Basic research into the mechanisms responsible for postmenopausal hypertension

Women typically experience increased cardiovascular disease (CVD) following menopause. Major risk factors for CVD include hypertension and, after menopause, blood pressure increases in women. The mechanism(s) responsible for this increase are not determined. Changes in oestrogen/androgen ratios, possible activation of the renin-angiotensin system, and increases in endothelin and oxidative stress, are hallmarks in postmenopausal women. Obesity, type 2 diabetes and activation of the sympathetic nervous system may also play important roles. However, progress in clarifying the mechanisms responsible for postmenopausal hypertension has been hampered by lack of a suitable animal model. We have recently characterised the ageing female spontaneously hypertensive rat (SHR) as a model of postmenopausal hypertension, since this strain exhibits many of the humoral characteristics of postmenopausal women. This review discusses some of the mechanisms that could play a role in postmenopausal hypertension, as well as the characteristics of the ageing female SHR as a model.     

Sex hormone replacement therapy and modulation of vascular function in cardiovascular disease

Epidemiological and experimental studies suggest vascular protective effects of estrogen. Cardiovascular disease (CVD) is less common in premenopausal women than in men and postmenopausal women. Cytosolic/nuclear estrogen receptors (ERs) have been shown to mediate genomic effects that stimulate endothelial cell growth but inhibit vascular smooth muscle proliferation. However, the Heart and Estrogen/Progestin Replacement Study (HERS), HERS-II and Women’s Health Initiative clinical trials demonstrated that hormone replacement therapy (HRT) may not provide vascular benefits in postmenopausal women and may instead trigger adverse cardiovascular events. HRT may not provide vascular benefits because of the type of hormone used. Oral estrogens are biologically transformed by first-pass metabolism in the liver. By contrast, transdermal preparations avoid first pass metabolism. Also, natural estrogens and phytoestrogens may provide alternatives to synthetic estrogens. Furthermore, specific ER modulators could minimize the adverse effects of HRT, including breast cancer. HRT failure in CVD could also be related to changes in vascular ERs. Genetic polymorphism and postmenopausal decrease in vascular ERs or the downstream signaling mechanisms may reduce the effects of HRT. HRT in the late postmenopausal period may not be as effective as during menopausal transition. Additionally, while HRT may aggravate pre-existing CVD, it may thwart its development if used in a timely fashion. Lastly, the vascular effects of progesterone and testosterone, as well as modulators of their receptors, may modify the effects of estrogen and thereby provide alternative HRT strategies. Thus, the beneficial effects of HRT in postmenopausal CVD can be enhanced by customizing the HRT type, dose, route of administration and timing depending on the subject’s age and cardiovascular condition.     

Sex hormone replacement therapy and modulation of vascular function in cardiovascular disease

Epidemiological and experimental studies suggest vascular protective effects of estrogen. Cardiovascular disease (CVD) is less common in premenopausal women than in men and postmenopausal women. Cytosolic/nuclear estrogen receptors (ERs) have been shown to mediate genomic effects that stimulate endothelial cell growth but inhibit vascular smooth muscle proliferation. However, the Heart and Estrogen/Progestin Replacement Study (HERS), HERS-II and Women's Health Initiative clinical trials demonstrated that hormone replacement therapy (HRT) may not provide vascular benefits in postmenopausal women and may instead trigger adverse cardiovascular events. HRT may not provide vascular benefits because of the type of hormone used. Oral estrogens are biologically transformed by first-pass metabolism in the liver. By contrast, transdermal preparations avoid first pass metabolism. Also, natural estrogens and phytoestrogens may provide alternatives to synthetic estrogens. Furthermore, specific ER modulators could minimize the adverse effects of HRT, including breast cancer. HRT failure in CVD could also be related to changes in vascular ERs. Genetic polymorphism and postmenopausal decrease in vascular ERs or the downstream signaling mechanisms may reduce the effects of HRT. HRT in the late postmenopausal period may not be as effective as during menopausal transition. Additionally, while HRT may aggravate pre-existing CVD, it may thwart its development if used in a timely fashion. Lastly, the vascular effects of progesterone and testosterone, as well as modulators of their receptors, may modify the effects of estrogen and thereby provide alternative HRT strategies. Thus, the beneficial effects of HRT in postmenopausal CVD can be enhanced by customizing the HRT type, dose, route of administration and timing depending on the subject's age and cardiovascular condition.     

