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Abstract

Cardiovascular disease is the leading cause of death in women, contributing to one in three female deaths. Despite improvements in overall cardiovascular outcomes, substantial gender and ethnic disparities remain. In order to improve outcomes among women, we recommend the following: every woman should undergo risk stratification for short-term and lifetime cardiovascular risk given the substantial long-term risk of cardiovascular disease; modifiable cardiovascular risk factors in women should be modified to the greatest extent possible; and these factors include lipid abnormalities, hypertension, smoking, diabetes, obesity, physical inactivity and, possibly, inflammatory markers. The rate of decline in heart disease is slower for women than men, highlighting the need for gender-specific interventions to address the outcomes gap.

Keywords

cardiovascular disease coronary artery disease dyslipidemia hypertension

Although heart disease has frequently been thought of as a ‘male’ disease, cardiovascular disease (CVD) is the leading killer of women both globally and in industrialized nations [101]. In the USA, CVD contributes to more than one in three deaths in women, and more than all cancer deaths combined [1]. Despite decades of improvements, the disturbing surge in obesity, diabetes and other comorbid conditions likely ensures that CVD will not just fade away. In fact, recent trends suggests that CVD is increasing among young adults, particularly females [2].

Many factors, including sex hormones, play a major role in biologic differences in CVD development between men and women, leading to differences in epidemiology, treatment and prognosis [3]. Women are approximately a decade older than men when presenting with CVD; however, premenopausal women who have myocardial infarctions (MI) have a worse prognosis than men [4,5]. Anatomically, women are more likely to present with nonepicedial coronary heart disease (CHD) including cardiac syndrome X or coronary microvascular disease and stress-induced cardiomyopathy. In addition, women are less likely to present with typical angina symptoms [6], more likely to have unrecognized MIs and receive less aggressive treatment than men [7,8]. Disparities exist in risk factor profiles as well. Men are more likely to engage in moderate physical activity, whereas women are more likely to maintain a healthy weight [9]. Since the majority of CVD including CHD and stroke is preventable, a thorough understanding of CVD determinants is imperative. This review will discuss the major predictors of CVD in women in western societies, focusing on atherosclerotic events and highlighting gender-specific factors.

Risk stratification models in women

Whether variations in outcomes stem from genetic differences or gender bias, epidemiologic studies suggest that significant challenges lie ahead. In women, the lifetime risk for developing CVD is at least 50%, implying that exhaustive risk stratification is warranted in all women [1]. Several different risk tools are available that predict cardiovascular outcomes.

The Framingham Risk Score (FRS) is the most commonly used model and was developed based on the prospective cohort Framingham Heart Study [10,11]. This validated scoring system utilizes age, gender, cholesterol profile, smoking and blood pressure to predict a person's chance of having a cardiac event in the next 10 years. In general, the FRS is known to underestimate CHD risk in women [12]. The Framingham risk factors form the basis for the National Cholesterol Education Program/Adult Treatment Panel III risk prediction model. The Adult Treatment Panel III predicts future cardiovascular events but not angina nor a need for revascularization; two important end points common in women [13]. The Reynolds Risk Score (RRS) was initially developed specifically for women and incorporates family history, inflammatory biomarkers and hemoglobin A1C, in addition to the above risk factors [12]. The RRS reclassified 40–50% of women at intermediate risk into higher or lower categories in a patient cohort from the Women's Health Study [12]. In addition, the RRS appears to improve discrimination in multiethinic populations in comparison with FRS, which was primarily developed from cohorts of white men and women [14]. A direct comparison of the above models showed that RRS is a more accurate short-term predictor but the overall gains of using that system are very modest [14]. Major society guidelines from the American College of Cardiology Foundation/American Heart Association (AHA) recommend using any of the above global risk scores for cardiac risk assessment [15]. The SCORE model is an alternative global risk tool based on pooled data from multiple European studies and is recommended by the European Society of Cardiology [16].

A major limitation of the above risk scores is the narrow focus on short-term risk and extrapolation of data from very high-risk, or apparently healthy, patients, which does not apply to the general population [1]. To address these limitations recent AHA guidelines on prevention of CVD in women, classified women into ‘high risk’, ‘at risk’ or ‘ideal cardiovascular health’ [1]. This simplified classification emphasizes the concept of increased lifetime risk for women and is easily accessible to patients and providers. In a validation cohort, the model proposed by AHA identified cardiac risk with an accuracy similar to FRS [17].

