Leukocyte count as a predictor of cardiovascular events and mortality in postmenopausal women: the Women's Health Initiative Observational Study

BACKGROUND: Increasing evidence supports a role for inflammation in the atherosclerotic process. The role of the leukocyte count as an independent predictor of risk of a first cardiovascular disease (CVD) event remains uncertain. Our objective was to describe the relation between the baseline white blood cell (WBC) count and future CVD events and mortality in postmenopausal women. METHODS: In this prospective cohort study set in 40 US clinical centers, the study population comprised 72 242 postmenopausal women aged 50 to 79 years, free of CVD and cancer at baseline, enrolled in the Women's Health Initiative Observational Study. Main outcome measures included incident fatal coronary heart disease (CHD), nonfatal myocardial infarction, stroke, and total mortality. RESULTS: At baseline, the mean +/- SD age of the women was 63 +/- 7.3 years, 84% were white, 4% had diabetes, 35% had hypertension, and 6% were current smokers. The mean WBC count was 5.8 +/- 1.6 x 10(9) cells/L. During a mean of 6.1 years of follow-up, there were 187 CHD deaths, 701 nonfatal myocardial infarctions, 738 strokes, and 1919 deaths from all causes. Compared with women with WBC counts in the first quartile (2.5-4.7 x 10(9) cells/L), women in the fourth quartile (6.7-15.0 x 10(9) cells/L) had over a 2-fold elevated risk for CHD death (hazard ratio, 2.36; 95% confidence interval, 1.51-3.68), after multivariable adjustment for age, race, diabetes, hypertension, smoking, hypercholesterolemia, body mass index, alcohol intake, diet, physical activity, aspirin use, and hormone use. Women in the upper quartile of the WBC count also had a 40% higher risk for nonfatal myocardial infarction, a 46% higher risk for stroke, and a 50% higher risk for total mortality. In multivariable models adjusting for C-reactive protein, the WBC count was an independent predictor of CHD risk, comparable in magnitude to C-reactive protein. CONCLUSIONS: The WBC count, a stable, well-standardized, widely available and inexpensive measure of systemic inflammation, is an independent predictor of CVD events and all-cause mortality in postmenopausal women. A WBC count greater than 6.7 x 10(9) cells/L may identify high-risk individuals who are not currently identified by traditional CVD risk factors.     

Prevalence and determinants of electrocardiographic left ventricular hypertrophy among a multiethnic population of postmenopausal women (The Women's Health Initiative)

Our objectives were to determine the prevalence and factors related to left ventricular hypertrophy (LVH) among older women for commonly used electrocardiographic criteria. LVH is a potent risk factor for cardiovascular disease, especially among women. However, its value has been limited, in part, by the use of different electrocardiographic criteria and the lack of a clearly defined standard for the general population. A total of 3,613 eligible women, aged 50 to 79 years, underwent medical history, physical measurements, and biochemical determinations and had behavioral factors recorded at baseline. Three LVH indexes were derived from computer measurement of the electrocardiogram: hypertrophied left ventricular mass > or =171.04 g (HLVM); Cornell voltage > or =2,200 microV; and Minnesota Code items. The prevalence of LVH ranged from <1% to 13% when stratified by age, ethnicity, and scoring technique. Baseline traits differed significantly for those meeting the LVH criteria. Predictors (p <0.01) of HLVM were age (odds ratio 0.66), height (odds ratio 1.47), waist/hip ratio (odds ratio 1.30), systolic blood pressure (odds ratio 1.18); low-density lipoprotein cholesterol (odds ratio 0.97), log insulin (odds ratio 2.10), dietary kilocalories (odds ratio 1.16), weekly energy expenditure (odds ratio 0.53), hypertension (odds ratio 1.61), current estrogen use (odds ratio 0.60), and current smoker (odds ratio 0.47). The presence of the metabolic syndrome was related to all LVH indexes, with odds ratios of 4.95, 2.24, and 2.35, respectively, for HLVM, Cornell voltage, and Minnesota Code. In conclusion, the prevalence of LVH varied by ethnicity and the electrocardiographic index used. However, the baseline traits, especially the factors associated with the metabolic syndrome, were consistently and strongly related to all LVH indexes, particularly HLVM. Intervention on these factors may provide strategies for reducing LVH, a strong independent risk factor for cardiovascular morbidity and mortality among women.     

