Specialty Corner: Gender Differences and Risk Factors in Coronary Heart Disease

Coronary heart disease (CHD) is the leading cause of death of men and women in the world but in younger age groups, the CHD-related death rate is strikingly higher in men compared to women.¹ Emerging evidence suggests that a disparity exists in regards to cardiovascular risks and outcomes among the sexes. The lifetime risk of developing CHD by age 40 is 50 percent for men and 33 percent for women.² In general, both CHD incidence and mortality in women lag by almost a decade behind that of men. However, this trend changes after the age of 75 and is mostly attributed to menopausal changes in women.

Because CHD has been thought of as a disease that plagues men, women often are not fully aware of their own risks of heart disease. Furthermore, there is a misperception that women are protected against CHD because it tends to emerge from seven to 10 years later compared to their male counterparts. Clinicians also often underestimate in women the same risk factors that they target with prevention and medications for men. This leads to differences in traditional diagnostic and therapeutic methods that are not necessarily optimized for women. Women, thus, arguably have had a poorer prognosis than men after myocardial infarction (MI). Mortality after a coronary bypass graft also has been shown to be higher in women as compared to men and may be attributed to comorbid conditions such as older age, smaller vessel size and the presence of hypertensive heart disease.³ However, over the past decade, there have been substantial efforts made to improve understanding of the sex and gender differences in cardiovascular disease. Studies have evolved to detect these differences, assess risk factors, and define goals for women as well as for men.

Hormonal Status

Unique to women is the influence of estrogen hormones on heart disease. Endogenous estrogen has been shown to delay the onset of atherosclerosis in women by influencing the process through a variety of mechanisms. Estrogen plays a role in regulating several metabolic factors, including lipoproteins and inflammatory markers. After menopause, atherosclerotic plaque composition develops into more vulnerable lesions with an increase in associated inflammatory factors.^3,4 Thus, incidence of CHD is lowest in premenopausal women as compared to men and to postmenopausal women of similar age.⁴ In the Women’s Ischemia  Syndrome  Evaluation (WISE) study, younger women with low blood estrogen were linked to a significantly greater prevalence — up to a seven-fold increase — in coronary artery disease.⁵

Conversely, because men die from heart disease at an earlier age than women do, it is instinctive to think that lower testosterone levels would be beneficial for cardiovascular protection. However, a number of studies have suggested a link between low testosterone levels in men and the development of heart disease and its associated mortality.⁶ Several mechanisms may explain this association, although the precise nature of the link remains unclear. Men whose levels are too low may experience obesity, diabetes mellitus, and other health problems that make them susceptible to heart disease. Men with higher testosterone levels have more muscle mass and may be at lower risk for cardiovascular disease. One study that evaluated low testosterone levels in male veterans over 40 years suggested a 40-percent increased risk in mortality over the following 20 years compared with men with normal testosterone, independent of age, adiposity, and lifestyle.⁷

Hyperlipidemia

Cholesterol goals for women are slightly different than those for men, as seen in the National Lipid Association (NLA) Recommendations for Patient-Centered Management of Dyslipidemia. Total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides vary in women. For example, total cholesterol and LDL, both major risk factors for CHD, are similar in men and women up to the second decade of life but rise more sharply in men during the next two decades. Following menopause, these same levels in women begin to exceed those of men. After the age of 65, average LDL is higher in women than in men.⁶ Much of this is because of estrogen’s effect on up-regulating LDL receptors. The lower estrogen levels seen during menopause decrease LDL receptor activity, resulting in higher LDL levels.⁴ Studies including the Scandinavian Simvastatin Survival Study (4S) and the Cholesterol and Recurrent Events (CARE) trial showed that women responded to treatment of cholesterol with statin therapy as much as men, with the latter showing a 46-percent reduction in the risk of combined coronary events as compared to men. HDL levels are known to correlate inversely to the risk of heart disease.^7,8 These levels are higher in women but decrease following menopause. The loss of this major protective factor also increases a woman’s risk of CHD. This forms the basis of the NLA recommendation of a higher HDL goal for women.⁹ Lastly, elevated triglyceride levels also increase the risk of CHD in men and women. A meta-analysis of nearly 46,000 men and 11,000 women showed that CV risk increased by 14 percent in men and 37 percent women with a 1 mmol/L increase in triglycerides.⁴