Lipids

Cholesterol is the sin qua non of coronary artery disease (CAD). A number of experimental animal studies, epidemiologic data and therapeutic trials have established a casual relationship between hyperlipidemia and CAD [18]. Conversations about low-density lipoprotein (LDL) cholesterol or ‘bad cholesterol’ and high-density lipoprotein (HDL) cholesterol ‘good cholesterol’ have become commonplace in today's society, even among lay populations. A number of important differences exist in cholesterol regulatory pathways between men and women. Estrogen-mediated effects influence hepatic expression of lipopoproteins, namely decreasing total cholesterol and LDL, while increasing HDL and triglycerides [19]. In addition, estrogen decreases lipoprotein(a), a molecule consisting of an LDL particle covalently bound to an apoprotein(a) molecule. Apoprotein(a) has significant homology to plasminogen and lipoprotein(a) has been shown to be an important determinant of CHD in pre- and post-menopausal women [20]. Serum lipids can increase modestly during the menopause transition, peaking during late peri- and early-postmenopausal periods [21]. Data from the Study of Women's Health Across the Nation showed that a mild increase in HDL and triglycerides accompanies the increase in total cholesterol and LDL observed during menopause [21]. These effects, however, are in conflict with other studies showing no effect between triglyceride levels and menopause when adjusting for age [22]. Regardless, it appears that hypertriglyceridemia is a stronger predictor of increased cardiac risk in women than in men [23]. In women, non-HDL cholesterol (total cholesterol minus the HDL cholesterol level) and the ratio of total cholesterol/HDL, appear to be better predictors of future cardiovascular events than other lipid parameters and apolipoprotein fractions [24]. AHA guidelines recommend screening all adults, both women and men, more than 20 years of age, with a standard fasting lipid profile at least once every 5 years, with more frequent measurements in patients with multiple risk factors or borderline previous measurements [13]. The Adult Treatment Panel III guidelines identifies LDL as the primary target of dyslipidemia treatment, with LDL goals influenced by the level of baseline risk as defined by presence of known CHD or other risk factors. Therapeutic lifestyle changes including aerobic exercise, weight loss and prudent diet are recommended for virtually all individuals with pharmacologic treatment recommended for LDL levels of >190 mg/dl for low-risk patients, >160 mg/dl for intermediate-risk and >100 mg/dl for high-risk group. The latter group is also given an optional LDL target of less than 70 mg/dl for very high-risk features. Although lifestyle modification remains a key ingredient in reducing cardiovascular risk, pharmacologic manipulation is often necessary, with statin drugs serving as the mainstay therapy. The rationale for initiating treatment stems from multiple cardiovascular primary prevention clinical trials [25 –27]. A major limitation of many of these trials is the disproportionate lack of women and inclusion of patients with known CAD or risk equivalents [28,29]. Other studies showed a significant decrease in cardiovascular events and in all-cause mortality in women with a similar degree of benefit in comparison with men [29 –31]. However, a recent meta-analysis showed mixed results, with reduction in cardiovascular events but not all-cause mortality; however, this analysis was criticized for omitting several important trials [32]. Finally, a Cochrane database review combining 14 trials found reductions in all-cause mortality and combined fatal and nonfatal CVD end points, but noted significant under-reporting of adverse events [33]. Major guidelines agree that statin therapy should be used in the appropriate clinical setting for primary prevention, regardless of sex.

Hypertension

Approximately a quarter of all adults in the USA suffer from hypertension, a strong predictor of cardiovascular risk. Across all ages, men tend to have higher mean blood pressure than women; however, after menopause the incidence of hypertension increases more rapidly in women [34]. Additionally, significant ethnic variation exists where non-Hispanic black men and women had the highest average systolic and diastolic blood pressure, whereas non-Hispanic white men and women had the lowest average blood pressures [34]. In fact, approximately 75% of African–American women older than 75 years of age suffer from hypertension [35]. National Health and Nutrition Examination Survey data suggest that women are more likely to be aware of their hypertension and receive appropriate treatment [36]. Gestational hypertension and proteinuria, commonly defined as pre-eclampsia, affects 5% of first pregnancies and is associated with an increased risk of future cardiovascular events including CHD, stroke and venous thromboembolism [37,38]. Therefore, a history of pre-eclampsia should be considered when evaluating cardiovascular risk in women.

