physically active women versus control subjects indicate that physical activity per se or some other closely related characteristics (body composition, dietary composition, and aerobic fitness) are associated with the favorable risk factor levels observed in the active women (Table 5Down). Univariate correlations showed significant, although primarily modest (R2 ranging from 12% to 49%), relations between body composition (body mass index, estimated percent body fat, and waist circumference), dietary composition (percentages of fat, carbohydrate, and protein in the diet), O2max, and the hemostatic, metabolic, and androgenic CHD risk factors. The only significant correlates of the level of physical activity were fasting plasma glucose concentrations and the areas under the insulin and glucose curves in response to an oral glucose tolerance test (R2 ranging from 28% to 45%).


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  		Table 5. Variance in Individual CHD Risk Factors Explained by Indexes of Body Composition, Dietary Composition, O2max, and Physical Activity as Assessed by Stepwise Regression Analysis

The results of the stepwise regression analyses indicated that abdominal fat (as estimated by waist circumference) and dietary composition were key correlates of levels of hemostatic factors (plasma PAI-1 activity and TPA antigen), plasma lipids and lipoproteins (HDL-C, TG, LDL-C, and the atherogenic index, TC/HDL-C), and the area under the insulin curve in response to an oral glucose tolerance test. Total body fat (as measured by estimated percent body fat and body mass index) was a primary determinant of levels of plasma SHBG and area under the insulin curve. Percent dietary fat was the strongest predictor of fasting plasma insulin concentrations. O2max was a key correlate of plasma HDL2-C concentrations and fasting glucose. The only CHD risk factor that included physical activity as a significant independent predictor was the area under the glucose curve in response to an oral glucose tolerance test.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The primary finding of this study is that physically very active postmenopausal women exhibit a superior hemostatic, metabolic, and androgenic risk factor profile for CHD relative to healthy, nonobese, but less active women. More specifically, to the best of our knowledge this is the first study to demonstrate more favorable plasma levels of PAI-1 activity and TPA antigen, plasma glucose regulation, and plasma SHBG concentrations in physically active women and one of few studies to show lower levels of abdominal fat in this population. A unique feature is the documentation of superior levels of a number of CHD risk factors in a single population of physically active postmenopausal women. An important secondary finding of the study is that the more favorable CHD risk factor profile observed in this population appears to be related to their body fat distribution, dietary composition, and aerobic fitness as much as or more than to their high levels of physical activity per se. Taken together, our findings provide experimental support for the hypothesis that the lower incidence of CHD in physically active middle-aged and older women may be due, in part, to this advantageous risk factor profile.

Hemostatic Factors
Blood clotting and intravascular thrombus formation are important in the development of acute coronary thrombosis.39 Plasma levels of fibrinogen, PAI-1 activity, and TPA antigen play a central role in the development of thrombosis and are associated with CHD.25 26 39 Fibrinogen has been shown to be an independent risk factor for CHD in women,39 whereas elevated levels of plasma PAI-1 activity and TPA antigen have been positively associated with myocardial reinfarction and CHD mortality.25 40 41

In our study, we found no difference in plasma fibrinogen concentration between the physically active women and control subjects; however, the levels of plasma PAI-1 activity and TPA antigen were markedly lower in the active women. A recent study on a large cohort of postmenopausal women 60 to 69 years of age reported an inverse relation between physical activity, as assessed by self-administered questionnaire, and levels of plasma fibrinogen.42 However, this relation was significant only within the subgroup of obese women; for nonobese women, plasma fibrinogen concentrations did not differ between women who exercised 4 or more times per week and those who exercised 0 or 1 time per week,42 consistent with our results. Another recent study on men reported a significant decrease in plasma fibrinogen levels in older (60 to 82 years) but not in young (24 to 30 years) healthy men after 6 months of endurance exercise training.27 However, the pretraining levels of the older men were substantially higher than those of the control subjects in our study (3.6 versus 2.9 g/L). The young men, with markedly lower baseline levels of plasma fibrinogen, exhibited no change after the 6-month exercise program (2.3 to 2.2 g/L). Hence, the nonsignificant difference in the plasma fibrinogen levels in the physically active women versus control subjects in our study may be due to the low levels in the control subjects.

To the best of our knowledge, no other studies have examined the relation between regular physical activity and plasma concentrations of PAI-1 activity and TPA antigen in postmenopausal women.43 In their study on men, Stratton et al27 reported significant reductions in plasma levels of both PAI-1 activity and TPA antigen after 6 months of endurance training in the older (60 to 82 years) but not in the young (24 to 30 years) subjects. Our results are consistent with this finding, although the differences between plasma levels of PAI-1 activity in our physically active women versus control subjects were greater than those reported by Stratton et al in older men before versus after exercise training. Taken together, our findings and those of Stratton et al indicate that physically active middle-aged and older men and women demonstrate plasma concentrations of PAI-1 activity and TPA antigen that should be associated with a lower risk of CHD.

