Advertisement
Mayo Clinic Proceedings Home

Endothelial Vascular Function as a Surrogate of Vascular Risk and Aging in Women

Published:January 22, 2020DOI:https://doi.org/10.1016/j.mayocp.2019.07.001

      Abstract

      Cardiovascular disease is the leading cause of morbidity and mortality in women. We suggest the need to develop a paradigm that connects sex- and age-specific nontraditional risk factors that serve as a common mechanism ultimately leading to an increased risk of cardiovascular events. Vascular injury with abnormal repair leading to functional, rather than structural, abnormalities can be regarded as accelerated vascular aging. It emerges as a common feature that can trigger the early diagnosis and risk stratification for cardiovascular disease in women. We discuss sex-specific risk factors that can contribute to vascular injury with age, and these might not always be considered by cardiovascular physicians. It is important for the primary physician to be aware of these risk factors to enable more intensified management of this at-risk population. Novel technologies that allow the assessment of vascular function noninvasively can serve as key diagnostic and therapeutic tools with which we can identify such individuals and target therapy to manage this important patient population appropriately and effectively. We hope that this article will stimulate interest in this field and encourage further research in these important areas.

      Abbreviations and Acronyms:

      CAD (coronary artery disease), CMD (coronary microvascular dysfunction), CVD (cardiovascular disease), MRI (magnetic resonance imaging), PCOS (polycystic ovarian syndrome), RRSO (risk-reducing salpingo-oophorectomy)
      Article Highlights
      • Assessment of endothelial function can improve cardiovascular disease risk prediction in symptomatic women.
      • Female-specific risk factors contribute to the early onset of endothelial dysfunction.
      • Persistent vasomotor symptoms are related to increased sympathetic activity.
      • Preeclampsia and gestational diabetes increase future cardiovascular disease risk.
      • Conventional cardiovascular disease risk factors including hypertension should be better managed.
      • Premature menopause increases the risk of developing endothelial dysfunction.
      • Continue traditional risk factor management, including healthy diet, weight loss, and lipid and glucose management.
      Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Over the past few decades, advanced cardiac imaging techniques have demonstrated important sex differences in the pathophysiology of vascular aging and the progression of atherosclerosis.
      • Shaw L.J.
      • Bugiardini R.
      • Merz C.N.
      Women and ischemic heart disease: evolving knowledge.
      • Maas A.H.
      • van der Schouw Y.T.
      • Regitz-Zagrosek V.
      • et al.
      Red alert for women's heart: the urgent need for more research and knowledge on cardiovascular disease in women: proceedings of the workshop held in Brussels on gender differences in cardiovascular disease, 29 September 2010.
      • Lerman A.
      • Sopko G.
      Women and cardiovascular heart disease: clinical implications from the Women's Ischemia Syndrome Evaluation (WISE) Study. Are we smarter?.
      As the population continues to age, it is increasingly important to understand these issues and to develop a methodical approach to assessment and management of age-related disease. For example, in the United States and worldwide as life expectancy increases, the prevalence of cardiovascular disease and cardiovascular risk factors increases. Moreover, medical advances allow us to treat advanced cardiovascular disease and further contributes to an increasing number of patients with cardiovascular disease. Despite scientific and therapeutic advances, cardiovascular death continues to increase overall. This increase has been partially attributed to aging, especially as cardiovascular disease continues to be the leading cause of death in senior citizens. Moreover, endothelial function is associated with cardiovascular risk factors including hyperlipidemia, hypertension, diabetes, and age. In addition, oxidative stress is an important cardiovascular risk factor that becomes more relevant with increasing age.
      • Bell S.P.
      • Saraf A.A.
      Epidemiology of multimorbidity in older adults with cardiovascular disease.
      The population will require optimal health care management for these diseases as they increase in prevalence, but we must also focus on preventive measures to reduce the overall cardiovascular burden. Moreover, multiple morbidities, the presence of multiple disease processes, continues to complicate cardiovascular management of patients.
      • Bell S.P.
      • Saraf A.A.
      Epidemiology of multimorbidity in older adults with cardiovascular disease.
      • Lee P.Y.
      • Alexander K.P.
      • Hammill B.G.
      • Pasquali S.K.
      • Peterson E.D.
      Representation of elderly persons and women in published randomized trials of acute coronary syndromes.
      Thus, we must address both the diagnosis and management of age-related cardiovascular disease in an effort to help prevent future cardiovascular events.
      The presence of symptoms of angina and nonobstructive CAD in women is strongly associated with cardiovascular events, which is a relatively new finding.
      • Jespersen L.
      • Hvelplund A.
      • Abildstrom S.Z.
      • et al.
      Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events.
      • Suwaidi J.A.
      • Hamasaki S.
      • Higano S.T.
      • Nishimura R.A.
      • Holmes Jr., D.R.
      • Lerman A.
      Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.
      • Ohman E.M.
      Chronic stable angina.
      • Lanza G.A.
      • Crea F.
      Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management.
      Although coronary angiography is still the gold standard to establish obstructive CAD in female patients in middle age, this method is not sufficiently sensitive or specific to detect the majority of the mechanisms of symptoms in this population. Furthermore, once a patient has obstructive CAD, they are resigned to the existing treatments to manage the atherosclerotic process. Ideally, increased focus on preventing the atherosclerotic process can result in identifying abnormal vascular health early, and addressing this will be the key to reducing overall cardiovascular burden. In women, there are a sex-specific risk factors that must be understood and considered by the primary provider in an effort to both assess vascular health and to prevent accelerated vascular aging and future cardiovascular events. Estrogen itself plays a key role that is important for understanding the vascular process, as early in life it can be protective and can improve endothelial function because of the upregulation of nitric oxide; however, as estrogen production slows and halts in women, they can become prone to accelerated vascular aging.
      • Jespersen L.
      • Hvelplund A.
      • Abildstrom S.Z.
      • et al.
      Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events.
      • Suwaidi J.A.
      • Hamasaki S.
      • Higano S.T.
      • Nishimura R.A.
      • Holmes Jr., D.R.
      • Lerman A.
      Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.
      • Ohman E.M.
      Chronic stable angina.
      • Lanza G.A.
      • Crea F.
      Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management.
      It is estimated that at least half of women with chest pain but no evidence of CAD have coronary microvascular dysfunction causing characteristic symptoms of ischemia. We propose that additional vascular function testing should be included in this patient population, and even before the onset of symptoms, to improve risk stratification and to potentially enable intensification of primary and secondary prevention interventions (Figure 1). Among traditional risk factors, hypertension is generally underdiagnosed and undertreated in women. As CAD is affected by hormonal status and other common comorbidities, a more sex-specific approach is justified for optimal prevention and treatment in aging women. Men and women require dedicated attention to detail and assessment of vascular function and traditional and nontraditional risk factors to help better understand an individual's cardiovascular risk. We have chosen to focus on sex-specific risk factors in women that predispose to increased vascular age, atherosclerosis, and cardiovascular risk; this can be challenging because menopausal status and estrogen levels are directly associated with age. With this article, we hope to stimulate physicians to engage in more intensive risk assessment and management for middle-aged women who have traditionally received poor management.
      Figure thumbnail gr1
      Figure 1The interaction of different female-specific conditions that can impair endothelial function.

