SPECIAL FEATURE Vol.6 No.5 (July 2001)

Women at Cardiovascular Risk:
Does Gender Alter Therapy?

Dr. Kathy Berra
Stanford Center for Research in Disease Prevention, United States

Introduction

Gender based differences in the prevalence, presentation and treatment for coronary heart disease (CHD) define an important area of research and controversy. Gender based differences include age at onset of CHD, typical presentation of CHD symptoms, relative importance of coronary risk factors, and the potential relationship of ovarian function/estrogen status to the development of CHD. The American Heart Association (AHA) reported in 1998 that the leading cause of death for American women is cardiovascular disease with CHD responsible for the majority of total deaths. This is true for Hispanic, Black, Asian/Pacific Islanders, American Indian/Alaska natives and White women. Percent of total deaths in each of these groups is 34%, 41.6%, 36.1%, 28.4% and 44.9% respectively. Unquestionably, women are at great risk for death and disability from CHD.

The risks for developing CHD and stroke for both men and women are closely related to well known cardiovascular risk factors. These include hypertension, cigarette smoking, dyslipidemia, diabetes, physical inactivity, nutrition and weight. Women appear to be protected from the development of CHD based upon ovarian function. The development of pre-menopausal CHD is uncommon, occurring mostly in diabetic women.Observational studies in American women who have chosen to take HRT following menopause suggest a significantly reduced risk of developing CHD. This includes women who have never taken HRT as well as those who are current users. The average reduction in risk related to HRT usage is nearly 50%. This observation has stimulated much research regarding potential mechanisms of protection. As a result of the apparent pre-menopausal protection, women generally develop signs and symptoms of CHD at age 65 – about 10-15 years later compared to men. This fact has led women to diminish their overall sense of perceived risk for the development of CHD. Pilote and coworkers showed that in a group of Stanford graduates, over 50 years of age, thought that breast cancer was their biggest risk for death and illness. In 1995, cardiovascular diseases (CVD) resulted in 50% more deaths compared to cancer from all causes in women. The knowledge that women believe cancer to be their biggest health risk as opposed to the real risk of CVD has led to important public education efforts by the American Heart Association and other organizations.

CAD in women is caused by all of the traditional risk factors such as cigarette smoking, high blood cholesterol, high blood pressure, diabetes and physical inactivity. In addition, women have a very unique risk factor which relates to their menopausal status. Women experience the onset of symptoms from CHD 10-15 years later than men do. This delay is due in part to the apparent protective effects of pre-menopausal estrogen exposure. Increasing age and postmenopausal status are hallmarks of rising CHD risk in women.

Cigarette smoking is a major treatable cause of CHD in women. Quitting smoking will greatly reduce the risk of CHD, lung cancer and other illnesses related to smoking. Participation in a smoking cessation class and, in some cases, use of nicotine replacement and other pharmacologic therapies show promise for helping women to quit smoking. Younger women are smoking more and the rates of lung cancer in women are rising rapidly. Gender specific research regarding the increased incidence of smoking in younger women as well as gender appropriate treatments is needed.

Abnormal lipids and lipoproteins carry increased risk for women as well as men. The influence of specific subfractions, however, indicate that there are gender differences. High LDL cholesterol is known to be a strong risk factor for men but may be a somewhat weaker risk factor for women. Eating a diet low in saturated fat and cholesterol remains the best protection against high cholesterol levels. Some women, however, will need to take medications for their cholesterol levels in addition to watching their diet and exercising regularly. Fortunately there are a number of safe and effective medications to help maintain normal cholesterol levels. What appears to be as important, if not more important for women is low HDL cholesterol. A diet low in fat, cholesterol and carbohydrates; regular physical activity; weighing close to your ideal body weight as well as not smoking cigarettes will help to increase levels of HDL cholesterol. There are certain medications that can help raise HDL cholesterol if lifestyle is ineffective.

Physical inactivity is a powerful risk factor for both women and men. Physically active women tend to gain less weight as they age and maintain higher HDL cholesterol levels (good cholesterol) when compared to less active women. It has also been shown that women who are more physically active tend to be less depressed and report less stress in their lives.

Obesity in women is associated with many risk factors for heart disease. This is especially true when the weight is carried around the trunk (abdominal pattern obesity). Women with a waist circumference which measures greater than their hip circumference are more likely to have high blood pressure, high triglycerides, low HDL cholesterol, diabetes and are more likely to develop heart disease. Exercise, weight loss, a diet low in fat and cholesterol are important in managing this problem.

Hypertension carries risk for both heart disease and stroke. Women, like men, are at risk when blood pressure readings are regularly above 140/90. Weigh loss, exercise, a diet low in sodium and stress management can all help in achieving and maintaining a normal blood pressure. In addition, there are many medications that are very helpful in reducing and maintaining a normal blood pressure. Medications are important if life style measures are unsuccessful in normalizing blood pressure (less than 140-90). Blood pressure research has shown that African American, Cuban, Puerto Rican and Hispanic women are at increased risk of developing high blood pressure and suffering from target organ damage as a result.