Hypertension and its treatment in postmenopausal women: baseline data from the Women's Health Initiative

Little is known about the patterns of treatment and adequacy of blood pressure control in older women. The Women's Health Initiative, a 40-center national study of risk factors and prevention of heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women, provides a unique opportunity to examine these issues in the largest, multiethnic, best-characterized such cohort. Baseline data from the initial 98 705 women, aged 50 to 79 years, enrolled were analyzed to relate prevalence, treatment, and control of hypertension to demographic, clinical, and risk-factor covariates, and logistic regression analyses were performed to estimate odds ratios after adjusting for multiple potential confounders. Overall, 37.8% of the women had hypertension, which is defined as systolic blood pressure >/=140 mm Hg and/or diastolic blood pressure >/=90 mm Hg or being on medication for high blood pressure; 64.3% were treated with drugs, and blood pressure was controlled in only 36.1% of the hypertensive women, with lower rates of control in the oldest group. After adjustment for multiple covariates, current hormone users had higher prevalence than did nonusers (odds ratio 1.25). Hypertensive women had more comorbid conditions than did nonhypertensive women, and women with comorbidities were more likely to be treated pharmacologically. Diuretics were used by 44.3% of hypertensives either as monotherapy or in combination with other drug classes. As monotherapy, calcium channel blockers were used in 16%, angiotensin-converting enzyme inhibitors in 14%, beta-blockers in 9%, and diuretics in 14% of the hypertensive women. Diuretics as monotherapy were associated with better blood pressure control than any of the other drug classes as monotherapy. In conclusion, hypertension in older women is not being treated aggressively enough because a large proportion, especially those most at risk for stroke and heart disease by virtue of age, does not have sufficient blood pressure control.     

Sexual satisfaction and cardiovascular disease: the Women's Health Initiative

Background

Sexual dysfunction in some men is predictive of occult cardiovascular disease. We investigated whether dissatisfaction with sexual activity, a domain of female sexual dysfunction, is associated with prevalent and incident cardiovascular disease in postmenopausal women.

Methods

Data from the Women′s Health Initiative-Observational Study were used. Subjects who were sexually active in the past year were classified at baseline as sexually satisfied or dissatisfied. We performed multiple logistic regression analyses modeling baseline cardiovascular conditions including myocardial infarction, stroke, coronary revascularization, peripheral arterial disease, congestive heart failure, and angina. We then created Cox proportional hazards models to determine hazard ratios for incident cardiovascular disease by baseline sexual dissatisfaction status.

Results

Dissatisfaction with sexual activity at baseline was significantly associated with prevalent peripheral arterial disease (odds ratio 1.44, 95% confidence interval, 1.15-1.84), but not prevalent myocardial infarction, stroke, coronary revascularization including coronary artery bypass graft and percutaneous transluminal coronary angioplasty, or a composite cardiovascular disease variable. The odds of baseline angina were decreased among those reporting sexual dissatisfaction at baseline (odds ratio 0.77, 95% confidence interval, 0.66-0.86). In both unadjusted and adjusted analyses, dissatisfaction with sexual activity was not significantly related to an increased hazard of any cardiovascular disease.

Conclusions

Dissatisfaction with sexual activity was modestly associated with an increased prevalence of peripheral arterial disease, even after controlling for smoking status. However, dissatisfaction did not predict incident cardiovascular disease. Although this may represent insensitivity of the sexual satisfaction construct to measure sexual dysfunction in women, it might be due to physiological differences in sexual functioning between men and women.     

Use of hormone replacement therapy by postmenopausal women after publication of the Women's Health Initiative Trial

