Biennial Report on Women's Health Issues
FY 2003 and FY 2004

The National Institutes of Health
National Heart, Lung, and Blood Institute


Contents

Executive Summary

Full Report

Initiatives

Research Pertaining to Special Populations

Gender Analysis



EXECUTIVE SUMMARY

The National Heart, Lung, and Blood Institute (NHLBI) provides leadership for a national program in diseases of the heart, blood vessels, lungs, and blood; sleep disorders; and blood resources. It plans and conducts—through work in its own laboratories and through grant- and contract-supported activities in extramural scientific institutions—an integrated and coordinated program of basic research, clinical investigations and trials, observational studies, and demonstration and education projects related to the causes, prevention, diagnosis, and treatment of the diseases under its purview and to the clinical use of blood and all aspects of the management of blood resources. For more than 30 years, the NHLBI Office of Prevention, Education, and Control has supported educational programs for physicians, patients, and the general public to improve awareness, diagnosis, treatment, and prevention of diseases and conditions under the Institute’s purview. Since FY 1993, the Institute has been the home of the National Center on Sleep Disorders Research and, since FY 1998, it has had responsibility for the NIH Women’s Health Initiative (WHI).

Highlights of NHLBI -supported activities during fiscal years 2003-2004 include the following:

• The WHI postmenopausal hormone component reported the main outcome of its trial of estrogen in women with a hysterectomy. Other publications provided detailed information about the effects of estrogen plus progestin on health-related quality of life, stroke, gynecologic cancers, bone health, and colorectal cancer.

• The Women’s Ischemia Syndrome Evaluation (WISE) Study, which has been examining issues of relevance to diagnosis of chest pain and myocardial ischemia in women, produced a number of new findings regarding predictors and correlates of cardiovascular disease (CVD) risk.

• The NHLBI women’s heart health education campaign, titled The Heart Truth, greatly expanded its activities to raise public awareness that heart disease is the leading cause of death among women in the United States, and that many things can be done to prevent it.

REPORT

NHLBI Entities With a Designated Focus on Women's Health

The NIH Women’s Health Initiative is administered by the NHLBI.

The NHLBI Office of Prevention, Education, and Control has responsibility for The Heart Truth, an educational campaign to raise public awareness that heart disease is the leading cause of death among American women.

Accomplishments

Women's Health Initiative (WHI) - Overview

The WHI is a 15-year study of strategies for preventing heart disease, breast and colorectal cancers, and osteoporosis in postmenopausal women. Launched by the NIH in 1991, it has been administered by the NHLBI since fiscal year 1998. More than 160,000 women from across the United States, who were between 50 and 79 years of age at the time of their recruitment, are enrolled in the WHI clinical trials and observational study; almost 30,000 of the participants are minorities. The clinical trial component consists of three prevention studies examining the effects of postmenopausal hormone therapy on risk of coronary heart disease (CHD), osteoporosis, and breast cancer; the effects of a low-fat diet on risk of breast and colorectal cancers and CHD; and the role of calcium and vitamin D supplementation in preventing fractures and colorectal cancer. The observational study component has focused on identifying predictors of disease. In addition, a Community Prevention Study was conducted in collaboration with the Centers for Disease Control and Prevention to examine strategies for enhancing adoption of healthful behaviors, particularly among minority and under-served women.

The WHI postmenopausal hormone trial included two placebo-controlled components – a study of estrogen plus progestin in women who had an intact uterus and a study of estrogen alone in women who had undergone a hysterectomy. Both studies were designed to test the hypothesis that long-term use of hormone therapy could reduce risk of CHD. As reported previously, the estrogen-plus-progestin trial was halted ahead of schedule in July 2002. Compared with women taking a placebo, study participants taking hormones experienced higher rates of heart attack, stroke, blood clots, and invasive breast cancer. Although the women taking hormones also had a lower incidence of colon cancer and fewer hip fractures, the overall balance of risks and benefits was unfavorable.

WHI - Major New Results from the Hormone Trials

Main Findings from Trial of Estrogen in Women with Hysterectomy

In March 2004, the second WHI postmenopausal hormone trial component also was halted ahead of schedule. With an average of nearly 7 years of follow-up completed, the trial revealed that estrogen-alone therapy had no effect on CHD risk, but it increased risk of stroke. No evidence of elevated breast cancer risk was found, and a favorable effect on bone health emerged. On balance, however, the trial indicated that postmenopausal hormone therapy should not be prescribed for chronic disease prevention, but only for short-term relief of menopausal symptoms. The results from the WHI hormone therapy trials have provided women and their physicians with a scientific basis for making informed decisions about hormone therapy use. [Journal of the American Medical Association, April 14, 2004]

Estrogen plus Progestin and Health-Related Quality of Life

The WHI collected information on a variety of health-related quality-of-life measures at the beginning of the trial and 1 and 3 years afterward. They found that women assigned to take estrogen plus progestin did not experience any significant changes in general health, physical or emotion limitations on usual role-related activities, vitality, social functioning, mental health, depressive symptoms, or sexual satisfaction. Moreover, hormone treatment was associated with only very modest and transient improvements in sleep disturbance, physical functioning, and bodily pain. These small benefits do not appear to outweigh the risks of heart attack, stroke, blood clots, and breast cancer that are associated with estrogen-plus-progestin therapy. [New England Journal of Medicine, May 8, 2003]

