The average age at which women develop CVD is roughly 10 years after the average age of men, in large part due to sex hormones. This has likely contributed to the misconception that women are less vulnerable to CVD. Sex hormones play a major role in the pathophysiology of cardiovascular disorders, and once post-menopausal females lose the protective benefits of estrogen, their risk of CVD is equal to that of men [15]. Estrogen is thought to play several roles in the pathophysiology and manifestations of heart disease in women. Estrogens are believed to be protective to coronary vessels by providing improved vascular tone. Experimental studies have shown that estrogens can adjust the response of vessels to various vasoactive substances, including angiotensin II, norepinephrine, and aldosterone, thereby preventing the same degree of vasoconstriction seen in men [16, 17]. Additionally, estrogen can increase the production or the release of relaxing factors from the endothelium, thus improving endothelial function [18]. Estrogen can also improve a woman’s lipid profile by reducing low-density lipoprotein cholesterol and increasing high-density cholesterol [19]. Women may have different clinical symptoms of ischemia because of two different mechanisms of estrogens: (1) they may directly alter pain perception in women, and (2) they may play a direct anti-anginal role by reducing the pain-producing effects of adenosine that cause the classic ischemic-like chest pain [20, 21]. In addition to the increased risk of CVD which comes with post-menopausal changes in sex hormone levels, increased age is also associated with a higher incidence of diabetes, hypertension, obesity, and other co-morbidities which also increase risk of CVD. Despite all of the previously noted benefits of estrogen for CVD prevention in women, not all estrogen is created equal. Specifically, exogenous estrogen in post-menopausal women has shown to be in fact even harmful. In fact, two studies in particular—the Heart and Estrogen/Progestin Replacement Study (HERS), and the Women’s Health Initiative (WHI)—did not support the beneficial effects of hormone therapy in post-menopausal women (in either secondary or primary cardiovascular prevention). The WHI trial was actually terminated early after finding a small but significant increase in cardiovascular events and other adverse outcomes in the hormone therapy group [8, 22, 23].

Tobacco use unfortunately continues to be the leading preventable risk factor for CHD in women, that has yet to be extinguished. Over the past 50 years, the risk of death from cigarette smoking continues to increase among women and the increased risk of death from all causes (lung cancer, COPD, any type of stroke, CVD, and all others) is now nearly identical for men and women, when compared to those who have not smoked [24]. Smoking has been associated with one-half of all coronary events in women. The meta-analysis by Rachel Huxley and Mark Woodward showed, that smoking confers a 25 % greater relative risk of coronary heart disease in women than in men [25]. The risk of death from ischemic heart disease in cigarette smokers is the same in men and women, almost three times higher than in those who have not smoked. A critical point to remember is that quitting smoking dramatically reduces mortality from all major smoking-related disease and it is never too late to quit. Early tobacco cessation is also important, as smoking cessation before 40 years of age reduces smoking-associated mortality by 90 % [26]. Another important point to recognize is that smokers on oral contraceptives are at even further increased risk of CHD. And while the prevalence of male smokers continues to be slightly higher than female smokers, there is smaller decline in tobacco use among women [27].

For both women and men, hypertension has been identified as a major cause of CVD [8]. With increasing age, there is progressive loss of arterial compliance, resulting in increasing overall prevalence of hypertension. Approximately 18 % of women are hypertensive prior to the age of 45, while nearly 80 % of elderly women are hypertensive (as compared to 25 % of men prior to the age of 45, and 72 % of men over 75) [7]. And in older women, the most common form of hypertension is actually isolated systolic hypertension. HTN is particularly prevalent among black women. Not only is there a disparity in the incidence of hypertension between men and women; there are also differences in the role that hemodynamic characteristics play in the pathology of hypertension and target end organ damage between men and women. In one study looking at 100 men and 100 women with similar rates of mild-to-moderate hypertension (also matched to equivalent age and race), hemodynamic differences were observed [28]. Men were on average found to have lower resting heart rates, longer left ventricular ejection fraction (LVEF) time, lower pulse pressures, and greater stress-induced rises in blood pressure and pulse pressure. Women on the other hand, were found to have lower total peripheral resistance, decreased blood volumes, and stress-responses related to hormonal status (the higher the estrogen activity, the less arterial pressure increased with mental stress) [28]. Also, in women taking oral contraceptives (especially those who are older, and with concomitant obesity), hypertension has been found to be two to three times more common than in women who are not on them [8].