Linking preeclampsia and cardiovascular disease later in life

Preeclampsia (PE), which is defined as new onset hypertension after 20 weeks of pregnancy accompanied by proteinuria, is characterized by inadequate placentation, oxidative stress, inflammation and widespread endothelial dysfunction. A link between PE and long-term risk of cardiovascular disease (CVD) was suggested by retrospective studies, which found that PE was associated with a 2–3-fold risk of CVD later in life, with a 5–7-fold risk in the case of severe and/or early-onset PE. Recently, meta-analyses and prospective studies have confirmed the association between PE and the emergence of an unfavorable CVD risk profile, in particular a 3–5-fold increased prevalence of the metabolic syndrome only 8 years after the index pregnancy. PE and CVD share many risk factors, including obesity, hypertension, dyslipidemia, hypercoagulability, insulin resistance and both entities are characterized by endothelial dysfunction. PE and CVD are complex traits sharing common risk factors and pathophysiological processes, but the genetic link between both remains to be elucidated. However, recent evidence suggests that genetic determinants associated with the metabolic syndrome, inflammation and subsequent endothelial dysfunction are involved. As the evidence now supports that PE represents a risk factor for the emergence of the metabolic syndrome and CVD later in life, the importance of long-term follow-up assessment of CVD risk beginning early in women with a history of PE must be considered and translated into new preventive measures.     

Gender‐specific features of plasmatic and circulating cell alterations as risk factors in cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of death in the Western countries. Several epidemiological studies have hypothesized a gender disparity in the pathogenesis and progression of CVD. For instance, women develop CVD when they are about 10 years older than men and, typically, after menopause. However, considering that women are often excluded from research studies, sex differences in CVD remains a frontier for discovery. Very important is thus the identification of risk factors allowing us to diagnose or predict cardiovascular events taking into account gender disparities. In this review, we will examine some of the major challenges in the discovery and validation of cardiovascular biomarkers in a gender perspective. In particular, we will consider classical (hypertension, smoking, diabetes, dyslipidemia, physical inactivity) and novel (inflammation markers, markers of endothelial dysfunction, markers of coronary disease) risk factors reporting gender differences. The aim of this review was to provide an overview on current knowledge on sex‐associated cardiovascular determinants with the aim to improve CVD diagnostic and prognostic clinical courses and to develop new and gender‐biased prevention strategies.     

The incidence of cardiovascular disease in menopausal women on hormone replacement therapy: a clinical evidence-based medicine review.

Postmenopausal women have looked to the scientific and medical community for conclusions on the effects of hormone replacement therapy (HRT) on cardiovascular disease. There have been many studies and clinical trials conducted in an attempt to address whether or not there is increased incidence of cardiovascular disease (CVD) among postmenopausal women on HRTs. The results of the Women Health Initiative study on HRTs and CVD have concluded that HRTs have no protective effect on the cardiovascular system. It has been suggested that HRTs may even promote the development of a cardiovascular event. Many researchers and members of the health-care community have disputed these claims. These opposing views have fostered more research in an attempt to draw a consensus in this debate. This clinical review examines evidence-based medical research literature and provides an overview of the outcomes.     

The evaluation of cardiovascular risk in postmenopausal women with osteopenia

The purpose of the study was to evaluate the prevalence of the most important cardiovascular risk factors in postmenopausal women in correlation with bone mineral density (BMD). A hundred and fifty postmenopausal women were included in a case control study. The subjects were distributed into three equal groups: normal bone mass; osteopenia; non-complicated osteoporosis. BMD was measured with lumbar double-energy X-ray absorptiometry. Cardiovascular risk factors were assessed. The level of triglycerides was significantly higher in patients with osteoporosis vs. subjects with normal BMD. Arterial hypertension and a 10-year fatal risk of more than 0% were significantly more prevalent in the group with normal BMD. Osteoporosis presents an independent cardiovascular risk factor. Postmenopausal women with decreased BMD should be considered to have a higher risk of cardiovascular events, because standard risk scales do not take BMD into account.     