Estrogen plus Progestin and Stroke

As noted above, the estrogen-plus-progestin trial was stopped early because treatment was associated with adverse effects, including stroke. Overall, 151 women assigned to take estrogen plus progestin and 107 women assigned to take a placebo had strokes, most of which were ischemic. Further analysis was conducted to determine whether it was possible to identify characteristics of the women taking hormones that rendered them particularly susceptible to stroke. Results indicated that the excess risk of stroke affected women regardless of age, hypertension, prior CVD, or prior use of hormones, statins, or aspirin. Moreover, accounting for other stroke risk factors, including smoking, diabetes, and blood levels of various indicators, did not alter the effect of the hormone regimen on stroke risk. The researchers concluded that estrogen plus progestin increases the risk of ischemic stroke across the board in healthy postmenopausal women. [Journal of the American Medical Association, May 28, 2003]

Estrogen plus Progestin and Gynecologic Cancers

During 5.6 years of follow-up in the WHI estrogen-plus-progestin trial, invasive gynecologic cancers were diagnosed in 111 women. A 58-percent increase in ovarian cancer and a 19-percent decrease in endometrial cancer were observed in women assigned to hormones, relative to those given placebos, but these findings were not statistically significant (i.e., they may represent a chance occurrence). However, women in the hormone group required significantly more endometrial biopsies (33 percent versus 6 percent), and twice as many of them required multiple biopsies as did women in the placebo group. The increased need for diagnostic procedures in response to bleeding represents an additional factor that must be considered in a woman’s decision to use postmenopausal hormone therapy. [Journal of the American Medical Association, October 1, 2003]

Estrogen plus Progestin and Bone Health

At the time the estrogen-plus-progestin trial was halted because of adverse effects, a significantly decreased risk of fractures was apparent among its participants who were assigned to take hormones. A subsequent analysis sought to determine whether the extent of benefit varied according to a woman’s susceptibility to sustain fractures, as determined by levels of known risk factors. Investigators found that the effect of the combined hormones on risk of fracture did not differ according to age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, or bone mineral density. When the women were categorized as having low, medium, or high fracture risk according to a summary score, no evidence was found that the efficacy of estrogen plus progestin differed among the three groups. When these results were considered in light of the overall trial findings with respect to important disease outcomes, it was apparent that hormone therapy conferred no net benefit, even among women deemed to be at high risk of fracture. [Journal of the American Medical Association, October 1, 2003]

Estrogen plus Progestin and Colorectal Cancer

WHI participants who were assigned to take combined hormone therapy developed colorectal cancer during the subsequent 5.2 years at about half the rate of those given a placebo. Further analysis considered additional follow-up data and assessed the features of the colorectal cancers that occurred in the hormone group versus the placebo group. The invasive colorectal cancers in the two groups were similar in location, tumor grade, and histologic features. However, the women assigned to hormone therapy who developed cancer had greater lymph-node involvement and their cancer was diagnosed at a more advanced stage. Although the reasons for these phenomena are unknown, the findings suggest the importance of bowel screening among postmenopausal women who use hormone therapy. [New England Journal of Medicine, March 4, 2004]

WHI - Selected Results from the Observational Study

The WHI Observational Study (OS) includes over 93,000 postmenopausal women between the ages of 50 and 79 who are being followed for an average of 9 years. Its goals are to provide reliable estimates of the extent to which known risk factors predict heart disease, cancers, and fractures; identify new risk factors for these and other conditions in women; correlate risk factors and presence of disease at the start of the study with subsequent disease incidence; and create a resource for identifying biological indicators of disease, especially in the blood.

Statin Use and Bone Health

Osteoporosis affects millions of older women, placing them at increased risk of bone fractures. Some, but not all, recent observational studies have raised the possibility that treatment with statins – drugs that are usually prescribed to lower blood cholesterol levels and thereby prevent CHD – may also prevent bone fractures. WHI-OS investigators examined this issue in their large cohort of postmenopausal women, which included nearly 8,000 statin users. They found that women who were taking statins at the start of the study, regardless of how long they had been doing so, experienced rates of bone fractures similar to those of women who did not take statins. Moreover, bone density levels were not significantly different between users and non-users of statins. Investigators concluded that current evidence does not support prescribing statins to prevent or treat osteoporosis in postmenopausal women. [Annals of Internal Medicine, July 15, 2003]

Physical Activity and Risk of Breast Cander

A number of studies have found that women who are physically active are less likely to develop breast cancer than women who are sedentary. However, the type of activity that may confer such a benefit and its optimal duration and timing have been unclear. Using the detailed assessments of physical activity reported by women who entered the WHI-OS, investigators analyzed associations between incidence of breast cancer and exercise, both past and present. Results showed that women who had engaged in regular strenuous physical activity when they were younger were not as likely as their less-active counterparts to develop breast cancer later in life. Moreover, physical activity lowered breast cancer risk among women who began to exercise later in life or who exercised so only moderately (e.g., walked briskly for 1.25 to 2.5 hours per week). Although the results suggest longer duration of exercise is better in terms of reducing breast cancer risk, they also indicate that the activity need not be strenuous to yield some benefit. [Journal of the American Medical Association, September 10, 2003]

