There is increasing evidence to support that women become vulnerable to cardiovascular disease (CVD) as early as perimenopause.1 Estrogen loss in perimenopause is associated with abdominal obesity (visceral fat) and insulin resistance, which contribute to dyslipidemia, oxidative stress, inflammation, altered coagulation, and atherosclerosis. These changes can set the stage for the modifiable cardiovascular risk (CVR) factors of hypertension, dyslipidemia, abdominal obesity, and impaired glucose tolerance. These modifiable CVR factors are also associated with the diagnosis of metabolic syndrome (MetS). The criteria for the diagnosis of MetS include any 3 of the 5 risks as recently defined by the National Cholesterol Education Program Adult Treatment Panel III (ATP III) and supported by the International Diabetes Foundation and the World Health Organization2 (Table 1). These include increased waist circumference, increased triglyceride (TG) level, decreased high-density lipoprotein (HDL) level, hypertension, and increased fasting glucose level. Metabolic syndrome leads to a 5-fold increase in risk of developing diabetes and a 3-fold increase in risk of CVD.3,4 It is essential that accurate tools for both identifying the components of MetS and in estimating CVR in perimenopausal and postmenopausal women be available for the clinician.
The purpose of this article was to describe the hormonal and vascular changes occurring during perimenopause and discuss how they set the stage for MetS in women using a case study. The available screening tools (the Framingham Assessment for Coronary Heart Disease, the Framingham General Cardiovascular Risk Profile, and Reynolds Risk Assessment) will be compared and contrasted within the context of the 2011 Updated Guidelines for the Prevention of Cardiovascular Disease in Women via case study. Targeted goals and interventions will be presented focusing on ideal cardiovascular health.
Cardiovascular Risk in Women
In the United States, 38.2 million women are living with CVD. In combination with their male counterparts, the cost of CVD is $475.3 billion per year. Meanwhile, CVD is the leading cause of death among women, claiming 480 000 lives each year, nearly 6 times that of all forms of cancer.1,3 The rate of CVD in women has risen slightly over the last 2 decades compared with that in men, especially among minority women. Nearly half of African American women (45%) have some form of CVD, compared with 32% of white women. Worldwide, 1 in 3 women will die of a CVD-related cause.1,3
In general, CVD manifests in women as coronary heart disease (CHD) and stroke.4 In addition, women are at increased risk of stroke secondary to risk factors such as hypertension, hyperlipidemia, atrial fibrillation, diabetes mellitus, and smoking.5,6
Experimental and observational data have demonstrated that estrogens have a cardiovascular protective effect. Thus, the menopause transition as well as comorbidity contributes to CVR in women. In addition, there are lifestyle factors, such as sedentary behavior, that increase CVR. A comprehensive assessment is needed to identify women at risk in order to implement appropriate and timely interventions.
Perimenopause and Postmenopause Transition as Prelude to Risk
A woman can usually tell if she is approaching menopause because her menstrual periods start changing. However, the definition for perimenopause, the time leading up to menopause, has remained elusive. The North American Menopause Society and the World Health Organization define perimenopause as “the two to eight years preceding menopause and one year following the final menses.”5 Postmenopause is defined as the time following 12 months of amenorrhea.
At an average age of 52 years for natural menopause, women lose the cardioprotective effect of estrogen.7 After menopause, women’s risk of CVD begins to parallel that of men. A recent meta-analysis of prospective studies concluded that MetS increased the risk of developing CVD. The risk was higher in women than men.7 This further emphasizes the need for early assessment and intervention.
Effects on Lipid Metabolism
Estrogen loss in perimenopause increases lipid levels. It also decreases fibrinolysis, the process that contributes to lysis of small blood clots. Perimenopausal changes in endothelial and vascular smooth muscle cells increase vasoconstriction and intima-media thickness and contribute to more significant vessel wall damage. The physiological changes associated with perimenopause are related to decreases in estrogen. These changes increase circulating levels of low-density lipoprotein (LDL) and TG and decrease circulating levels of HDL, all of which significantly contribute to coronary artery disease and lipid atherogenesis.8 Perimenopausal changes in LDL and TG levels are greater than those after menopause.9 In perimenopausal women, significant correlations have been observed among HDL/TG cholesterol, lean body mass, visceral fat, high-sensitivity c-reactive protein (hs-CRP) (protein synthesized in the liver significantly correlated with fibrinogen levels), and 2-hour glucose tolerance test.10 These findings again highlight the perimenopause as a time when CVR emerges.