Obese women and the relation between cardiovascular risk profile and hormone therapy, glucose tolerance, and psychosocial conditions

OBJECTIVE: To evaluate the relation between cardiovascular disease (CVD) risk factors and hormone therapy, serum hormone levels, glucose tolerance, and psychosocial and psychological conditions in subjectively healthy obese female subjects. RESEARCH DESIGN AND METHODS: The study included 606 women, aged 50-64 years, with BMI 30-40 kg/m(2) and no history of cardiovascular or other severe diseases. One group with a CVD risk profile (n = 473) (i.e., cholesterol >7.0 mmol/l, HDL cholesterol <1.2 mmol/l, triglycerides >2.0 mmol/l, systolic or diastolic blood pressure >140/90 mmHg, or waist-to-hip ratio >0.85) was compared with women without such risk (n = 133). Steroid hormones, leptin, insulin, and oral glucose tolerance tests (OGTTs) were analyzed. A subgroup of women with baseline impaired glucose tolerance (IGT) completed a 2.5-year follow-up OGTT. RESULTS: Fewer obese postmenopausal women with CVD risk had ever used hormone therapy (odds ratio 0.24 [95% CI 0.07-0.75]), after multivariate adjustments. Furthermore, women with CVD risk had a higher testosterone index (1.07 [1.01-1.13]) and more had insulin resistance (1.04 [1.00-1.08]) and IGT (2.92 [1.50-5.69]), while OGTT was similar at follow-up. No differences were observed regarding family history or lifestyle, except that fewer women with CVD risk consumed fruits, boiled vegetables, or whole-grain cereals. More women with CVD risk lived alone (3.26 [1.28-8.31]) and had more mental problems (1.16 [1.05-1.28]). CONCLUSIONS: Previously healthy obese women with a CVD risk profile seemed to have a high risk of diabetes, as well as psychosocial or psychological problems. Hormone therapy was associated with reduced CVD risk. Obesity's growing burden on society makes it more important to further target individuals that are at greatest risk of future health hazards.     

Hypertension alone or related to the metabolic syndrome in postmenopausal women

Cardiovascular risk is poorly perceived by women, especially during the peri- and postmenopausal period when susceptibility to cardiovascular events increases. Nevertheless in Europe, 55% of women versus 43% of men currently die of cardiovascular disease. Blood pressure is one of the most powerful and accurate determinants of cardiovascular status and risk. Despite its importance, hypertension is often underestimated and undiagnosed, especially in women. Various mechanisms are implicated to play a role in the blood pressure increase in women at the time of menopause. Hypertension can be considered an isolated disease, more typical of elderly women, or part of the metabolic syndrome, more frequent in early postmenopausal women. The metabolic syndrome, a clustering of lipid and nonlipid cardiovascular risk factors, is estimated to affect approximately 20-30% of the middle-aged population and its prevalence appears to be increasing in the worldwide population.     

Gender differences in the metabolic syndrome and their role for cardiovascular disease

Summary Women live longer than men and develop cardiovascular disease (CVD) at an older age. The metabolic syndrome represents a major risk factor for the development of CVD, and gender¹ differences in this syndrome may contribute to gender differences in CVD. In recent years, the metabolic syndrome has been more prevalent in men than in women. Prevalence is increasing and this increase has been steeper in women, particularly in young women, during the last decade. The contributions of the different components of the metabolic syndrome differ between genders and in different countries. In a recent survey in Germany, 40% of the adult population had been diagnosed with disturbed glucose tolerance or type 2 diabetes. Undiagnosed diabetes was more frequent in men than in women, and risk factors for undiagnosed diabetes differed between the sexes. Worldwide, in individuals with impaired glucose tolerance, impaired fasting glucose was observed more frequently in men, whereas impaired glucose tolerance occurred relatively more often in women. Lipid accumulation patterns differ between women and men. Premenopausal women more frequently develop peripheral obesity with subcutaneous fat accumulation, whereas men and postmenopausal women are more prone to central or android obesity. In particular, android obesity is associated with increased cardiovascular mortality and the development of type 2 diabetes. Visceral adipocytes differ from peripheral adipocytes in their lipolytic activity and their response to insulin, adrenergic and angiotensin stimulation and sex hormones. Visceral fat is a major source of circulating free fatty acids and cytokines, which are directly delivered via the portal vein to the liver inducing insulin resistance and an atherogenic lipid profile. Inflammation increases cardiovascular risk particularly in women. A relatively greater increase in cardiovascular risk by the appearance of diabetes in women has been reported in many studies. Thus, the presently available data suggest that the pathophysiology of the metabolic syndrome and its contribution to the relative risk of cardiovascular events and heart failure show gender differences, which might be of potential relevance for prevention, diagnostics, and therapy of the syndrome. ¹ "Gender" is used to include biological sex as well as gender in its strict sense Supported by the DFG (grants to V. Regitz–Zagrosek) and the BMBF (Competence Network Heart Failure) An erratum to this article can be found at     