Compliance with Lifestyle Recommendations to Lower Blood Cholesterol

The NHLBI National Cholesterol Education Program (NCEP) recommends therapeutic lifestyle changes (i.e., reducing dietary intake of saturated fat and cholesterol, increasing physical activity, controlling weight) as a first step toward reducing high blood cholesterol levels. An analysis of postmenopausal women participating in the WHI-OS indicates that many women are not complying with NCEP recommendations. Of the 13,777 participants who reported having been prescribed drug therapy for high cholesterol levels, only 20 percent had dietary habits (i.e., intake of total fat, saturated fat, and dietary cholesterol) that were in line with NCEP recommendations. Consistent with other studies, the WHI-OS found that women who smoked, were inactive, or had a higher body mass index were less likely to follow dietary guidelines. Better health promotion approaches are needed to help older women modify their lifestyles in order to reduce the burden of CVD. [The American Journal of Medicine, October 1, 2002]

WHI - Future Plans

Although the hormone therapy clinical trials were stopped early, other WHI activities are continuing until their scheduled end in March 2005 (i.e., the clinical trials of low-fat diet and calcium/vitamin D supplementation and the WHI-OS). Hormone trial participants will receive additional monitoring (e.g., review of annual mammogram reports) through 2007. The NHLBI also is negotiating with WHI centers for continued follow-up of participants through a WHI Extension Study, which will run through 2010; volunteers will be asked annually to complete health forms. The NHLBI also plans to support additional research on a large biologic specimen repository collected through the WHI.

The NHLBI recognizes that data from the WHI constitute an important scientific resource that should be made available, under appropriate terms and conditions consistent with the informed consent provided by individual participants, to the largest possible number of qualified investigators. A time schedule has been established for appropriate release of the data.

Other Findings Related to Postmenopausal Hormone Therapy

Women's Angiographic Vitamin and Estrogen (WAVE) Trial

Adding to the WHI findings with respect to primary prevention of CVD, results from the NHLBI-sponsored WAVE trial indicate that postmenopausal hormone therapy is also not beneficial for secondary prevention. WAVE randomly assigned more than 400 postmenopausal women with CHD to receive hormone therapy or a placebo and high doses of vitamins C and E or a placebo. Angiograms were performed when women entered the study and approximately 3 years later to evaluate the extent and progression of coronary artery blockages. Researchers analyzed the results using a ranking system that incorporated both clinical events (e.g., heart attack, death) and angiographic changes. They found, much to their surprise, that the death rate was highest among women who took hormones and vitamins, and lowest among women who took placebos. Furthermore, participants taking hormonesand vitamins experienced as much or more progression of their coronary artery blockages as those on placebos. These findings add to the growing body of evidence that postmenopausal hormone therapy is not helpful in preventing or treating heart disease and may, indeed, be harmful. [Journal of the American Medical Association, November 20, 2002]

Another analysis of WAVE data considered the effects of postmenopausal hormone therapy on coronary atherosclerosis in women with abnormal glucose tolerance (AGT, defined as diabetes or impaired fasting glucose) versus with women with normal glucose tolerance. After 3 years of follow-up, the study found that hormone therapy accelerated progression of existing blockages in all the women, and appeared to enhance atherosclerosis development in previously non-diseased artery segments in the women with AGT. These findings demonstrate that hormone therapy use is not warranted in diabetic women. [Circulation, July 13, 2004]

Trends in Use of Postmenopausal Hormone Therapy


The recent evidence that postmenopausal hormone therapy should not be used for prevention of chronic diseases has had a rapid impact on prescribing behavior in the United States. An analysis funded by the NHLBI and the Agency for Healthcare Research and Quality found a dramatic change in hormone prescribing in the aftermath of the July 2002 publication of findings from the WHI and the industry-sponsored Heart and Estrogen/Progestin Replacement Study (HERS) II. Specifically, researchers documented a decline of 66 percent for Prempro® and 33 percent for Premarin® between the periods January-June 2002 and January-June 2003. For a broader perspective, investigators examined trends from 1995 to 2003. Prescriptions for hormone therapy, which had been on the rise for 2 decades, increased from 58 million in 1995 to 90 million in 1999, where they remained stable until June 2002. At that time, approximately 15 million American women were using hormone therapy. Assuming the prescription rates observed in July 2003 remain stable throughout the year, it was estimated that only 57 million prescriptions were dispensed in 2003, nearly the same number as seen in 1995. These data underscore the need for evidence-based results and the value of translating those results into clinical practice. [Journal of the American Medical Association, January 7, 2004]

Results from the Women's Ischemia Syndrome Evaluation (WISE)