The benefit from antihypertensive therapies appears to be similar for both men and women, although most of the positive effects have been shown in African–American and elderly women [39,40]. Adequate long-term follow-up and control of blood pressure has been associated with increased survival [41]. Current national guidelines, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure [10], recommends an initial trial of lifestyle modification in most patients with hypertension [35]. If lifestyle modification fails to lower blood pressure to desired levels, then initiation of pharmacologic therapy is warranted. The choice of antihypertensive treatment is similar in men and women. Special consideration, however, is given to pregnant women in whom angiotensin converting enzyme inhibitors and angiotensin receptor blockers are contraindicated because of known teratogenicity. An increase in blood pressure can be associated with oral contraceptive use, so regular monitoring of blood pressure during oral contraceptive pill therapy is recommended [42]. Postmenopausal women taking hormone replacement therapy (HRT) have minimal increase in systolic blood pressure over time [43].

Family history

Family history of premature CAD is an independent risk factor for future cardiovascular events [44,45]. Family history is defined as MI or sudden death before 55 years of age, in fathers or other male first-degree relatives, or before 65 years of age in mothers or other female first-degree relatives [13].

The Aggregation of CHD within families epitomizes the complex interplay of genetics and environmental triggers in influencing complex traits. Unbiased genetic studies have identified multiple genetic loci that increase susceptibility to CAD [46,47]. Screening for family history of premature CHD is recommended by major society guidelines and denotes elevated risk status when stratifying patients. Family history of a premature heart attack doubles the risk of a cardiac event in men and increases the risk in women by approximately 70% [9]. In a cohort of European patients, maternal history of MI before the age of 60 years was the strongest predictor of CVD incidence among responders with a parental history of MI [48].

Smoking

Approximately one in five deaths in the USA are attributed to tobacco use, with a third of these related to CVD [49]. Many mechanisms of cigarette smoking-induced CVD have been postulated and smoking is known to increase inflammation, thrombosis and oxidation of LDL cholesterol, all of which are important contributors to atherosclerosis [50]. Women are particularly susceptible to smoking's deleterious effects; smoking one to four cigarettes per day can triple cardiovascular event risk [51]. In a pooled analysis of 26 trials comprised of 2.4 million patients, the relative risk ratio of smokers to nonsmokers for developing atherogenic CVD was 25% higher in women than in men [52]. In addition, women tend to be less successful at quitting smoking than men [53]. While the overall smoking rate has dropped by approximately 20% over the last decade, gender-specific barriers to care remain a challenge. Smoking cessation measures can reduce cardiovascular morbidity and mortality for smokers. Unfortunately, data suggest that young smokers and women smokers are less likely to receive appropriate advice to quit smoking compared with older or male smokers [9].

Diabetes

Among the risk factors, diabetes mellitus is of particular importance in women. When comparing men and women that suffer from diabetes, women have double the risk of fatal cardiovascular events and poorer quality of life [54]. In addition, retinopathy, a serious complication of diabetes, appears to be more prevalent in women and predicts all-cause and cardiovascular mortality, independent of other risk factors [55].

Approximately 20 million adults in the USA have been formally diagnosed with diabetes [9]. Diabetes is not only an important predictor of CVD risk but is now considered a risk equivalent for CVD. Recent analysis based on National Health and Nutrition Examination Survey data suggest that total prevalence of diabetes is expected to double by 2050, with the rate of increase expected to be higher in women than men [9,56]. In addition, insulin-resistant states such as ‘prediabetes’ or polycystic ovarian syndrome, carry an increased cardiovascular risk. Studies suggest that these syndromes, remain significantly underdiagnosed [57].

Diabetes is known to be associated with other risk factors, particularly hypertension and dyslipidemia. Women with diabetes were less likely than men to achieve optimal treatment for their diabetes or other modifiable risk factors [58]. Analogous to patients with diabetes, impaired glucose tolerance without overt diabetes appears to associate with a mild increase in cardiovascular risk. This effect is independent of the subsequent risk of developing overt diabetes [59]. Initiation of lifestyle modification, particularly weight loss, is an important management strategy for patients with diabetes or those at increased risk for developing it.

