Elaine N. Meilahn

Menopause and risk factors for coronary heart disease

Abstract Postmenopausal women are believed to have a higher risk of coronary artery disease than premenopausal women. In this study, we prospectively determined changes in coronary risk factors that were attributable to natural menopause in 541 healthy, initially premenopausal women 42 to 50 years of age. After approximately 2 1/2 years, 69 women had spontaneously stopped menstruating for at least 12 months, and 32 women had stopped natural menstruation and received hormone-replacement therapy for a period of at least 12 months. An equal number of age-matched premenopausal women in the study group served as controls. In women who had a natural menopause and did not receive hormone-replacement therapy, serum levels of high-density lipoprotein (HDL) cholesterol declined as compared with those of premenopausal controls (-0.09 vs. 0.00 mmol per liter; P = 0.01), and levels of lowdensity lipoprotein (LDL) cholesterol increased (+0.31 vs. +0.14 mmol per liter; P = 0.04). In menopausal women who received hormone...

Relationship of C-Reactive Protein to Risk of Cardiovascular Disease in the Elderly Results From the Cardiovascular Health Study and the Rural Health Promotion Project

Markers of inflammation, such as C-reactive protein (CRP), are related to risk of cardiovascular disease (CVD) events in those with angina, but little is known about individuals without prevalent clinical CVD. We performed a prospective, nested case-control study in the Cardiovascular Health Study (CHS; 5201 healthy elderly men and women). Case subjects (n = 146 men and women with incident CVD events including angina, myocardial infarction, and death) and control subjects (n = 146) were matched on the basis of sex and the presence or absence of significant subclinical CVD at baseline (average follow-up, 2.4 years). In women but not men, the mean CRP level was higher for case subjects than for control subjects (P < or = .05). In general, CRP was higher in those with subclinical disease. Most of the association of CRP with female case subjects versus control subjects was in the subgroup with subclinical disease; 3.33 versus 1.90 mg/L, P < .05, adjusted for age and time of follow-up. Case-control differences were greatest when the time between baseline and the CVD event was shortest. The strongest associations were with myocardial infarction, and there was an overall odds ratio for incident myocardial infarction for men and women with subclinical disease (upper quartile versus lower three quartiles) of 2.67 (confidence interval [CI] = 1.04 to 6.81), with the relationship being stronger in women (4.50 [CI = 0.97 to 20.8]) than in men (1.75 [CI = 0.51 to 5.98]). We performed a similar study in the Rural Health Promotion Project, in which mean values of CRP were higher for female case subjects than for female control subjects, but no differences were apparent for men. Comparing the upper quintile with the lower four, the odds ratio for CVD case subjects was 2.7 (CI = 1.10 to 6.60). In conclusion, CRP was associated with incident events in the elderly, especially in those with subclinical disease at baseline.

High blood pressure and bone-mineral loss in elderly white women: a prospective study

Summary Background High blood pressure is associated with abnormalities in calcium metabolism. Sustained calcium loss may lead to increased bone-mineral loss in people with high blood pressure. We investigated the prospective association between blood pressure and bone-mineral loss over time in elderly white women. Methods We studied 3676 women who were initially assessed in 1988–90 (mean age 73 years [SD 4, range 66–91 years]; mean bodyweight 65·3 kg [11·5]; blood pressure 137/75 mm Hg [17/9]) who were not on thiazide diuretics. Mean follow-up was 3·5 years. Anthropometry, blood pressure, and bone-mineral density at the femoral neck were measured at baseline and bone densitometry was repeated after 3·5 years by dual-energy X-ray absorptiometry. Findings After adjustment for age, initial bone-mineral density, weight and weight change, smoking, and regular use of hormone-replacement therapy, the rate of bone loss at the femoral neck increased with blood pressure at baseline. In the quartiles of systolic blood pressure, year bone losses increased from 2·26 mg/cm2 (95% CI 1·48–3·04) in the first quartile to 3·79 mg/cm2 in the fourth quartile (3·13–4·45; test for heterogeneity, p=0·03; test for linear trend, p=0·01), equivalent to yearly changes of 0·34%(0·20–0·46) and 0·59% (0·49–0·69; test for heterogeneity, p=0·02; test for linear trend, p=0·005). There was no significant interaction with age. The exclusion of women on antihypertensive drugs did not alter the results. For diastolic blood pressure, there was an association with bone loss in women younger than 75 years. Interpretation Higher blood pressure in elderly white women is associated with increased bone loss at the femoral neck.This association may reflect greater calcium losses associated with high blood pressure, which may contribute to the risk of hip fractures.