      Assessment of Endothelial Function

      Angina or ischemia-induced breathlessness (angina equivalent) is the result of myocardial ischemia occurring because of an imbalance between oxygen supply and demand.
      • Ohman E.M.
      Chronic stable angina.
      • Lanza G.A.
      • Crea F.
      Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management.
      The coronary microcirculation is the main regulator of myocardial perfusion. Thus, even in the absence of occlusive epicardial disease, coronary microvascular dysfunction can lead to angina, myocardial ischemia, myocardial infarction, and heart failure Moreover, vascular reactivity and arterial function are important markers of vascular aging that may be the first step of the atherosclerotic process, and early identification of abnormal vascular reactivity can help to stratify patients according to risk more effectively.
      The endothelium is a single-cell layer that separates the blood and vascular supply from other tissues and is important in maintaining hemostatic balance between thrombosis and anticoagulation, regulating vascular tone, and regulating angiogenesis at the level of the epicardium and microcirculation. Shear stress causes vasodilation owing to endothelium-dependent release of nitric oxide.
      • Baeyens N.
      • Bandyopadhyay C.
      • Coon B.G.
      • Yun S.
      • Schwartz M.A.
      Endothelial fluid shear stress sensing in vascular health and disease.
      Endothelial dysfunction occurs at an early stage of atherosclerosis, and it is characterized by an imbalance in vasodilatation and vasoconstriction. It has also been linked to traditional cardiovascular risk factors such as hypertension, hyperglycemia, smoking, advancing age, and nontraditional risk factors particularly in women, such as polycystic ovaries, preeclampsia of pregnancy and autoimmune diseases.
      • Lian B.Q.
      • Keaney Jr., J.F.
      Predicting ischemic heart disease in women: the value of endothelial function.
      • Creager M.A.
      • Cooke J.P.
      • Mendelsohn M.E.
      • et al.
      Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans.
      • Hamasaki S.
      • Al S.J.
      • Higano S.T.
      • Miyauchi K.
      • Holmes Jr., D.R.
      • Lerman A.
      Attenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hypertrophy.
      • Taddei S.
      • Virdis A.
      • Mattei P.
      • et al.
      Aging and endothelial function in normotensive subjects and patients with essential hypertension.
      Endothelial dysfunction is a significant independent risk factor for future cardiovascular events, and this has often been attributed to the relationship between arterial function and vascular aging.
      • Lanza G.A.
      • Crea F.
      Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management.
      • Mieno S.
      • Boodhwani M.
      • Clements R.T.
      • et al.
      Aging is associated with an impaired coronary microvascular response to vascular endothelial growth factor in patients.
      • Shimbo D.
      • Grahame-Clarke C.
      • Miyake Y.
      • et al.
      The association between endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort.
      • Gepner A.D.
      • Korcarz C.E.
      • Colangelo L.A.
      • et al.
      Longitudinal effects of a decade of aging on carotid artery stiffness: the multiethnic study of atherosclerosis.
      A number of modalities are available to assess vascular aging, and they will be useful as we further establish the role of screening in the management of patients with increased risk of cardiovascular disease.
      Endothelial function can be measured both invasively and noninvasively. The gold standard of assessing coronary endothelial function involves the responses of both the epicardial arteries and the microcirculation to an endothelium-dependent vasodilator such as acetylcholine
      • Hasdai D.
      • Lerman A.
      The assessment of endothelial function in the cardiac catheterization laboratory in patients with risk factors for atherosclerotic coronary artery disease.
      • Flammer A.J.
      • Anderson T.
      • Celermajer D.S.
      • et al.
      The assessment of endothelial function: from research into clinical practice.
      (a “functional angiogram”). Epicardial coronary artery diameter is measured using quantitative coronary angiography or intravascular ultrasound. The assessment of the microvasculature is done with a Doppler or pressure wire that measures microvascular endothelial coronary flow reserve.
      • Hasdai D.
      • Lerman A.
      The assessment of endothelial function in the cardiac catheterization laboratory in patients with risk factors for atherosclerotic coronary artery disease.