The WISE is a multicenter study initiated by the NHLBI in 1996 to evaluate ischemic heart disease in women. It focuses on three areas of particular relevance to heart disease in women: (1) optimizing symptom evaluation and diagnostic testing for ischemic heart disease; (2) understanding the biological mechanisms responsible for myocardial ischemia in the absence of epicardial coronary artery disease (CAD); and (3) evaluating the influence of reproductive hormones on heart disease symptoms and responses to diagnostic tests. Secondary objectives of WISE are to develop safe and cost-effective diagnostics for evaluating women with suspected ischemic heart disease, to determine the frequency of myocardial ischemia in the absence of significant epicardial coronary stenosis, and to determine the frequency of nonischemic or noncardiac chest pain. In fiscal year 2001, the NHLBI extended follow-up of WISE to study the long-term prognostic value of new tests developed in earlier phases of the program, to develop sex-specific outcome models to evaluate the prognostic value of female reproductive variables, and to maintain a WISE database and infrastructure. Some of the results published by the WISE investigators in 2004 are described below

Low Hemoglobin Levels and Outcomes in Women with Chest Pain

Several studies have shown that low hemoglobin (Hgb) levels are associated with increased CVD-related morbidity and mortality in patients who suffer a heart attack or who have heart failure. A recent WISE study investigated whether low Hgb levels are also associated with adverse cardiovascular outcomes in women who experience chest pain. Results showed that women with chest pain who have low Hgb levels are more likely than women with normal Hgb levels to die, suffer a heart attack, develop heart failure, suffer a stroke, or experience other adverse cardiovascular events. Surprisingly, in this study the Hgb levels associated with adverse events were only mildly to moderately low by current standards. Also unexpected was the finding that low Hgb levels were a better predictor of adverse cardiovascular events than were most traditional risk factors such as smoking, hypertension, age, and family history of heart disease. The researchers also showed that markers of inflammation, which are a risk factor for CVD, were higher in the women with low Hgb. Researchers are now focusing on understanding why low Hgb levels are linked to poorer outcomes, determining whether treatment to raise Hgb levels will improve outcomes, and determining the level of Hgb that should be defined as “high risk.” [Journal of the American College of Cardiology, June 2, 2004].

Metabolic Syndrome and CAD

The metabolic syndrome – characterized by co-occurrence of abdominal obesity, low HDL cholesterol, elevated triglycerides, high blood pressure, and abnormal glucose – is thought to be an intermediate step in progression from normal glucose homeostasis to a diabetic state. Currently the relationship between the metabolic syndrome, CAD, and risk of other adverse cardiovascular events is not entirely clear. To gain a better understanding of the usefulness of the metabolic syndrome as a predictor of CVD risk, the WISE investigators tested women to determine their metabolic status (normal, metabolic syndrome, or diabetic) and whether they had CAD. They then followed the women for 4 years and assessed the relationship between metabolic status, CAD, and risk of experiencing a major cardiovascular event. Results showed that the 4-year risk of experiencing such an event increases across the metabolic continuum from normal to diabetic — women with diabetes had the highest risk, women with a normal metabolic status had the lowest risk, and women with the metabolic syndrome had an intermediate risk of adverse cardiovascular events. The researchers looked at the results to determine the effect of the presence or absence of CAD. Interestingly, they found that the metabolic syndrome was associated with an increased risk for major cardiovascular events only in women with the syndrome who had CAD at the time of entry into the study. The result is consistent with previous observations that the risk associated with the metabolic syndrome is variable and suggests that measurement of both metabolic status and CAD provides a better indicator of risk for future cardiovascular events risk than assessment of metabolic status alone. [Circulation, February 17, 2004].

Obesity and CVD Risk

The recent rise in obesity prevalence is a major public health concern because obesity is often associated with CVD risk factors such as metabolic abnormalities (i.e., the metabolic syndrome, diabetes) and a lack of physical activity. Although obesity is also associated with CVD, controversy is growing over whether it is obesity itself that increases an individual’s risk of CVD or the presence of the risk factors that often accompany obesity. The distinction is important because not all obese individuals have the metabolic syndrome or lead sedentary lifestyles. Two recent WISE studies evaluated the relationship between obesity and CVD risk.

In the first study, the researchers classified 780 of the WISE participants as normal, overweight, or obese, according to their body mass index, and as normal, metabolic syndrome, or diabetic, according to their metabolic status. After 3 years of follow-up, the risk of CVD in obese women with a normal metabolic status was relatively low. Conversely, normal-weight women who had the metabolic syndrome were at a relatively high risk for CVD. The authors concluded that metabolic status rather than being overweight or obese predicts future CVD. [Circulation, February 17, 2004]

A second study looked at whether physical fitness affects CVD risk. Interestingly, results showed that women with the highest self-reported physical fitness scores had the lowest risk of adverse cardiovascular events whether they were normal weight, overweight, or obese. In fact, obese women with a high fitness level were at lower risk than normal-weight women who were not fit. [Journal of the American Medical Association, September 8, 2004]

While the two studies suggest that metabolic factors and physical fitness are more important predictors of CVD risk than obesity alone, they also underscore the importance of controlling all modifiable risk factors in both normal and overweight women.