Non-invasive cardiovascular risk assessment in women with type 2 diabetes.

This study assessed and compared carotid intima-media thickness (IMT) in postmenopausal women with type 2 diabetes with that in postmenopausal women without type 2 diabetes and compared risk factors that contribute to increased carotid IMT in these groups of women. Carotid IMT, a non-invasive assessment of cardiovascular risk, was measured using high-resolution ultrasound in 20 postmenopausal women with type 2 diabetes and 20 postmenopausal women without type 2 diabetes who had no known coronary heart disease. Risk factors (age, race, family history, diabetes, hypertension, high cholesterol, years past menopause, use of hormone replacement therapy, perceived level of physical activity, and body mass index) known to contribute to coronary heart disease were also assessed. Mean carotid IMT was .88 mm for women with type 2 diabetes compared with .74 mm for women without type 2 diabetes. There were no differences between groups in age, race, cholesterol, and perceived level of physical activity. Women with type 2 diabetes, however, reported more hypertension ( P = .004), greater body mass index ( P = .026), and less use of hormone replacement therapy ( P = .027). Of concern is that 10% of the women with diabetes had stenosis that required surgical intervention. Findings suggest that carotid IMT is a valid way to screen for cardiovascular risk, particularly in postmenopausal women who are at high risk for coronary heart disease. It may also be a feasible, non-invasive method for the detection and prevention of the macrovascular complications of diabetes.     

Menopausal hot flushes and vascular health

Abstract

Hot flushes are complained of by approximately 75% of all postmenopausal women, and hormone therapy (HT) is the most effective way to alleviate them. Hot flushes are characterized by altered vascular function and sympathetic nervous system activity. Hot flushes occurred more often in women attending large, non-randomized observational studies (e.g. Nurses’ Health Study), where HT use protected against cardiovascular disease (CVD). However, they were absent (or mild) in randomized HT trials where HT use was accompanied with an elevated risk for CVD. Hot flushes, if a factor for cardiovascular health, could partly explain the conflict between observational and randomized trials.

Several cross-sectional studies imply that hot flushes are detrimental to the cardiovascular system. However, the data are not uniform, and hot flushes were recalled retrospectively or during HT use. In our prospective study hot flushes were accompanied with a vasodilatory effect during endothelial testing, and this was related to the severity of hot flushes. Night-time hot flushes were followed with transient rises in ambulatory blood pressure (BP). However, no effect of hot flushes on diurnal BP was detected. The use of estradiol showed no harmful effects on endothelial function in women with hot flushes, but in non-flushing women oral, but not transdermal, estradiol led to vasoconstrictive changes. Estradiol complemented with medroxyprogesterone acetate eliminated the vasoconstrictive effect of sole oral estradiol. Thus, both oral and transdermal estradiol are applicable in flushing women, whereas a transdermal route should be favored in non-flushing women if used e.g. for bone protection.     