BACKGROUND: After publication of the Women's Health Initiative (WHI) trial in July 2002, many physicians discontinued hormone replacement therapy (HRT) in most of their postmenopausal patients. However, little is known about the women who remain on HRT. METHODS: We performed a retrospective chart analysis of 1000 postmenopausal women seen at an internal medicine practice to establish the prevalence of continued HRT use after publication of the WHI trial, determine the reasons for its use, and establish the prevalence of conditions adversely affected by HRT. RESULTS: Of 1000 postmenopausal women, mean age 66 +/- 9 years, 445 (45%) had used or still were on HRT (HRT users) at the time of the review. Of 445 HRT users, 159 (36%) were still on HRT, whereas 286 women (64%) had discontinued therapy. Of the latter, 181 women (63%) had stopped using HRT after the WHI publication, and 136 women (48%) reported the study as the direct cause of HRT cessation. Of the 159 women still on HRT, the main reasons for continued use were severe menopausal symptoms in 39 women (25%), osteoporosis or osteopenia in 31 women (20%), and patient preference in 20 women (13%). Of the 159 women still on HRT, 41 had atherosclerotic disease (26%), 7 had previous venous thromboembolic disease (4%), 8 had a history of breast cancer (5%), and 12 had a family history of breast cancer (8%). CONCLUSIONS: Despite the widespread impact of the WHI trial results, many women still remained on HRT in an internal medicine practice for a variety of reasons and despite relative contraindications to its use.     

Cardiovascular risk in women with non-specific chest pain (from the Women's Health Initiative Hormone Trials)

Women discharged with diagnoses of nonspecific chest pain (NSCP) may be at increased risk for subsequent coronary artery disease (CAD) events. The influence of hormone therapy on NSCP is unknown. The Women's Health Initiative (WHI) enrolled postmenopausal women aged 50 to 79 years. The duration of follow-up was 7.1 years in the WHI Estrogen-Alone trial (E-Alone) and 5.6 years in the WHI Estrogen Plus Progestin trial (E+P). After excluding women with previous cardiovascular disease, 9,427 women in E-Alone and 15,105 women in E+P were included in this analysis. NSCP, defined as having a primary hospital discharge diagnosis of NSCP by International Classification of Diseases, Ninth Revision, code, was reported in 322 women in E-Alone and 249 in E+P. Risks for subsequent CAD events were estimated using intent-to-treat Cox proportional-hazards models stratified by clinic and adjusted for age and other risk factors. In the fully adjusted models of the combined trials, women with NSCP had a twofold greater risk for subsequent nonfatal CAD events, including nonfatal myocardial infarction (2.3% vs 1.7%, hazard ratio [HR] 2.10, 95% confidence interval [CI] 1.11 to 3.98), revascularization (3.5% vs 2.6%, HR 1.99, 95% CI 1.20 to 3.30), and hospitalized angina (3.7% vs 2.3%, HR 2.39, 95% CI 1.46 to 3.92). Hormone therapy did not appear to have a significant effect on either the incidence of NSCP hospitalizations (E-Alone: HR 1.04, 95% CI 0.81 to 1.32; E+P: HR 0.78, 95% CI 0.59 to 1.02) or the risk for a subsequent CAD event. In conclusion, a hospitalization for NSCP doubles the risk for a subsequent CAD event in postmenopausal women over the next 5 to 7 years and identifies them as candidates for aggressive risk factor treatment.     

Prevalence and correlates of panic attacks in postmenopausal women: results from an ancillary study to the Women's Health Initiative

BACKGROUND: Panic attacks are known to be more common in women than in men, but the prevalence and correlates of panic in the postmenopausal period have not been well defined. METHODS: Cross-sectional survey of 3369 community-dwelling postmenopausal women enrolled between December 1, 1997, and November 30, 2000, in the Myocardial Ischemia and Migraine Study, a 10-center ancillary study of the 40-center Women's Health Initiative. Participants, aged 50 to 79 years and predominantly white (73%), completed questionnaires about the occurrence of panic attacks in the previous 6 months and about migraine headaches and underwent 24-hour ambulatory electrocardiographic monitoring. The 6-month prevalences of full-blown and limited-symptom panic attacks were calculated, and their associations with other sociodemographic and clinical variables were examined in multivariate analyses. RESULTS: One of the panic attack types was reported by 17.9% (95% confidence interval, 16.6%-19.2%) of women (full-blown attacks, 9.8%; limited-symptom attacks, 8.1%). Adjusting for age and race or ethnicity, full-blown panic attacks were more common in women with a history of migraine, emphysema, cardiovascular disease, chest pain during ambulatory electrocardiography, and symptoms of depression. Full-blown panic attacks were associated in a dose-response manner with negative life events during the past year. Panic attacks were associated with functional impairment even after adjusting for comorbid medical conditions and depression. There was no significant association with self-reported use of hormone replacement therapy. CONCLUSIONS: Panic attacks may be relatively common among postmenopausal women and seem to be associated with stressful life events, medical comorbidity, and functional impairment.     