Serum Amyloid A and CVD Risk

A growing body of evidence suggests that inflammation – a process by which the body responds to injury – is associated with the development of CVD. Blood proteins whose levels increase during inflammation are now being used to develop tests for the presence of inflammation. WISE investigators recently evaluated one such protein, serum amyloid-a (SAA), to determine whether it might be useful in predicting which women would develop CAD and other forms of CVD. The results showed that SAA was moderately associated with development of CAD. They also showed that a high level of SAA was a good predictor of the 3-year risk of suffering an adverse cardiovascular event. Based on these results, SAA shows promise for helping doctors to identify women at high risk for CVD. [Circulation, February 17, 2004]

Coronary Vascular Dysfunction and CVD Risk

Normal coronary arteries dilate in response to the chemical acetylcholine. Impaired coronary reactivity to acetylcholine is an indication of vascular dysfunction that is believed to be a precursor to atherosclerosis and CAD. To determine whether coronary vascular dysfunction predicts adverse outcomes in women, the WISE investigators measured coronary artery reactivity in 163 study participants who had been referred for clinically indicated coronary angiography. After assessing arterial response to acetylcholine, the researchers followed the women for an average of 2 years to ascertain subsequent cardiovascular status. Results showed that impaired coronary vascular response to acetylcholine was independently linked to cardiovascular events such as heart attack or coronary revascularization. The finding is striking because most of the women in the study did not have significant angiographic CAD and were, therefore, at relatively low risk for imminent coronary events. [Circulation, February 17, 2004]

Gender Differences in Heart Failure

Trends in Incidence and Survival

Investigators used long-term data from the Framingham Heart Study to assess temporal trends in incidence of heart failure and survival after its diagnosis. The analysis revealed that, over the past 50 years, incidence of heart failure decreased by about one-third among women, whereas it changed very little among men. The researchers hypothesize that the availability of better drugs for controlling high blood pressure, the most prominent cause of heart failure in women, might explain why fewer women are developing the disease. The study also found that improved survival after onset of heart failure has occurred in both genders – on average, age-adjusted death rates for women and men diagnosed with heart failure dropped 12 percent during each decade between 1950 and 1999. Further research is needed to determine the factors underlying this trend. [New England Journal of Medicine, October 31, 2002]

Remodeling Following Heart Attack

A number of studies have showed that women with symptomatic heart failure tend to fare better than men, but the reasons for this gender difference have been unclear. A recent study of patients undergoing cardiac transplantation for end-stage heart failure has shed light on this issue. The researchers found that men and women undergo quite different changes in the morphology of the heart muscle – a process known as remodeling – following a heart attack. Men developed much larger hearts (caused only in part by increased left ventricle size) than women, and their individual heart cells also were larger. The larger cells were found throughout the hearts of men rather than just in tissue near the area damaged during the heart attack, and the researchers concluded that damage during a heart attack triggers remodeling in distant cells. Further understanding of the gender-specific remodeling process may provide a key to developing new approaches to prevent development of heart failure in heart attack survivors. [Journal of the American College of Cardiology, January 15, 2003]

Use of Digoxin Therapy for Women

In 1997, the NHLBI-supported Digitalis Investigation Group reported the findings of a controlled clinical trial of digoxin therapy in patients with heart failure and depressed left ventricular function. Although digoxin did not confer a mortality benefit, it reduced the rate of hospitalization during the 3-year follow-up period. A subsequent analysis sought to determine whether gender differences existed in response to digoxin therapy. It revealed an increased risk of death for the subgroup of women receiving digitalis compared with women assigned to the placebo arm of the trial. Moreover, women experienced a smaller digoxin-associated reduction in hospitalization for worsening heart failure than men. These findings underscore the importance of examining gender differences in treatment efficacy, and suggest that re-evaluation of the appropriate use of digoxin therapy in women is warranted. [New England Journal of Medicine, October 31, 2002]

Plasma Homocysteine and Risk of Heart Failure

Researchers have found the first evidence that increased plasma levels of homocysteine, a known risk factor for CHD and stroke, also may raise risk of developing heart failure. The relation between heart failure and homocysteine did not vary with age, systolic blood pressure, or use of diuretic or cholesterol-lowering drugs. However, gender differences were found in women, progressively higher levels of homocysteine were correlated with higher heart failure rates even when homocysteine was below the average level for women, whereas in men the relation became apparent only at above-average levels. Although the connection between heart failure and homocysteine level and the differences in risk for men and women need to be corroborated by other studies, these findings may ultimately have public health implications, given the considerable morbidity, mortality, and economic burden associated with heart failure. [Journal of the American Medical Association, March 12, 2003]

Other Findings Related to CVD Risk and Its Modification

Predictors of Future CVD in Young Women

Results from a study begun in 1967 demonstrate that it is never too early to pay attention to heart health. Researchers from the Chicago Heart Association Detection Project found that young women who had two or more major CVD risk factors (diabetes, high blood pressure, an unhealthy cholesterol profile, BMI 25.0, smoking) when they joined the study were less likely to be alive in 2001 than counterparts who had none of the risk factors. Specifically, the higher-risk women were seven times more likely to have died of CHD, six times more likely to have died of CVD, and more than twice as likely to have died of any cause. Although the relation between CVD risk factors and decreased longevity had been established for young adult men and middle-aged men and women, the Chicago project is the first to measure the link for young women. Coupled with the observation that only 20 percent of the women in this cohort could be classified as "low risk," these findings underscore the urgency of establishing heart-healthy habits among women early in life. The NHLBI is currently supporting two clinical trials in adolescent girls addressing physical activity and weight gain, respectively that are expected to guide enhanced CVD prevention efforts in young women. [Journal of the American Medical Association, October 6, 2004]