Hormone Replacement Therapy, Inflammation, and Hemostasis in Elderly Women

Lipid-lowering by postmenopausal hormone therapy (HRT) explains only partly the assumed coronary risk reduction associated with therapy. To explore other possible mechanisms, we studied associations of HRT use with inflammation and hemostasis risk markers in women >/=65 years of age. Subjects were selected from 3393 participants in the fourth year examination of the Cardiovascular Health Study, an observational study of vascular disease risk factors. After excluding women with vascular disease, we compared levels of inflammation and hemostasis variables in the 230 women using unopposed estrogen and 60 using estrogen/progestin, with those of 196 nonusers selected as controls. Compared with nonusers, unopposed estrogen use was associated with 59% higher mean C-reactive protein (P<0.001), but with modestly lower levels of other inflammation indicators, fibrinogen, and alpha-1 acid glycoprotein (P<0.001). Factor VIIc was 16% higher among estrogen users (P<0.001), but this was not associated with higher thrombin production (prothrombin fragment 1-2), or increased fibrin breakdown (D-dimer). Concentration of plasminogen activator inhibitor-1 was 50% lower in both using groups (P<0.001) compared with nonusers, and this was associated with higher plasmin-antiplasmin complex: 8% higher in estrogen and 18% higher in estrogen/progestin users (P<0. 05). Relationships between the markers and hormone use were less pronounced in estrogen/progestin users, with no association for C-reactive protein except in women in upper 2 tertiles of body mass index (P for interaction, 0.02). The direction and strength of the associations of HRT use with inflammation markers differed depending on the protein, so it is not clear whether HRT confers coronary risk reduction through an inflammation-sensitive mechanism. Associations with hemostasis markers indicated no association with evidence of procoagulation and a possible association with increased fibrinolytic activity.

Waist to hip ratio in middle-aged women. Associations with behavioral and psychosocial factors and with changes in cardiovascular risk factors.

Waist to hip ratio (WHR) was measured in 487 middle-aged women participating in the Healthy Women Study. Upper body fat distribution was found to be associated with numerous behaviors that affect cardiovascular risk, including smoking, low exercise levels, weight gain during adulthood, and higher caloric intake. Moreover, WHR was also associated with higher levels of anger, anxiety, and depression and lower levels of perceived social support. Women with upper body fat obesity had higher systolic blood pressure, total cholesterol, low density lipoprotein cholesterol, triglycerides, and apolipoprotein B and lower levels of high density lipoprotein (HDL) and the HDL subfractions 2 and 3. These associations remained significant after adjusting for body mass index. Among 108 women who had repeat measurements of WHR, changes in WHR over a 3-year period were significantly correlated with changes in activity and with decreases in HDL2. Thus, WHR appears to be an integral component of the cardiovascular risk profile. WHR is related to those behaviors and psychosocial attributes that influence cardiovascular risk.

The Relationship of Fibrinogen and Factors VII and VIII to Incident Cardiovascular Disease and Death in the Elderly Results From the Cardiovascular Health Study

Little is known about the prospective associations of fibrinogen, factor VII, or factor VIII with cardiovascular disease (CVD) and mortality in the elderly. At baseline in the Cardiovascular Health Study (5888 white and African American men and women; aged >/=65 years), we measured fibrinogen, factor VIII, and factor VII. We used sex-stratified stepwise Cox survival analysis to determine relative risks (RRs) for CVD events and all-cause mortality (up to 5 years of follow-up), both unadjusted and adjusted for CVD risk factors and subclinical CVD. After adjustment, comparing the fifth quintile to the first, fibrinogen was significantly associated in men with coronary heart disease events (RR=2.1) and stroke or transient ischemic attack (RR=1.3), and also with mortality within 2.5 years of follow-up (RR=5.8) and later (RR=1.7). Factor VIII was significantly associated in men with coronary heart disease events (RR=1.5) and mortality (RR=1.8), and in women with stroke/transient ischemic attack (RR=1.4). For both factors, values were higher in those who died, whether causes were CVD-related or non-CVD-related, but highest in CVD death. Factor VII exhibited associations with incident angina (RR=1.44) in men and with death in women (RR, middle quintile compared with first=0.66). However, in general, factor VII was not consistently associated with CVD events in this population. We conclude that, if confirmed in other studies, the measurement of fibrinogen and/or factor VIII may help identify older individuals at higher risk for CVD events and mortality.

The relationship of smoking cessation to coronary heart disease and lung cancer in the Multiple Risk Factor Intervention Trial (MRFIT)

The impact of smoking cessation on coronary heart disease (CHD) and lung cancer was assessed after 10.5 years of follow-up in the 12,866 men in the Multiple Risk Factor Intervention Trial (MRFIT). Those men who died of lung cancer (n = 119) were either cigarette smokers at entry or ex-smokers; no lung cancer deaths occurred among the 1,859 men who reported never smoking cigarettes. The risk of lung cancer for smokers, adjusted for selected baseline variables using a Cox proportional hazards model, increased as the number of cigarettes smoked increased (B = 0.0203, SE = 0.0076). There was not the same graded response for CHD among smokers at entry. The risk of CHD death was greater among smokers than nonsmokers (RR = 1.57) (B = -0.0034, S.E. = 0.0048). After one year of cessation, the relative risk of dying of CHD for the quitters as compared to non-quitters (RR = 0.63) was significantly lower even after adjusting for baseline differences and changes in other risk factors. The relative risk for smokers who quit for at least the first three years of the trial was even lower compared to non-quitters (RR = 0.38). However, the relative risk for lung cancer for quitters versus non-quitters was close to 1 both for quitters at 12 months and at three years. These data support the benefits of cessation in relation to CHD and are consistent with other epidemiologic studies which suggest that the lag time for a beneficial effect of smoking cessation on lung cancer may be as long as 20 years.