Obesity

Major risk stratification scores do not include obesity as a primary risk factor for CVD but major guidelines recommend screening for obesity since its presence is independently associated with increased cardiovascular risk [1]. Based on National Health and Nutrition Examination Survey data, a frightening 68% of US adults are either obese or overweight [9]. The annual medical burden of obesity is an estimated 10% of all medical spending and expected to grow to 18% in less than two decades [60]. To complicate matters, the current childhood obesity epidemic is a major public health concern, affecting both sexes and signals an expected exponential increase in disease burden. The Nurses’ Health Study conducted exclusively in women showed a graded increase in CVD death and all-cause mortality with increasing BMI for obese women [61]. Despite its hazardous cardiac effects, a number of association studies have shown improvement in outcomes in certain obese populations such as heart failure and hypertension, a phenomenon referred to as the ‘obesity paradox’ [62]. Use of better surrogate markers than BMI, such as waist circumference and hip to waist ratio appears to abrogate the ‘paradox’ [63,64]. Regardless, weight reduction is recommended in obese patients to reduce cardiovascular risk and overall mortality.

Physical inactivity

Increasing level of activity confers a protective effect on cardiovascular risk. Data from the Framingham Heart Study found a protective effect of long-term physical activity on all-cause and cardiovascular mortality for both men and women [65]. However, despite the known benefits, the number of women who are physically active continues to decline, paralleling the increase in obesity [66]. A prospective trial from Taiwan, enrolling over 400,000 participants, found that exercising as little as 90 min a week reduced all cause mortality and increased survival by 3 years [67]. Simple interventions geared to women, such as tailored newsletters and counseling, can lead to significant improvements in the level of physical activity [68].

Inflammatory markers

Inflammatory mediators play a major role in the pathogenesis of CAD [69]. Patients with inflammatory conditions, such as rheumatoid arthritis and chronic obstructive pulmonary disease, have increased risk of cardiovascular events independent of other risk factors, such as smoking [70,71]. Mechanisms relating the above conditions to plaque development and progression remain unclear, but experimental studies suggest elevation in local and systemic inflammatory mediators induced by environmental pollutants, as well as changes in local bacterial colonization [71,72]. Although women tend to have higher C-reactive protein (CRP) levels than men, elevations of CRP are highly predictive of cardiovascular events, regardless of gender [73]. Data from the Women's Health Study found CRP to independently predict cardiovascular risk in patients in the highest quartile having five-times the risk of those in lowest [74]. Cardiology Foundation/AHA guidelines state that the measurement of CRP can be useful in deciding lipid-lowering therapy in certain groups of intermediate-risk patients [15]. The routine measurement of CRP in all patients is not recommended.

Menopause & HRT

As stated above, women on average are a decade older than men when diagnosed with CVD. Many changes occur during the menopausal transition and a likely factor in the cardiovascular changes seen in women is the gradual decline in the effects of estrogen. Whether menopause is a risk factor in itself or a marker of an increased risk state is highly debated. Women who have early onset menopause appear to have increased cardiac mortality [75]. Supported by animal data and experimental models, early observational studies suggested a cardiovascular benefit to HRT in postmenopausal women [76,77]. A decade later, however, larger randomized trails showed no benefit of HRT and in fact evidence of harm [78 –80]. Consequently, the US Preventive Services Task Force recommends against the use of HRT for the prevention of CVD [77]. An important issue to remember about the above randomized trials, is that initiation of HRT usually began many years after the onset of menopause. Intriguingly, the Danish Osteoporosis Prevention Study study showed reduced risk of mortality and cardiovascular events with early use of HRT [81]. Overall, the use of HRT for cardiac prevention is not recommended but is reasonable therapy for managing menopausal symptoms [23]. Recent AHA statement guidelines do not list menopause as a ‘high risk’ or ‘at risk’ criteria in classification of CVD risk [1].