It has been hypothesized that lipoprotein(a) (Lp(a)), an atherosclerotic risk factor, and homocysteine are causal risk factors for CVD. Excess Lp(a) is the most common inherited lipid disorder in patients with premature coronary artery disease or CHD and affects about 25% of the population. However, the genetic factor associated with Lp(a) remains unclear. The Emerging Risk Factor Collaboration, in a meta-analysis that included a total of 126 634 subjects in 36 prospective studies, concluded that under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with the risk of both CHD and stroke,11 but it is not part of a standard screening. Homocysteinemia has been implicated in the development of CVD, particularly with the incidence of stroke. However, the contribution of homocysteine related to the development of CVD in women has not been firmly established and is also not included in standard screening.12
Estrogen and Vascular Integrity
Lower estrogen levels are correlated with increased thrombosis and increased coagulation factors during perimenopause. In turn, these changes are significantly correlated with CHD in women.13
Menopause down-regulates the pathway affecting vascular wall integrity and pliability, making women more vulnerable to an increase in vascular resistance and platelet aggregation.14 It is uncertain at what point in the menopausal transition this process begins. The Study of Women’s Health Across the Nation addressed the effect of endogenous sex hormones on the vasculature. The strengths of the Study of Women’s Health Across the Nation include the frequent assessment of risk factors and the multiethnic composition of the cohort.15,16 Late perimenopause, beginning as 2 or more missed periods with an interval of 60 days or more between periods to no period up to 11 months,17 was identified as the most critical time period influencing arterial diameter enlargement, an adverse CVR factor.7,15 Dilated carotid arteries are less pliable and more vulnerable to damage.7,15 This is supported by evidence that in individuals older than 50 years, increased carotid intima-media thickness increases CVD risk by 5 times.4 Perimenopausal pulse pressure is also a consistent predictor of intima-media thickness. Increased pulse pressure influences elastin degeneration, increases in collagen, and arterial wall thickening.9 These vascular changes are all associated with increased risk of CHD and stroke.
The risk for hypertension increases during perimenopause when plasma renin levels increase and endothelial dysfunction causes arterial remodeling and inflammation. In addition, sympathetic activity increases. However, evidence suggests that blood pressure, systolic and diastolic, is a function of body mass index and not ovarian failure.16 Weight gain in midlife, especially after the menopause transition, is common, although it remains debated whether changes in the hormonal milieu and/or lifestyle behaviors altering energy balance is responsible.15–19 Body composition changes can indirectly lead to weight gain. A redistribution of body fat mass toward an android type occurs during the menopausal transition. It is reflected in increases in body mass index, waist-hip ratio, and intra-abdominal fat accumulation. The increase in visceral fat in postmenopausal women has been related to increased insulin and TG levels and a reduction in HDL level. In a study evaluating body composition during the menopause transition, the results indicated that menopause independently influences fat mass and distribution.20 Both body fat and abdominal fat increased with years from menopause. These clinical and biologic changes are characteristic of insulin resistance leading to the development of MetS, glucose intolerance, and type 2 diabetes.21–23 There is also evidence that suggests that central adiposity is a significant predictor of mortality. The distribution of central obesity is important with visceral fat versus subcutaneous abdominal fat representing a greater risk factor. Central obesity manifests during the menopausal transition, at an average rate of 0.8 kg/y during the perimenopausal years.13
An increase in the inflammatory marker hs-CRP is correlated with central obesity. Both are considered significant CVR factors as well as components of MetS. In the Women’s Health Study, levels of hs-CRP were found to increase linearly as the number of MetS criteria increased (P trend < 0.0001), from 0.68 mg/L for women who met none of the criteria to 5.75 mg/L for women who met all 5 criteria (Table 3). In survival analyses, a high hs-CRP level was similarly predictive of MetS (≥3 criteria present) and of a first cardiovascular event.24
Cardiovascular Risk Assessment for Midlife Women
Cardiovascular risks for CHD have typically been assessed using the Framingham Risk Assessment for CHD as part of the ATP III guidelines25 (Tables 2 and 3). This assessment relies on traditional risk factors and was developed in the decade between 1956 and 1966. Investigators in Framingham, Massachusetts, defined age, hypertension, smoking, diabetes, and hyperlipidemia as major determinants of CHD and coined the term coronary risk factors.25
Over the past half-century since this original Framingham Assessment for CHD, understanding of the biological processes underlying atherosclerosis in women has markedly shifted to encompass the complex biology of hemostasis, endothelial and vascular smooth muscle cell dysfunction leading to thrombosis, intima-media thickness, systemic vascular resistance, and inflammation. Women’s risk for stroke and heart failure through middle and older age typically exceeds their risk of CHD in contrast to the pattern seen in men, where coronary artery disease occurs earlier.6