Women’s Healthy Lifestyle Project: A Randomized Clinical Trial Results at 54 Months

Background—The Women’s Healthy Lifestyle Project Clinical Trial tested the hypothesis that reducing saturated fat and cholesterol consumption and preventing weight gain by decreased caloric and fat intake and increased physical activity would prevent the rise in LDL cholesterol and weight gain in women during perimenopause to postmenopause. Methods and Results—There were 275 premenopausal women randomized into the assessment only group and 260 women into the intervention group. The mean age of participants at baseline was 47 years, and 92% of the women were white. The mean LDL cholesterol was 115 mg/dL at baseline, and mean body mass index was 25 kg/m2. The follow-up through 54 months was excellent. By 54 months, 35% of the women had become postmenopausal. At the 54-month examination, there was a 3.5-mg/dL increase in LDL cholesterol in the intervention group and an 8.9-mg/dL increase in the assessment-only group (P =0.009). Weight decreased 0.2 lb in the intervention and increased 5.2 lb in the assessment-only group (P =0.000). Triglycerides and glucose also increased significantly more in the assessment-only group than in the intervention group. Waist circumference decreased 2.9 cm in the intervention compared with 0.5 cm in the assessment-only group (P =0.000). Conclusions—The trial was successful in reducing the rise in LDL cholesterol during perimenopause to postmenopause but could not completely eliminate the rise in LDL cholesterol. The trial was also successful in preventing the increase in weight from premenopause to perimenopause to postmenopause. The difference in LDL cholesterol between the assessment and intervention groups was most pronounced among postmenopausal women and occurred among hormone users and nonusers.

Carotid Atherosclerosis in Premenopausal and Postmenopausal Women and Its Association With Risk Factors Measured After Menopause

BACKGROUND AND PURPOSE In women, symptoms of coronary artery disease are delayed by 10 to 15 years in comparison with men, most likely because of the protective effect of ovarian hormones. This report compares the prevalence and degree of carotid atherosclerosis between 292 premenopausal women and 294 women at 5 to 8 years after menopause. METHODS Scans were performed in the same laboratory over the same time period for both groups. Intima-media thickness (IMT) was averaged across the common, bulb, and internal carotids. The plaque index summarized degree of focal plaque based on the size and number of plaques throughout both carotid systems. RESULTS Mean IMT was 0.69 mm for premenopausal women and 0.77 mm for postmenopausal women (P < 0.001). Prevalence of plaque was 25% among premenopausal women and 54% among postmenopausal women (P < 0.001). In both premenopausal and postmenopausal women, risk factors measured before menopause were associated with carotid atherosclerosis. Premenopausal risk factors independently associated with IMT were higher pulse pressure (P < 0.001), triglycerides (P = 0.002), body mass index (P < 0.001), and study group (a surrogate for both age and menopausal status; P < 0.001). Premenopausal risk factors independently associated with focal plaque were ever smoking (P = 0.002), higher pulse pressure (P = 0.028), higher LDL (P = 0.003), age at baseline (P = 0.050), and study group (P < 0.001). CONCLUSIONS Subclinical carotid atherosclerosis can be observed in middle-aged women. Risk factors measured before menopause are clearly associated with subclinical disease measured both concurrently and at 5 to 8 years after menopause.

Psychological, biological and health behavior predictors of blood pressure changes in middle-aged women.

A long-standing hypothesis is that feelings of anger and anxiety increase the risk for essential hypertension. Most studies examining this hypothesis have been cross-sectional in design or undertaken with men only. We tested this hypothesis along with determination of the other behavioral and biological predictors of increases in systolic (SBP) and diastolic (DBP) blood pressure from baseline to a follow-up examination 3 years later in a prospective study of 468 middle-aged women whose blood pressure at the baseline examination was less than 140/90 mmHg. Analyses showed that increases in the Spielberger Trait Anger Scale between the baseline and 3-year follow-up examination, as well as Framingham Tension scores (a measure of anxiety) at baseline, independently predicted an increase in SBP (P less than 0.01). Other factors that independently predicted an increase in SBP were baseline fasting insulin, parental history of hypertension and increases in body mass index and in alcohol intake across the 3 years of follow-up. Increases in the Spielberger Trait Anger Scores independently predicted increases in DBP (P less than 0.02), as did black race, increases in body mass index and hematocrit and decreases in potassium intake. Although menopausal status and hormone replacement therapy were unrelated to changes in blood pressure, postmenopausal women on hormone replacement therapy did show significant increases in DBP in the univariate analysis. Anxiety at baseline, along with parental history of hypertension, baseline fasting insulin and baseline body mass index, predicted a later onset of hypertension, i.e. on pharmacologic treatment for hypertension, in the univariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)