CVD Screening Tool Also Applies to Women

Exercise testing, often performed using a treadmill, is a valuable screening tool for identifying potential heart problems in apparently healthy men, but its usefulness in women has been questioned. Long-term follow-up of the NHLBI Lipid Research Clinical Prevalence Study has shed new light on this issue, revealing that the test parameters having prognostic significance in women are somewhat different from those in men. Specifically, an electrocardiographic finding of ST-segment depression which indicates low blood flow to the heart muscle and is an ominous sign in men was found to be unrelated to increased risk in women. However, two measures of cardiovascular fitness exercise capacity and heart rate recovery proved to be quite useful for predicting risk in women. The findings have particular public health significance because the fitness measures presaged CVD deaths 20 years later even among women who were considered to be at low risk for heart disease. Because approximately two-thirds of women who die suddenly of CVD have no previous symptoms, a straightforward, noninvasive approach to identifying asymptomatic women who may benefit from aggressive primary prevention could save many lives. [Journal of the American Medical Association, September 24, 2003]

C-Reactive Protein (CRP) Level and CVD Risk

Based on recent evidence suggesting that serum levels of CRP an indicator of inflammation independently predict risk for CVD, doctors have begun to incorporate assessment of CRP into clinical practice. However, many questions remain about the significance of CRP measurements, particularly at very high or very low levels or in the context of other CVD risk factors. Recent findings from the NHLBI-supported Women's Health Study (WHS) have shed light on some of these issues.

Individuals with the metabolic syndrome are at increased risk for developing diabetes and CVD, and many of the syndrome's defining characteristics are associated with increased C-reactive protein (CRP) levels. WHS researchers investigated whether measuring CRP levels in women with the metabolic syndrome would provide additional information about individual risk of CVD. They found that CRP levels at the beginning of the study were strongly related to severity of the metabolic syndrome i.e., CRP levels were lowest in women who had none of the abnormalities associated with metabolic syndrome and highest in women who had all of them. Follow-up 8 years later revealed that CRP levels added clinically relevant prognostic information concerning future CVD risk among women with and without the metabolic syndrome. For example, in the subgroup of women who had 3 characteristics associated with the metabolic syndrome, those with CRP levels >3.0 mg/L had nearly twice the rate of cardiovascular events of those with lower CRP levels. The results suggest that CRP levels can be useful in refining assessments of cardiovascular risk in women. [Circulation, January 28, 2003]

Many researchers have speculated that hypertension is part of an inflammatory disorder, and findings from the WHS have added support for this hypothesis. Investigators found that CRP levels at the beginning of the study were significantly related to the likelihood of developing hypertension during the followup period, which averaged 7.8 years. This relation held even for women who had no traditional CVD risk factors or very low baseline blood pressures. These results provide further evidence that inflammation may play a role in the development of hypertension and also indicate that CRP may be useful in predicting a person's risk of hypertension as well as heart attack and stroke. [Journal of the American Medical Association, December 10, 2003]

As routine measurement of CRP by community physicians has become more common, questions have emerged about the predictive value of very high or very low CRP levels. For instance, concern exists that a low CRP level might give patients a false sense of security, especially when other risk factors are present. Conversely, a very high level might represent a temporary response to an acute condition rather than a predictor of future risk. A new analysis of WHS data indicates that the predictive value of high-sensitivity CRP is linear across a full range of values, even after other risk factors are taken into account. The researchers concluded that CRP can be used to assign individuals to low, moderate, or high risk categories for future cardiovascular events. [Circulation, April 27, 2004].

Moderate Physical Activity Promotes Weight Loss As Well As Intense Exercise

Women trying to lose weight can benefit as much from moderate physical activity as from intense workouts. This conclusion came from a clinical trial involving 201 overweight but otherwise healthy women, 21-45 years of age, who were provided with meal plans and instructed to limit their food intake to 1,200-1,500 kilocalories per day. Participants also were assigned randomly to one of four physical activity regimens that varied by intensity (moderate versus vigorous exercise) and duration (2½-3½ versus 3½-5 hours per week). Women in all four groups lost a significant amount of weight – about 13-20 pounds – and maintained their weight loss for a year. They also improved their cardiorespiratory fitness. [Journal of the American Medical Association, September 10, 2003]

Women's Heart Disease Awareness Campaign

The Heart Truth campaign, with its Red Dress icon and slogan “Heart Disease Doesn’t Care What You Wear—It’s the #1 Killer of Women,” is raising awareness among women of their risk of heart disease and motivating them to take steps to reduce it. Groundbreaking partnerships with the fashion industry and corporate America have greatly expanded coverage of the campaign since it was launched in September 2002. The Red Dress symbol and information about heart disease are appearing in homes across America through everyday products such as cereal boxes and fashion magazines. Although they may be somewhat unconventional health education approaches, these partnerships are enabling the campaign to reach millions of women.

The Heart Truth Road Show also delivered information directly to women throughout the nation. The traveling exhibit, which featured red dresses from America’s leading fashion designers, provided health screenings to 4,000 women and information to more than 86,000 individuals during its five-city tour. The campaign team also addressed the interests of state and local government agencies, health professional organizations, and community groups by offering them opportunities to implement activities in their communities and participate in national events. One such event is National Wear Red Day, which encouraged individuals to wear red to show their support for raising awareness that far more American women die of heart disease than of any other cause.