Menopausal hot flushes and vascular health

Hot flushes are complained of by approximately 75% of all postmenopausal women, and hormone therapy (HT) is the most effective way to alleviate them. Hot flushes are characterized by altered vascular function and sympathetic nervous system activity. Hot flushes occurred more often in women attending large, non-randomized observational studies (e.g. Nurses' Health Study), where HT use protected against cardiovascular disease (CVD). However, they were absent (or mild) in randomized HT trials where HT use was accompanied with an elevated risk for CVD. Hot flushes, if a factor for cardiovascular health, could partly explain the conflict between observational and randomized trials. Several cross-sectional studies imply that hot flushes are detrimental to the cardiovascular system. However, the data are not uniform, and hot flushes were recalled retrospectively or during HT use. In our prospective study hot flushes were accompanied with a vasodilatory effect during endothelial testing, and this was related to the severity of hot flushes. Night-time hot flushes were followed with transient rises in ambulatory blood pressure (BP). However, no effect of hot flushes on diurnal BP was detected. The use of estradiol showed no harmful effects on endothelial function in women with hot flushes, but in non-flushing women oral, but not transdermal, estradiol led to vasoconstrictive changes. Estradiol complemented with medroxyprogesterone acetate eliminated the vasoconstrictive effect of sole oral estradiol. Thus, both oral and transdermal estradiol are applicable in flushing women, whereas a transdermal route should be favored in non-flushing women if used e.g. for bone protection.     

Preventing cardiovascular disease in women

Cardiovascular disease (CVD) has been the primary cause of death in women for almost a century, and more women than men have died of CVD every year since 1984. Although CVD incidence can be reduced by adherence to a heart-healthy lifestyle and detection and treatment of major risk factors, preventive recommendations have not been consistently or optimally applied to women. The American Heart Association guidelines for CVD prevention in women provide physicians with a clear plan for assessment and treatment of CVD risk and personalization of treatment recommendations. The emphasis of preventive efforts has shifted away from treatment of individual CVD risk factors in isolation toward assessment of a woman's overall or "global" CVD risk. In addition to accounting for the presence or absence of preexisting coronary heart disease or its equivalents (e.g., diabetes, chronic kidney disease), cardiovascular risk can be further calculated with the Framingham risk score, which is based on age, sex, smoking history, and lipid and blood pressure levels. Intervention intensity and treatment goals are tailored to overall risk, with those at highest risk receiving the most intense risk-lowering interventions. Women at high risk for CVD and without contraindications should receive aspirin, beta blockers, and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in addition to pharmacologic therapy for hyperlipidemia, hypertension, and diabetes. Women who already are at optimal or low risk for CVD should be encouraged to maintain or further improve their healthy lifestyle practices. Optimal application of these preventive practices significantly reduces the burden of death and disability caused by heart attack and stroke in women.     

Prevention: the key to reducing cardiovascular disease risk in women

More than 500,000 US women die of cardiovascular disease (CVD) annually, exceeding deaths for cancer, accidents, and diabetes combined. Yet women are largely unaware of this and fear breast cancer more. One way of changing this number is to change the way we approach CVD, that is, to practice preventive healthcare. Until recently, guidelines for women with CVD were derived largely from research conducted primarily on white middle-aged men. Although evidence-based medicine is still lacking, guidelines and recommendations specifically for women are now available and include aggressive management of the risk factors of smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity. Unless women are educated regarding these risk factors and are enabled to make lifestyle changes, their chances of modifying and reducing their risks are severely impaired.     

THE IMPACT OF CORONARY HEART DISEASE IN DETERMINING USE OF HORMONE REPLACEMENT THERAPY IN A GENERAL PRACTICE POPULATION

The use of hormone replacement therapy (HRT) for cardiovascular risk reduction remains uncertain. Although previous epidemiological surveys have suggested a clear benefit and nearly 50% mortality risk reduction with HRT in postmenopausal women, recent randomised trials have largely failed to support this. The epidemiological surveys may have been biased in a number of ways including the possibility that HRT users in these studies may have been healthier and taken a greater interest in modifying cardiovascular risks. The aim of the present study was to determine to what extent the revelations from all these trials have influenced HRT prescribing in general practice, in relation to cardiovascular disease. We reviewed 140 women on HRT and 140 age-matched controls from one city centre general practice in the west of Birmingham who were randomly selected by computer. The main indication for HRT use was presence of symptoms associated with oestrogen deficiency. The prevention of osteoporosis accounted for 7.1% of HRT indications, while the primary prevention of CHD was not an issue discussed by either the patient or the GP. Among non-users, 86.4% did not have a known contraindication and many did not have serum lipid measurements or estimations of cardiovascular risk. There was no difference between HRT users and non-users for smoking habits and presence of cardiovascular risk factors including diabetes, hypertension and coronary heart disease. HRT users were also less likely to undergo investigations, such as cervical smear tests and mammograms. In conclusion, this survey reflects the current uncertainty surrounding the use of HRT for cardiovascular risk prevention. Importantly, women on HRT may not be any healthier than non-users, nor do they seek more preventive care than non-users. This is contrary to previous presumptions that selection and prevention bias were the explanation for the apparent cardioprotective effects of HRT.     