Another well-known cardiac risk factor, the contribution of dyslipidemia to CVD also differs between men and women. For both sexes, LDL-C is the major atherogenic lipoprotein [29]. Typically in the United States, the levels of LDL-C and triglycerides (TG’s) are higher in men than in women. This holds true until women turn 55, at which point a shift occurs and women have higher levels. Regardless of the absolute level however, LDL-C remains the primary target for intervention in both sexes as noted in the NCEP guidelines. Despite higher levels of TGs in men, there is actually a stronger association between the TG level and CVD risk in women. This was demonstrated by a meta-analysis that showed that a 1 mmol/L (89 mg/dL) increase in TG levels was associated with a 32 % increased risk of CVD in men, versus a 76 % increased risk in women [29, 30]. HDL-C is the third important component of the lipid panel associated with increased CVD risk and several studies have shown that HDL-C is the most powerful predictor of CVD risk in women [29, 31–33]. Low levels of HDL-C have been shown to be a significant risk predictor in older women, but not in older men [34]. As will be later discussed, there are specific guidelines for lipid management in women to reduce risk.

CVD and diabetes are closely related, largely due to the effects of diabetes on vasculature. Diabetics are up to four times more likely to have CVD than non-diabetics [35]. One of the major mortality events in diabetics is CVD, and nearly two out of three diabetics will die from some sort of CVD. Men and women with diabetes often have subclinical vascular disease. And specifically in women, diabetes has been shown to confer greater prognostic information than any of the other traditional risk factors. It is thought of as a more devastating risk factor for women than men, often eliminating the other age- or hormone- protective cardiovascular disease advantages. Women with diabetes thus require intensive cardiovascular screening. This is also true in young women with gestational diabetes, who are prone to develop both subsequent diabetes mellitus and adverse coronary risk profiles [36].

Obesity is increasingly frequent across all cultures and is recognized as a risk for cardiovascular disease. A report from Roger et al. in 2011 found that nearly two of every three US women >20 years of age is now overweight or obese [37]. The Nurses’ Health Study, a prospective study by Manson et al., looked at 115,886 U.S. women between the ages of 30 and 55 who were free of diagnosed coronary disease, stroke, and cancer. They found a strong positive association between obesity and the occurrence of CVD (specifically in this study, non-fatal MI and fatal coronary disease) [38]. Obesity was categorized into five different groups based on body mass index (BMI; weight in kilograms divided by the square of the height in meters): BMI <21, 21- <23, 23 to <25, 25 to <29, and ≥29. The risk of both non-fatal MI and fatal coronary disease was three times higher in the ≥29 group when compared to the leanest group, who had the lowest rates of coronary disease. Surprisingly, even women considered to be of “average weight” had a nearly 30 % higher risk of coronary events when compared to the leanest group [38]. There are several CHD risk factors affected by obesity, including hypertension, low HDL cholesterol, elevated triglycerides, diabetes mellitus, and elevated levels of inflammatory markers. Even relatively modest weight gain during the adult years is highly related to developing an increased risk factor burden. Nearly 23 % of CHD in men, and 15 % in women were obese in long-term analysis of Framingham data. Individuals with central obesity, largely because of concomitance of other risk factors or co-morbidities (very often present in obese women), have an increased risk of cardiovascular events [27, 39].