Building on its strong partnership base, the campaign continues to expand its outreach activities, especially with women of color, to ensure that women know The Heart Truth and take their heart health seriously. The Heart Truth is being conducted in partnership with the American Heart Association, the Office on Women’s Health of the U. S. Department of Health and Human Services, WomenHeart–the National Coalition for Women with Heart Disease, and other organizations committed to the health and well-being of women.

Hypertension in Pregnancy

NHLBI Working Group

In 2003, the NHLBI Working Group on Research in Hypertension During Pregnancy published a summary of what is known about pregnancy-relatedhypertension and recommendations for research to address key unanswered questions. Although much has been learned about preeclampsia during the past decade, gaps remain in the knowledge necessary to direct therapeutic strategies. For example, because oxidative stress is a biologically plausible contributor to the disorder, a clinical trial of antioxidant therapy for prevention is warranted. The trial should be complemented by research to increase understanding of the genetics and pathogenesis of preeclampsia. Recognizing that chronic hypertension in pregnancy is becoming increasingly common as women delay childbearing, the group also recommended clinical research to determine the best choice of antihypertensive medication in terms of blood pressure control, fetal growth and safety, and genetic variation in response to therapy. [Hypertension, March 2003]

Role of Neutrophils and Inflammation in Preeclampsia

Recent evidence indicates that neutrophils the bacteria-eating cells of the immune system may play a role in hypertension, proteinuria, and edema during preeclampsia. Building on knowledge that neutrophils are activated during pregnancy and are capable of damaging host tissues, researchers looked at interactions between neutrophils and blood vessels from pregnant women with preeclampsia, healthy pregnant women, and nonpregnant women. Compared with the vascular smooth muscle tissue of healthy pregnant or nonpregnant women, tissue from women with preeclampsia showed evidence of inflammation and expressed significantly more of a molecule that attracts and activates neutrophils. Neutrophils were found in a greater percentage of vessels from preeclampsia patients, and in greater numbers within their blood vessels. Furthermore, additional neutrophils had infiltrated spaces within tissues surrounding the vessels of women in the preeclampsia group, a finding not observed in tissues from the other groups. Taken together, these results the first to find vascular smooth muscle inflammation and neutrophil infiltration in women who have preeclampsia offer a possible explanation for the endothelial and vascular smooth muscle dysfunction that characterizes preeclampsia. [Hypertension, July 2004]

Lymphangioleiomyomatosis (LAM)

LAM is a rare and devastating lung disease that primarily affects young women. Lung function worsens steadily in LAM patients because of overgrowth of smooth muscle cells and formation of numerous cysts throughout the lungs. Supplemental oxygen may be useful in alleviating the hypoxemia, or low blood oxygen, associated with LAM in its early stages, but as the disease progresses, lung transplantation often becomes the only treatment option. In some patients, loss of lung function occurs gradually, but in others disease progression is rapid, necessitating transplantation after only a few years. Previously, lung diffusion studies and measurements of forced expiratory volume were routinely used by clinicians to guide them in treatment of LAM patients. Recently, however, NHLBI-supported intramural investigators used cardiopulmonary exercise testing (CPET) to evaluate lung function in 217 LAM patients. The researchers found that CPET was a better predictor of hypoxemia than the usual diffusion and expiratory volume tests, which are done on resting patients. During CPET, hypoxemia occurred in some patients who otherwise had normal diffusion and expiratory volume tests. The CPET method of evaluating lung function in LAM patients appears to be a better predictor of overall lung function and may be useful in determining which patients are likely to need transplantation. [American Journal of Respiratory and Critical Care Medicine, December 15, 2003]

Sarcoidosis

Sarcoidosis is a systemic disease involving multiple organ systems that appears to affect women disproportionately. The NHLBI sponsored a working group on Future Directions in Sarcoidosis Research in August 2002. The panel recommended developing a tissue bank to collect lung and other affected tissues, identifying genetic factors involved in sarcoidosis, studying the immunopathogenesis of sarcoidosis in relevant animal models and in human tissue, improving the management of patients with sarcoidosis, and conducting randomized controlled trials using new therapies for sarcoidosis. The NHLBI is working with the scientific community to implement the recommendations. [American Journal of Respiratory and Critical Care Medicine, September 2004]

Smoking Cessation and Lung Health

Cigarette smoking is a leading cause of chronic obstructive pulmonary disease (COPD), so smokers who develop COPD are strongly urged to quit. The NHLBI Lung Health Study of middle-aged smokers with mild-to-moderate airflow obstruction found that in the first year after quitting smoking, women’s lung function improved more than twice as much as men’s. Among participants who quit smoking, improved lung function remained greater for women than for men throughout the duration of the 5-year study. While both men and women benefit from quitting smoking, results of the study should be especially encouraging to women who are considering kicking the habit. [American Journal of Epidemiology, June 1, 2003]

Bleeding Disorders in Women

The NHLBI is increasing its efforts to improve diagnosis and treatment of bleeding disorders in women, which are a significant source of illness and diminished quality of life. A panel of experts convened in June 2004 identified research areas needing additional attention, and the Institute is working with the scientific community to address them. Additionally, the NHLBI, in consultation with the American Society of Hematology, has formed a working group to examine the current science in the area of von Willebrand disease, a bleeding disorder that affects women, and develop science-based clinical recommendations for its diagnosis, treatment, and management. The audience for the recommendations is practicing primary care physicians, including general practitioners, family practitioners, internists, gynecologists, and pediatricians. The guidelines are scheduled for completion by December 2005, and they will be widely disseminated by the NHLBI, the American Society of Hematology, and other interested groups.