Guidelines for the prevention of cardiovascular disease in women: international challenges and opportunities

Women are victims of cardiovascular disease (CVD) at rates similar to men. A reduction in CVD within developed nations has been noted and is primarily due to preventive efforts focused on risk factor modification. Middle- and low-income nations, however, have noted an increase in CVD. Efforts to reduce the occurrence of CVD risk factors targeting women’s health in these populations are lacking and need to be encouraged. Risk factor modification with regards to hypertension, dyslipidemia, diabetes, tobacco use, abdominal obesity and psychosocial factors would provide the greatest reduction in CVD occurrence.     

Abdominal fat distribution and disease: an overview of epidemiological data.

Recent prospective, epidemiological research has demonstrated the power of an increased waist/hip circumference ratio (WHR) to predict both cardiovascular disease (CVD) and non-insulin dependent diabetes mellitus (NIDDM) in men and women. Obesity, defined as an increased total body fat mass, seems to interact synergistically in the development of NIDDM, but not of CVD. Increased WHR with obesity (abdominal obesity) seems to be associated with a cluster of metabolic risk factors, as well as hypertension. This metabolic syndrome is closely linked to visceral fat mass. Increased WHR without obesity may instead be associated with lift style factors such as smoking, alcohol intake, physical inactivity, coagulation abnormalities, psychosocial, psychological and psychiatric factors. Direct observations show, and the risk factor associations further strengthen the assumption, that abdominal (visceral) obesity is more closely associated to NIDDM than CVD, while an increased WHR without obesity may be more closely linked to CVD than NIDDM. It remains to be established to what extent, if any, an increased WHR in lean men, and particularly in lean women, indicates fat distribution. Other components of the WHR measurement might be of more importance in this connection.     

Cultural challenges to secondary prevention: implications for Saudi women

Like other highly developed countries, cardiovascular disease (CVD) and coronary heart disease (CHD) are major health problems in Saudi Arabia. The aetiology of cardiovascular disease (CVD) burden within the Saudi population is similar to Western countries with atherosclerosis, hypertension, ischemic heart disease and diabetes highly prevalent with the main risk factors being smoking, obesity and inactivity. There are differences between Saudi men and women in epidemiology, risk factors and health service provision for CHD. These sex and gender based factors are important in considering the health and well-being of Saudi women. Currently, there is Limited focus on the cardiovascular health of Saudi women. The aim of this paper is to examine culturally specific issues for Saudi women and the implications for secondary prevention.     

The metabolic syndrome and cardiovascular disease

The metabolic syndrome, which is very common in the general population, is defined by the clustering of several classic cardiovascular risk factors, such as type 2 diabetes, hypertension, high triglycerides and low high-density lipoprotein cholesterol (HDL). Central obesity and insulin resistance, which are the two underlying disorders of the syndrome, are further risk factors for cardiovascular disease. Moreover, a panel of novel (non-traditional) risk factors are ancillary features of the metabolic syndrome. They include biomarkers of chronic mild inflammation (e.g. C-reactive protein, CRP), increased oxidant stress (e.g. oxidized low density lipoprotein, LDL), thrombophilia (e.g. plasminogen activator inhibitor-1, PAI-1) and endothelial dysfunction (e.g. E-selectin). Therefore, subjects with the metabolic syndrome are potentially at high risk of developing atherosclerosis and clinical cardiovascular events.In recent years several longitudinal studies have confirmed that subjects with the metabolic syndrome present with atherosclerosis and suffer from myocardial infarction and stroke at rates higher than subjects without the syndrome. The risk of cardiovascular disease (CVD) is particularly high in women with the syndrome and in subjects with pre-existing diabetes, CVD and/or high CRP. However, an increased risk is already present in subjects with a cluster of multiple mild abnormalities. The risk related to the metabolic syndrome is definitely higher when subjects affected are compared to subjects free of any metabolic abnormality.