Metabolic syndrome, which is defined by the presence of three or more risk factors described below (including central obesity), is more common in women with CHD when compared to men. The risk factors include increased abdominal obesity as defined by waist circumference (in men, greater than 40 in.; in women, greater than 35 in.), fasting blood triglycerides level greater than or equal to 150 mg/dL, low blood HDL cholesterol (in men, less than 40 bmg/dL; in women, less than 50 mg/dL), blood pressure greater than or equal to 130/85 mmHg, or fasting blood glucose greater than or equal to 110 mg/dL [27].

Psychological stress also likely influences the onset and clinical course of CHD, which growing evidence suggests may be especially true for women. The previously mentioned INTERHEART study suggested that AMI was strongly associated with the combined exposure to psychosocial risk factors (including major life events, depression, perceived stress at home or work). Congruous with this, lower socioeconomic status (with increased psychosocial stressors and hardened lifestyle factors) has consistently been associated with increased cardiovascular morbidity and mortality. These psychosocial factors (well-documented to be more prevalent in women than in men), may also affect the adherence to, and ability to maintain a healthy lifestyle [40, 41].

The chronic inflammation associated with systemic inflammatory diseases is felt to accelerate the development of cardiovascular disease. Women with rheumatoid arthritis have a two to four times higher risk of myocardial infarction or new cardiovascular events compared with women who do not have rheumatoid arthritis and the mortality rate is 50 % higher for cardiovascular death in patients with rheumatoid arthritis compared to those without [42]. After controlling for common risk factors, patients with systemic lupus had a ten-fold higher relative risk for nonfatal myocardial infarction, 17 fold higher risk for death due to coronary heart disease, sevenfold higher risk for overall coronary heart disease, and an almost eightfold higher risk of stroke [43]. Studies have linked carotid atherosclerosis with disease duration in rheumatoid arthritis and systemic lupus [44, 45]. The increased risks associated with systemic collagen vascular inflammatory disease are not limited to women but these diseases predominantly affect women compared to men, making identification and management important. Aggressive control of the underlying inflammatory disease is recommended to decrease morbidity and mortality from cardiovascular disease [42, 43, 45–47]. Systemic collagen-vascular inflammatory disease is an independent risk factor for cardiovascular disease, as noted in the 2011 AHA guidelines, so presence of this condition should prompt further assessment of cardiovascular risk and risk factor modification [48–50].

Without dedicating the remainder of this chapter to the other 200+ risk factors associated with CVD, it is worthwhile to note that there has been interest in potential risk factors. The U.S. Preventive Services Task Force (USPSTF) published a review of “Emerging Risk Factors for CAD” [51], based on nine systematic reviews of novel risk factors recently receiving attention. The factors evaluated included C-Reactive Protein (CRP), coronary artery calcium score (as measured by electron-beam computed tomography), lipoprotein (a) level, homocysteine level, leukocyte level, fasting blood glucose, periodontal disease, ankle-brachial index, and carotid intima-media thickness. Based on the current evidence available, the review did not find the routine use of any of these nine aforementioned risk factors to be valuable for further risk stratification of intermediate-risk persons [41, 51]. That being said, CRP has been shown to be of some utility when incorporated into risk assessment scores, and particularly the Reynolds Risk Score. Specifically, a CRP level of >3.0 mg/L did reclassify approximately 5 % of intermediate-risk women in the Women’s Health Study (however, it failed to reclassify any in the Cardiovascular Health Study), which suggests a small and inconsistent effect when CRP is used [8, 52].

While lifestyle recommendations to decrease risk of cardiovascular disease may seem intuitive, they should not be overlooked or underestimated. Women who are in the “ideal cardiovascular health” group as defined in the AHA 2011 guidelines have a significantly decreased incidence of CVD compared to those with risk factors [10]. In addition, data from the Nurse’s Health Study showed that women who adhered to lifestyle recommendations (similar to the ideal cardiovascular health group) had a relative risk reduction of about 80 % compared to those women not in this group [9]. Recommendations for optimization of modifiable risk factors (cigarette smoking, diet, physical activity, weight management) are as detailed in Table 2.1.