Smoking

The American College of Cardiology/ American Heart Association (ACC/AHA) and the NLA have indicated that cigarette smoking is a major yet preventable risk for CHD. Tobacco use has been shown to increase the relative risk of first acute myocardial infarction (MI) more in women than in men.¹¹ Smoking cessation can considerably decrease this risk, regardless of gender. After one year, risk of CHD is reduced by 50 percent and after two to three years, the risk becomes similar to that of non-smokers.^4,12 Smoking seems to be a stronger risk factor for MI in middle-aged women than in men. It also decreases the natural age of menopause by two years in current smokers and one year in former smokers. Smoking also may decrease HDL to a greater extent in women than in men.⁴

Hypertension

Systolic blood pressure affects women more considerably than men in terms of cardiovascular outcomes. This may be related to a decrease in estrogen levels following menopause, as well as an up-regulation of the renin-angiotensin system, increase in plasma renin activity, salt sensitivity, and sympathetic activity.¹¹ Isolated systolic hypertension (ISH), defined as systolic blood pressure > 160 mmHg and diastolic blood pressure < 90 mmHg, also is associated with an increased risk of CV disease, stroke and all-cause mortality in both men and women.⁴ However, the prevalence of ISH seems to be increasing more sharply in women than in men > 55 years of age. Women with a history of pre-eclampsia — defined as blood pressure >140/90 mmHg and proteinuria (0.3 g/24 hrs) after 20 weeks of gestation — have twice the CHD risk as compared to normotensive women during pregnancy. Despite these risks, blood pressure reduction has been shown to benefit both men and women as evidenced in the Systolic Hypertension in the Elderly Program (SHEP). Antihypertensive treatment reduced the incidence of stroke and non-fatal MI by 36 and 27 percent, respectively.¹³

Diabetes

Diabetes has long been recognized as a major risk factor for CHD and has been incorporated in numerous guidelines, including the current ACC/AHA guidelines10 and NLA Recommendations.⁹ Not surprisingly, CHD accounts for 75 percent of the deaths in adult diabetics. Diabetes is more prevalent among women > 20 years of age than among men. Furthermore, women with diabetes have a three- to seven-fold increased risk of CHD as compared to a two- to three-fold increase in men with diabetes.4 Mortality from MI also is significantly higher in diabetic women than it is in non-diabetic women and diabetic or non-diabetic men.4 Because of the high mortality rate in these patients, aggressive treatment is strongly recommended. A high level of evidence supports the use of a moderate-intensity statin in diabetics ages 40 to 75 years, regardless of gender.10

In summary, CHD continues to be the leading cause of death among men and women. Despite varying hormonal composition between men and women, risk factors remain consistent between the sexes. On closer review, however, several factors — including lipids, diabetes, tobacco use, and high blood pressure — have been shown to play a larger role in women’s risk. This has led to an increase in research and a focus on more aggressive preventive strategies and treatment strategies in women with the goal of reducing the incidence of heart disease. There has been a near doubling of the rate of awareness of heart disease as the leading cause of death in women between 1997 and 2009 and a 50 percent decrease in the number of deaths resulting from CHD.³ At this time, secondary prevention of CHD in women with hormone replacement therapy is not recommended, because its use has not been shown to be favorable in this endeavor.¹⁴ Similarly, with men, clinical studies have yet to establish a role for testosterone replacement in reducing heart disease. Other agents — such as statins, ACE-inhibitors, and insulin — have been proven to be beneficial in risk reduction and should be considered as first-line options along with smoking cessation, if applicable.

Disclosure statement: Dr. Naina has no disclosures to report.

References are listed on page 40 of the PDF.