Plasma Insulin and Glucose
Elevated fasting levels of plasma insulin and impaired glucose tolerance have been widely recognized as major independent risk factors for the development of CHD.10 11 14 In addition, there is evidence that individuals with normal glucose tolerance who have the highest plasma glucose concentrations in response to a glucose challenge are at an elevated risk of developing CHD.44

As emphasized recently by Haskell et al,43 no data exist on the relation between physical activity and fasting levels of glucose and insulin or glucose tolerance in postmenopausal women. Previous studies have examined these issues in older men or in mixed groups of men and women in which the results were not reported separately by sex.45 46 Our study is the first to report on healthy, nonobese postmenopausal women. Our data are consistent with the findings of previous studies on men and suggest that physically active postmenopausal women also demonstrate favorable fasting levels of glucose and insulin, as well as superior glucose tolerance and insulin responsiveness to an oral glucose challenge compared with less active control subjects. Although we did not measure insulin sensitivity directly, a strong correlation between fasting levels of plasma insulin and insulin sensitivity has recently been reported in nondiabetic humans.47 This finding, considered together with the markedly lower plasma insulin responses to the oral glucose tolerance test, suggests that the active women in our study were more insulin sensitive than the control subjects.

Body Composition
Body mass index, total body fat mass,48 and, more recently, abdominal body fat accumulation12 13 49 have all been associated with elevated risk of CHD. Of these factors, abdominal fat accumulation is generally recognized as the strongest independent risk factor for CHD.12 50 In our study we found significantly lower body weight, body mass index, sum of skin folds, estimated percent body fat, and waist circumference in the active women compared with the control subjects (Table 3Up). Waist-to-hip ratio did not differ between the two groups.

Although previous studies on postmenopausal women have generally reported an association between high levels of physical activity and reduced body weight and total body fat,4 8 45 51 there are few data on the relation between physical activity and regional body fat distribution in this population. Waist-to-hip ratio, one of the commonly used measures of body fat distribution, has typically been shown to remain unchanged with physical activity.45 Recently, it has been shown that waist circumference is a better correlate of computed tomography–determined visceral adipose tissue level than waist-to-hip ratio and hence is a preferred index of cardiovascular risk.50 52 The lower waist circumference associated with high levels of physical activity in the present study is directionally consistent with the reduction observed after exercise training in older women by Kohrt and colleagues,45 although the magnitude of the physical activity–related difference was much greater in our cross-sectional comparison.

Androgenicity
SHBG is a circulating steroid-binding protein that binds testosterone with high affinity and estrogen with lower affinity. Hence, low SHBG levels are associated with a high ratio of free to bound testosterone, suggesting elevated androgenicity. Previous findings indicate that plasma SHBG levels are lower in postmenopausal than in premenopausal women and that these lower levels are associated with increased body mass index.28 The present study, in which the physically active women exhibited significantly higher levels of plasma SHBG than the control subjects, provides the only available data on the association between physical activity and plasma SHBG concentrations in women, either premenopausal or postmenopausal. Our findings suggest that a physically active lifestyle is related to lower androgenicity in this population. Because of its proposed link to CHD risk as a key component of the insulin resistance syndrome,14 24 this lower androgenicity is probably associated with reduced coronary risk in women.

Plasma Lipids and Lipoprotein Levels
Plasma lipid and lipoprotein abnormalities have been identified as major risk factors for the development of CHD.53 54 The findings of our study suggest that in general, a physically active lifestyle is associated with a more favorable lipid and lipoprotein profile in healthy, nonobese postmenopausal women. In particular, our physically active women demonstrated lower plasma TG and atherogenic indexes, TC/HDL-C and TC/HDL2-C, as well as higher plasma HDL2-C and HDL-C/LDL-C. In addition, the active women tended to have lower levels of plasma TC and LDL-C and higher levels of total plasma HDL-C than the control subjects. These findings are generally consistent with those from previous studies in postmenopausal women and, thus, confirm a reduced lipid-related CHD risk in this population.5 6 7 8 55 56 57

Influence of Hormone Replacement Therapy on Risk Factors for CHD
Because hormone replacement has been independently associated with risk factors for CHD, it is possible that in our cross-sectional comparison, some or all of the observed CHD risk factor differences between the active women and control subjects were due to hormone replacement rather than to the high level of chronic physical activity per se. Our findings indicate that although hormone replacement may have influenced the plasma levels of PAI-1 activity and TPA antigen in this population of women, it was not a major determinant of the other CHD risk factors. It should be emphasized, however, that the number of women using hormone replacement in our study was small and, hence, some relations may have gone undetected.

