Biennial Report on Women's Health Issues
FY 2003 and FY 2004
Contents
Executive Summary
Full Report
NHLBI Entities With A Designated Focus on Women's Health
Accomplishments
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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