The Women's Initiative for Nonsmoking (WINS) XI: age-related differences in smoking cessation responses among women with cardiovascular disease

Smoking cessation has immediate health benefits; however, the efficacy of smoking cessation interventions among older adults and women has received limited research attention. The original Women's Initiative for Nonsmoking (WINS) study was a randomized controlled trial that tested the efficacy of a smoking cessation intervention for Bay Area women hospitalized with cardiovascular disease. The current study, which used the WINS dataset, compares participants 62 and older with those younger than 62 years. The sample (n=277) contained 136 older smokers and 141 younger smokers. At the 6-month follow-up, 52.1% of older smokers had quit smoking compared with 40.6% of younger smokers. At the 12-month follow-up, 52.0% of older smokers had quit smoking compared with 38.1% of younger smokers. The difference at 12 months was statistically significant, and a Kaplan-Meier survival analysis further supported these findings. Clinicians should be sure to also include older smokers in smoking assessments and smoking cessation interventions.     

Normal standards for computer-ECG programs for prognostically and diagnostically important ECG variables derived from a large ethnically diverse female cohort: The Women's Health Initiative (WHI)

Background

Substantial new information has emerged recently about the prognostic value for a variety of new ECG variables. The objective of the present study was to establish reference standards for these novel risk predictors in a large, ethnically diverse cohort of healthy women from the Women's Health Initiative (WHI) study.

Methods and Results

The study population consisted of 36,299 healthy women. Racial differences in rate-adjusted QT end (QT_ea) and QT peak (QT_pa) intervals as linear functions of RR were small, leading to the conclusion that 450 and 390 ms are applicable as thresholds for prolonged and shortened QT_ea and similarly, 365 and 295 ms for prolonged and shortened QT_pa, respectively. As a threshold for increased dispersion of global repolarization (T_peakT_end interval), 110 ms was established for white and Hispanic women and 120 ms for African-American and Asian women. ST elevation and depression values for the monitoring leads of each person with limb electrodes at Mason-Likar positions and chest leads at level of V1 and V2 were first computed from standard leads using lead transformation coefficients derived from 892 body surface maps, and subsequently normal standards were determined for the monitoring leads, including vessel-specific bipolar left anterior descending, left circumflex artery and right coronary artery leads. The results support the choice 150 μV as a tentative threshold for abnormal ST-onset elevation for all monitoring leads. Body mass index (BMI) had a profound effect on Cornell voltage and Sokolow–Lyon voltage in all racial groups and their utility for left ventricular hypertrophy classification remains open.

Conclusions

Common thresholds for all racial groups are applicable for QT_ea, and QT_pa intervals and ST elevation. Race-specific normal standards are required for many other ECG parameters.     

Normal standards for QT and QT subintervals derived from a large ethnically diverse population of women aged 50 to 79 years (the Women's Health Initiative [WHI])

Available normal standards for rate-adjusted QT intervals in women are based on samples that include only whites, and no normal standards are available for QT subintervals. This study derived normal limits from percentile distributions for QT as well as QT and T-wave subintervals in 22,311 participants in the Women's Health Initiative (WHI), including 19,059 white, 1,771 African-American, 819 Hispanic, 82 American Indian, and 580 Asian women. Excluded were women with cardiovascular disease or who were using cardioactive drugs at baseline and cardiovascular morbidity or death during the subsequent mean 6.3-year follow-up. Normal limits for QT adjusted by Bazett's formula were strongly rate dependent, invalidating their use in practical applications. QT adjusted as a linear function of RR (QTrr) or by power functions of RR with exponent 0.5 (QTsqr) or 0.42 (QT0.42) using an appropriate regression function produced rate-invariant upper and lower normal limits for rate-adjusted QT. Adjusted QT is preferable to adjusted JT because the latter requires the incorporation of QRS duration as a covariate with RR. Normal limits were also derived for T-wave subintervals. Normal limits of QTrr in Asian women were 10 ms longer than in other ethnic groups. In conclusion, QT adjusted for rate as a linear function of RR is preferable to JT and other QT subintervals in the evaluation of QT prolongation. The adaptation of considerable revisions of the currently used limits for prolonged QT in women is suggested, with an additional race-specific adjustment in Asian women. Bazett's formula is inappropriate for testing new drugs or other applications.