Conclusion

Therapeutic and preventive strategies for patients with CVD and associated conditions have improved dramatically over the last few decades, resulting in an approximately 50% reduction in cardiovascular mortality. Despite recent improvements, approximately 2200 Americans die on a daily basis from CVD; astonishingly, more than half of these deaths are in women [9]. We have come a long way dispelling the conventional myth that women are ‘immune’ from CVD; yet according to a recent AHA survey, only 53% of women would call 911 if they thought they were having a heart attack [1]. These disturbing trends, galvanize efforts to better understand disease predictors and facilitate the education of both patients and providers on the heavy burden of CVD.

Executive summary

Heart disease in women

Cardiovascular disease is the leading cause of mortality of women both globally and in industrialized nations.

Significant gender and ethnic disparities exist in cardiovascular disease outcomes and risk factor profile.

Risk stratification models

Risk stratification is warranted in all women and various risk scores including Framingham Risk Score or Reynolds Risk Score are considered acceptable.

Major predictors of cardiovascular risk include lipid abnormalities, hypertension, family history, smoking, diabetes, obesity, physical inactivity and inflammatory markers.

Lipids

Non-high-density lipoprotein cholesterol (total cholesterol minus the high-density lipoprotein cholesterol level) and ratio of total cholesterol/high-density lipoprotein cholesterol appear to be better predictors of future cardiovascular events in women.

Major society guidelines recommend screening all women age greater than 20 years with a standard fasting lipid profile at least once every 5 years with low-density lipoprotein cholesterol as major target of dyslipidemia treatment.

Hypertension

Hypertension is a common risk factor amongst women and strong predictor of cardiovascular events.

Gestational hypertension and contraceptive-induced hypertension are two unique causes of hypertension in women that warrant further attention.

Family history

Family history is defined as myocardial infarction or sudden death before 55 years of age in father or other male first-degree relative, or before 65 years of age in mother or other female first-degree relative.

Family history of premature coronary artery disease increases risk of future events in women to a degree greater than men.

Smoking

Smoking one to four cigarettes per day can triple cardiovascular event risk in women.

Women tend to be less successful at quitting smoking than men.

Diabetes

Women with diabetes have worse outcomes than men.

Polycystic ovarian syndrome – a cause of impaired glucose levels – remains underdiagnosed.

Obesity

Two-thirds of US adults are obese or overweight.

Weight reduction is recommended in obese patients to reduce cardiovascular risk and overall mortality.

Physical inactivity

Increasing level of activity confers a protective effect on cardiovascular risk.

Simple interventions geared to women, such as tailored newsletters and counseling, can lead to significant improvements in the level of physical activity.

Inflammatory markers

Patients with inflammatory conditions have an increased risk of cardiovascular events independent of other risk factors.

Routine measurement of C-reactive protein is not recommended, but is considered acceptable for intermediate-risk patients.

Menopause & hormone replacement therapy

Remains unclear whether menopause is a risk factor in itself or marker of an increased risk state.

The use of hormone replacement therapy for cardiac prevention is not recommended but is a reasonable therapy for managing menopausal symptoms.

Future perspective

In an era where cost containment has become increasingly important in healthcare, the need for stronger emphasis on cost-effective preventive strategies is even more imperative. Physicians and healthcare systems will need to address the major contributors to modifiable diseases, such tobacco use or obesity. Intriguingly, the rate of decline in heart disease is slower for women than men, particularly among young adults [23], suggesting the continued need for increased public awareness about CVD and gender-specific interventions to bridge the outcomes gap. In addition, elucidating relative contributions of ‘bias versus biology’ in shaping gender-specific events remains prudent. For example, women with diabetes have significantly worse outcomes than men despite improved compliance, monitoring and follow-up [82]. Does this trend stem from provider-specific attitudes or genetic predisposition? Continued investment in experimental and clinical studies should help better understand gender disparities.

Financial & competing interests disclosure

E Watson is a consultant at Aegerion Pharmaceuticals; Clinical Trials Adjudication Committee, Merck and Company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Predictors of Cardiovascular Risk in Women

Abstract

Keywords

Risk stratification models in women

Lipids

Hypertension

Family history

Smoking

Diabetes

Obesity

Physical inactivity

Inflammatory markers

Menopause & HRT

Conclusion

Future perspective

Financial & competing interests disclosure

References