A diet high in saturated fat and cholesterol and low in fruit and fiber is associated with an increased risk of heart disease as well as certain cancers in women. Learning to eat a diet that contains whole grains and fruit as well as one that is low in cholesterol and saturated fat will help lower LDL cholesterol and raise HDL cholesterol. These diets can also help to maintain a normal body weight.

Hormone replacement therapy (HRT) for postmenopausal women is a subject receiving much attention. The observed lipid and lipoprotein benefits of HRT include a reduction in Lipoprotein(a) [Lp(a)] and LDL cholesterol levels. Lp(a) is a modified type of LDL cholesterol formed by apolipoprotein (a) binding to the LDL particle. This particle has similar properties to plasminogen and thereby interferes with fibrinolysis and enhances thrombosis. Lp(a) is also associated with increased deposition of LDL cholesterol in the arterial wall and increases oxidation of the LDL particle. HRT also raises HDL cholesterol, a lipoprotein particle known to protect against the development of atherosclerosis. These relationships between HRT and the lipoprotein subfractions, in addition to other benefits to the vascular system, appear to benefit the atherosclerotic process. Additional intriguing data suggests that estrogen alone has a beneficial influence on endothelial function. In the absence of estrogen, a woman's arteries tend to constrict which decreases the flow of blood. Estrogen has been shown to help arteries relax and dilate in a normal fashion similar to the effect of Nitric Oxide. There is also much interest in the relationship of post menopausal estrogen use on various physiological functions including memory and cognition. Clinical research is underway at this time evaluating the role of estrogen and neurological function.

It is important to remember that the use of HRT is associated with a probable increased risk of breast cancer and a small, but definite, increased risk of deep vein thrombosis and pulmonary embolism. In addition, gallbladder disease and elevations in Triglycerides are seen in women on postmenopausal HRT. Women reporting a history of breast cancer, uterine or cervical cancer, deep vein thrombosis or pulmonary embolism, active gall bladder disease, high triglycerides or abnormal liver function are generally not appropriate candidates for HRT. The type, dosage and duration of estrogen therapy to provide maximum benefit to the lipoprotein profile with the least risk for cancer and other negative side effects is unknown. To further complicate the issue, women with an intact uterus must be given an additional hormone, progestin, to protect the uterus from endometrial cancer secondary to hyperplasia. Data also suggests that progestins may somewhat blunt the beneficial effects of estrogen on the lipoprotein profile.

An important clinical trial was recently published regarding the use of post menopausal HRT in women with known coronary heart disease. The Heart and Estrogen-progestin Replacement Study (HERS) asked the question: "Does HRT (estrogen and progestin) prevent heart related death and acute myocardial infarction in women with heart disease?" This nationwide study included 2,763 women with coronary disease, younger than 80 years of age, with an intact uterus. The study was blinded to both participants as well as investigators. The women were randomly assigned to either placebo or estrogen plus progestin and were followed for an average of 4.1 years. The HERS study found no difference in fatal heart attack and heart disease related death between women randomized to estrogen plus progestin and those randomized to placebo. These results, although surprising, have important implications for those who care for postmenopausal women with heart disease. In addition to no difference in overall myocardial infarction and coronary death between the groups, there was an early (in the first 8 months of treatment) increased risk of death from acute myocardial infarction and other coronary death in women randomized to estrogen/progestin compared to women on placebo. This early increased risk was balanced with a later (in years 3 and 4) decreased risk of these same endpoints. In addition, a small but definite increased risk of thromboembolic events (Deep Vein Thrombosis [DVT] and Pulmonary Embolism [PE]) as well as gall bladder disease was also found. Increased risk of gallbladder disease, DVT and PE have been found in other studies of postmenopausal HRT.

More questions than answers remain regarding HRT as a protection against the development of CAD or as a treatment for women with CAD. The Women's Health Initiative (WHI) is a 12-year prospective, randomized, controlled study of 164,500 post menopausal women (64,500 have been randomized into a variety of interventions with 100,000 being followed in an observational study). It is scheduled to be completed in 2010. WHI is asking three important questions. "How does HRT influence CHD, osteoporosis, breast and uterine cancer in post menopausal women? Does a diet low in fat and cholesterol and high in fruit, vegetables and fiber influence the rate of CHD, breast and bowel cancer in women? Does calcium replacement effect bone fractures and colorectal cancer in women?" The Women's Health Initiative should help us understand many of the questions we have concerning the risks and benefits of HRT as it relates to coronary artery disease.

Low socioeconomic status, social isolation, depression, anger and hostility are additional risk factors for women and men. These issues must be addressed when evaluating and managing a woman's risk for either a primary or a secondary coronary event or stroke.

Although the onset of coronary heart disease in women is delayed for 10-15 years compared to men, more women will actually die from this disease than men. In addition, the perception of risk for diseases of the vascular system is significantly overshadowed by the perception of risk for breast cancer in women. The public health message for women must be one that can convey the appropriate message about their risk for coronary artery disease and stroke. An important new organization for women with and at risk for heart disease (womenheart.org) now exists. This organization is dedicated to the advancement of information through their website and through other programs including advocacy for women with heart disease.