As the development of the Framingham tool progressed, the CHD markers were codified into global risk scores for assessment of general, overall CVR instead of CHD risk and coincided with this knowledge concerning the pathophysiology of atherosclerosis in women.26,27
Along with this new knowledge of pathophysiologic changes and shift in focus to general CVR, it was noted that patients who are 50 years or older may have a high lifetime risk amenable to risk factor reduction but may be considered to be at low risk because they have a low 10-year risk with the Framingham Risk Assessment for CHD (see Box, MetS case review, as example). Long-term CVD risk, not just CHD risk, is supported by recent data indicating that 56% of adults, including 47.5 million women overall and 64% of women 60 to 79 years of age, have a 10-year risk for CHD of less than 10% but a predicted lifetime risk for CVD of 39% or higher. Among people free of CVD at the age of 50 years, more than 50% of men and nearly 40% of women will have CVD during their lifetime. It is for this reason that the Framingham General CVD Risk Profile was developed (Table 4). In an attempt to develop a cardiovascular prediction algorithm specific to women, the Reynolds Risk Score was developed and validated using data from a large panel of traditional and novel risk markers (Table 5).28 Recently updated guidelines for the prevention of CVD in women highlight the use of the Framingham General CVD Risk Profile as well as the Reynolds Risk Score as appropriate tools for assessment but do not support the routine screening of hs-CRP (as seen with the Reynolds Risk Assessment) because there is not yet enough data to support that a reduction in hs-CRP improves clinical outcomes. Instead, the American Heart Association (AHA) and other national groups have recommended that novel markers and modalities be reserved for use in refining risk estimates in intermediate-risk patients when medication therapy needs to be determined. It is therefore why the AHA Effectiveness-Base Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update recommends the use of the Framingham General CVD Risk Profile as the assessment tool of choice.6 The case review seen in Box, with the clinical characteristics in Table 6, demonstrates that both the Framingham General CVD Risk Profile score and the Reynolds Risk Assessment score place this patient at high to moderately high risk warranting more aggressive prevention therapy to reduce her MetS and, thus, her general, overall CVD risk. In comparison, she is ranked at less than 10% risk by the standard Framingham Risk Assessment for CHD.
Contribution of Metabolic Syndrome to Cardiovascular Disease Risk
Metabolic syndrome is defined as a cluster of risk factors for CVD and type 2 diabetes that occur more often together than by chance alone and for which the cause is uncertain. Because it lacks factors associated with absolute risk such as age, sex, LDL level, and cigarette smoking, MetS is not an independent risk indicator. Metabolic syndrome leads to a 5-fold increase in risk of developing diabetes and a 3-fold increase in risk of CVD.29 In addition, individuals with these characteristics commonly manifest a prothrombic and inflammatory state as well as abdominal obesity and insulin resistance. The criteria for the clinical diagnosis of MetS include any 3 of the 5 risks as seen in Table 1. In the MetS case study seen in Box, the patient has all 5 components of MetS26,30 (Table 6): a waist circumference greater than 35 in, a TG level greater than 150 mg/dL, an HDL cholesterol level less than 50 mg/dL, a blood pressure of 130/85 mm Hg, and a fasting glucose level greater than 100 mg/dL. The MetS criteria, as updated in 2005 by the AHA and the National Heart, Lung, and Blood Institute,26,30 changed the acceptable fasting glucose level from 110 to 100 mg/dL, based on the definition of MetS developed by the National Cholesterol Education Program ATP III.29 In summary, the greater the number of MetS components, the greater the risk of cardiovascular events. In this case, hs-CRP was available, which, with its addition in the Reynolds Risk Score, demonstrated a moderately high risk for this patient. With additional findings from the Women’s Health Study, an analysis of women with MetS (n = 3597) indicated that CVD risk increased with categorical hs-CRP level; age-adjusted rates were 3.4 events per 1000 person-years for women who had a baseline hs-CRP level less than 3.0 mg/L when compared with 5.9 events per 1000 person-years for women who had a baseline hs-CRP level greater than 3.0 mg/L (P < .001). Considering these outcome measures, the patient in this case is clearly at high risk for cardiovascular events with the Framingham General CVD Risk Profile, moderately high risk with the Reynolds Risk Score, and moderate risk with the Framingham Risk for CHD. This would also be interpreted as intermediate to high risk according to the Guidelines for Prevention of CVD in women6 (Table 7). An accurate assessment in this case would yield outcomes requiring more aggressive preventative therapy. This case demonstrates the rationale and validity for the use of the Framingham General CVD Risk Profile as the preferred tool recommended within the guidelines even in the presence of an elevated hs-CRP in this patient.