Influence of Body Composition, Dietary Intake, Aerobic Fitness, and Level of Physical Activity on Risk Factors for CHD
One of the aims of this study was to determine the contributions of both high levels of physical activity per se and the associated low levels of total body and abdominal fat, a high-carbohydrate/low-fat and low-protein diet, and high aerobic fitness to hemostatic, metabolic, and androgenic CHD risk factors. The results of the stepwise multiple regression analyses (Table 5Up) indicate that waist circumference, rather than percent total body fat or waist-to-hip ratio, was responsible for a significant portion of the explained variability in the plasma levels of PAI-1 activity and TPA antigen as well as lipid and lipoproteins of the healthy, nonobese postmenopausal women in this study. This confirms previous findings concerning the importance of abdominal adiposity rather than levels of total body fat to risk factors for CHD.12 50 The finding that waist circumference was a better predictor of these risk factors than waist-to-hip ratio is not surprising in light of recent reports on the preference of waist circumference over waist-to-hip ratio as a measure of abdominal adiposity.50 52 Another finding from the stepwise regression analysis is that aerobic fitness (as assessed from O2max) explained a significant portion of the explained variability in plasma levels of HDL2-C. This is consistent with the hypothesis that HDL2-C is the HDL-C subfraction most modulated by physical activity.58 59 A third observation was that the estimated physical activity levels of the subjects accounted for the largest portion of the variability in the area under the glucose curve during the oral glucose tolerance test. This link between physical activity and glucose tolerance may be due in part to the acute effects of muscle contraction (exercise) on peripheral glucose uptake.60 Finally, the finding that body mass index was responsible for most of the explained variability in plasma SHBG levels is consistent with previous findings28 61 as well as with the reported link between obesity and elevated androgenicity.62

Clinical Significance
Recently a multiple risk factor syndrome, referred to variously as syndrome X or the metabolic or insulin-resistance syndrome,14 15 16 has been identified as an important antecedent to CHD in middle-aged and older adults. This syndrome refers to a clustering of CHD risk factors that is often observed in a single individual, including hyperlipidemia, hyperinsulinemia, glucose intolerance and insulin resistance, whole-body and abdominal obesity, alterations in fibrinogen and modulators of fibrinolytic activity, and elevated androgenicity (as reflected by decreased levels of SHBG in women). Part of the marked increase in risk of CHD with advancing age appears to be due to an increased prevalence of this clustering of risk factors. Postmenopausal women, in particular, experience an accelerated development of the syndrome and its individual components. Hence, it is clinically important to examine lifestyle characteristics that may exert a beneficial modulatory influence on a number of these risk factors. In the present study, we show that a physically active lifestyle is favorably associated with most of the factors of this syndrome in a single population of healthy, nonobese postmenopausal women. In addition, we show that in these women, body fat and its distribution, dietary composition, and aerobic fitness are also important correlates of the individual components of this syndrome. Thus, our findings suggest that the lower risk of CHD observed in physically active middle-aged and older women may be in part the result of their superior levels of these hemostatic, metabolic, and androgenic risk factors.

Limitations
The primary limitation of this cross-sectional study is that genetic makeup may influence coronary risk factors independently of physical activity or its correlates. Thus, the physically active women may both be active and demonstrate a superior risk factor profile because of a genetic predisposition. Second, the control group in our study was exceptionally healthy. Although they were not exercising regularly, most of them were at least minimally physically active. Moreover, the control subjects were nonobese. Obesity per se is associated with adverse levels of these risk factors and with the insulin resistance syndrome.14 15 Because of this, our control subjects may not have been representative of the more sedentary overweight postmenopausal American woman. If so, differences between physically active versus sedentary postmenopausal American women were probably underestimated in our study.

Conclusions
We have shown that a physically active lifestyle is associated with a favorable hemostatic, metabolic, and androgenic risk factor profile for CHD in healthy, nonobese postmenopausal women. In addition to high levels of physical activity, low levels of total body and abdominal fat, a high-carbohydrate/low-fat and low-protein diet, and high aerobic fitness also appear to contribute to the activity-related differences in CHD risk factors in this population.


*    Acknowledgments
 
This investigation was supported by Public Health Services research grant 5-01-RR-00051 from the Division of Research Resources, Andrus Foundation grant AARPAF-OCG0937B, and National Institutes of Health (NIH) grants HL-39966 and AG-06537. Drs Stevenson and Davy were supported by individual National Research Service Awards HL-08870 and HL-08834, respectively, from the National Heart, Lung, and Blood Institute, NIH. Dr Seals was supported in part by National Institute on Aging Research Career Development Award AG-00423.

Received November 21, 1994; accepted February 21, 1995.


*    References
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