Lupus and Atherosclerosis

Although systemic lupus erythematosus (SLE) has been linked to an increased risk of CAD and myocardial infarction, the association between SLE and atherosclerosis is not well understood. Two groups of NHLBI-supported investigators recently studied the prevalence of atherosclerosis in SLE patients, compared with matched controls. The first group used ultrasonography to measure carotid artery atherosclerosis, while the second used computed tomography (CT) to assess coronary artery calcification. Results from the ultrasonography studies indicated that atherosclerosis develops earlier in patients with SLE, while the CT results indicated that the prevalence of coronary-artery atherosclerosis is higher and has an earlier age of onset in patients with SLE. These results suggest the need for earlier clinical evaluation and aggressive treatment for SLE patients in order to reduce the risk of atherosclerosis. [New England Journal of Medicine, December 18, 2003]

Initiatives

Requests for Proposals (RFPs)

Field Centers for the Women's Health Initiative Extension (NHLBI-WH-04-17)
The NHLBI issued this RFP to extend the existing Women’s Health Initiative (WHI) Field Center contracts to ensure continued health surveillance of the WHI Hormone Therapy trial participants through September 2007. During the additional 2 1/2 years of participant follow-up, health outcomes will be ascertained and mammography data will be collected.

Renewal of the Jackson Heart Study (NHLBI-04-25 and NHLBI-04-26)
These RFPs provide funding for the Jackson Heart Study (JHS) through FY 2009. Expansion of the JHS, a large study of CVD risk in African American women and men in Jackson, Mississippi, will enable support for additional clinical examinations and data collection. It will also sustain and enlarge the Jackson-area community health education component, which uses data derived directly from the JHS cohort to develop and disseminate practical, up-to-date information on reduction of risk factors, practice of healthy lifestyles, and adherence to proven risk-reducing therapies.

Request for Applications (RFA)

Granulomatous Lung Inflamation in Sarcoidosis (RFA-HL-04-009)

Based on recommendations of the NHLBI working group on future research directions in sarcoidosis, the NHLBI issued this RFA to identify the innate and/or adaptive immune pathways that affect lung lymph nodes or tissue in early disease and to study the immunopathogenesis of granulomatous inflammation similar to that found in sarcoidosis so that therapeutic targets for cinical trials can be identified.

Program Announcements (PAs)

Pathogenesis and Treatment of Lymphedema and Lymphatic Diseases (PA-04-071)

The NHLBI issued this program announcement with the National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Cancer Institute, the National Center for Complementary and Alternative Medicine, the National Institute on Biomedical Imaging and Bioengineering, and the National Institute of Nursing Research to stimulate research on the biology of the lymphatic system, to characterize the pathophysiologic mechanisms that cause the disease, to develop new methods for quantitating and imaging lymph flow, to discover new therapeutic interventions, and to determine the safety and efficacy of complementary and alternative therapies. Lymphedema, which is characterized by abnormal fluid accumulation and swelling, is a particular concern of women who have surgery or radiation treatment for breast cancer.

Exploratory and Developmental Research Grants for Investigations in Rare Diseases (R21) (PA-03-171)

Using the R21funding mechanism, which supports exploratory and developmental research projects, the NHLBI and the NIH Office of Rare Diseases issued this program announcement to encourage innovative approaches to understanding, treating, and preventing rare diseases in the areas of heart, lung, and blood and sleep disorders, such as LAM and sarcoidosis, both of which disproportionately affect women.

Workshops/Working Groups
NHLBI Workshop on Women and Ischemia Syndrome Evaluation (WISE): Diagnosis and Pathophysiology of Ischemic Heart Disease
October 2-4, 2002

Women with Bleeding Disorders Working Group
June 2, 2004

Research Pertaining to Special Populations

While heart disease and stroke remain the first and third most common causes of death of all Americans, African Americans suffer disproportionately from these diseases. For example, in Mississippi the age-adjusted CVD mortality for African American women is 75 percent higher than for white women, and African American men have rates 47 percent higher than those of white men. To investigate disparities in CVD prevalence, severity, and mortality among African Americans, the Jackson Heart Study (JHS) was initiated in 1998. The project has enrolled 5,500 African American women and men living in the Jackson, Mississippi, area, and it will continue through 2009. The JHS is uniquely positioned to identify factors that influence the development and worsening of CVD in African Americans, with an emphasis on manifestations related to hypertension such as CAD, heart failure, stroke, peripheral arterial disease, and renal disease.

Gender Analysis

As noted under Accomplishments, researchers recently identified a number of gender differences with regard to heart failure mortality, survival, risk, and response to treatment.

 

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