Targets and Interventions
The emergence of CVR factors, specifically MetS, has been identified as important to a woman’s overall CVD risk. The risk for MetS increases in women during the perimenopause transition. The risk continues after menopause. The development of MetS associated with weight gain, and metabolic changes act as strong promoters of both CVD and breast cancer.31
The prevalence of MetS can be reduced through lifestyle interventions. It has been shown that these interventions are often more effective than drug therapy.30,31 Goals for treatment should embrace the AHA’s recently defined concept of ideal cardiovascular health as seen in Table 7. A healthy dietary pattern (Mediterranean/Dietary Approaches to Stop Hypertension diet pattern) mainly characterized by high consumption of fiber; high consumption of vegetables, fruits, nuts, virgin olive oil, legumes, and fish; moderate consumption of alcohol; and low consumption of red meat, processed meats, sodium (<1500 mg/d), refined carbohydrates, and whole-fat dairy products and no trans-fatty acids is beneficial for patients at high risk for MetS, for individuals with established MetS, for those at high risk for general CVD, and in those wishing to achieve overall ideal cardiovascular health. In addition, a physical activity program combined with diet has been shown to reduce weight and visceral fat as well as help to maintain cognitive function. Therapeutic targets as well as evidence-based treatment to reduce MetS and overall CVR is included in Table 8. Resources to assist in both patient assessment and education are also included.6,32
Early identification of CVR factors, particularly the components of MetS in both men and women, could have an enormous impact on lives and the welfare of the country.6 The best high-risk approach to CVD prevention lies in consistent routine testing for CVR factors and risk score assessment.35 It has been recommended that healthcare providers discuss both the 10-year risk of CHD and the lifetime risk of CVD with each patient to explore individual future risk.33,36 Use of both assessments will hopefully engage a greater number of people in the need for early and prolonged interventions on risk factors.31 Although all risk assessment tools compared here look at 10-year risk rather than lifetime risk, the Framingham General CVD Risk Profile makes the information translatable to patients by providing the meaning of the value of the scores in terms of vascular age.8 With an “at age” or slightly younger vascular age possible in most cases, this goal can act as a motivator for “turning back the clock” by moving from high or intermediate risk to achieving ideal cardiovascular health. Although some aspects of CVD risk are nonmodifiable, such as age, gender, and family history, others are a result of lifestyle, which can be influenced by appropriate changes in diet and activity as well as early pharmacologic interventions.7 This is particularly true with women in their perimenopause transition, when CVD risk begins to emerge. Metabolic syndrome is a major risk factor for first cardiac event in women and can be easily identified in a thorough risk assessment. Early screening, with accurate tools that best define the level of risk, provide the window of opportunity for providers to intervene and to make a significant difference in the lives of women as they transition through perimenopause.
- Follow the Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update by first calculating general cardiovascular disease (CVD) risk using the Framingham Risk of General CVD Assessment Tool if there is no evidence of clinically manifest coronary heart disease, CVD or peripheral vascular disease, abdominal aortic aneurysm, diabetes mellitus, or renal disease.
- Establish risk for CVD including factors directly associated with metabolic syndrome.
- Establish CVD risk through the Framingham General CVD Risk Assessment.33
- Institute class I or class II recommendations as provider or in conjunction with the provider based on CVD risk evaluation.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
abdominal obesity; cardiovascular health in women; cardiovascular risk; metabolic syndrome; perimenopause; prevention; risk; risk assessment; risk reduction behavior; vascular risk