      • Flammer A.J.
      • Anderson T.
      • Celermajer D.S.
      • et al.
      The assessment of endothelial function: from research into clinical practice.
      The main limitation of these techniques is their invasive nature, making them less applicable in daily clinical practice. Therefore, in a wide range of clinical settings, noninvasive testing can be used and would be preferable to assess endothelial function.
      Endothelial function can be measured through various clinically validated techniques in a noninvasive fashion as well. This approach is ideal for screening and is a good adjunct to consider when seeing women with risk factors for cardiovascular disease. Noninvasive means of measurement of endothelial function include the use of dedicated algorithms designed to assess vascular reactivity and function using cardiac magnetic resonance imaging (MRI), or the use of positron emission tomography to measure coronary flow reserve. In addition, a peripheral technique using venous plethysmography of the forearm, ultrasound of the brachial artery or radial artery, or digital arterial tonometry using flow-mediated vasodilatation or infusion of vasoactive agents, such as acetylcholine or nitroglycerin, can also be used to quantify endothelium-dependent and nondependent vasodilation.
      • Flammer A.J.
      • Anderson T.
      • Celermajer D.S.
      • et al.
      The assessment of endothelial function: from research into clinical practice.
      The main and common principles for the noninvasive assessment of endothelial function are based on the seminal role of the endothelium in reactive hyperemia as a response to ischemia. This process involves placement of a pressure cuff on the arm and inflation for 5-10 minutes to induce absence of flow and local ischemia. The release of the cuff induces the endothelium-dependent process of reactive hyperemia that can be quantified, and it serves as a subsequent assessment of peripheral endothelial function. Importantly, measurements of peripheral endothelial function correlate with coronary artery endothelial function.
      • Anderson T.J.
      • Uehata A.
      • Gerhard M.D.
      • et al.
      Close relation of endothelial function in the human coronary and peripheral circulations.
      • Bonetti P.O.
      • Pumper G.M.
      • Higano S.T.
      • Holmes D.R.
      • Kuvin J.T.
      • Lerman A.
      Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia.
      Even noninvasively assessed impaired endothelial function has been shown to be independently predictive of future cardiovascular events, as the function of the endothelium may be a marker of vascular aging.
      • Mieno S.
      • Boodhwani M.
      • Clements R.T.
      • et al.
      Aging is associated with an impaired coronary microvascular response to vascular endothelial growth factor in patients.
      • Anderson T.J.
      • Uehata A.
      • Gerhard M.D.
      • et al.
      Close relation of endothelial function in the human coronary and peripheral circulations.
      • Donato A.J.
      • Gano L.B.
      • Eskurza I.
      • et al.
      Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase.
      • Laurent S.
      • Marais L.
      • Boutouyrie P.
      The noninvasive assessment of vascular aging.
      • Bortolotto L.A.
      • Blacher J.
      • Kondo T.
      • Takazawa K.
      • Safar M.E.
      Assessment of vascular aging and atherosclerosis in hypertensive subjects: second derivative of photoplethysmogram versus pulse wave velocity.
      • Nilsson P.M.
      • Boutouyrie P.
      • Laurent S.
      Vascular aging: a tale of EVA and ADAM in cardiovascular risk assessment and prevention.

      Sex Differences in Endothelial Function

      In middle-aged women, functional rather than structural coronary abnormalities are a main cause of chest pain syndromes.
      • Shaw L.J.
      • Bugiardini R.
      • Merz C.N.
      Women and ischemic heart disease: evolving knowledge.
      • Bugiardini R.
      • Bairey Merz C.N.
      Angina with “normal” coronary arteries: a changing philosophy.
      It has been shown that coronary flow reserve is lower in women than in men, suggesting possible sex-specific mechanisms contributing to microvascular dysfunction. In women without obstructive CAD, the presence of endothelial dysfunction has been shown to be an important predictor of ischemic heart disease.
      • Matsuzawa Y.
      • Sugiyama S.
      • Sugamura K.
      • et al.
      Digital assessment of endothelial function and ischemic heart disease in women.
      • Gulati M.
      • Cooper-DeHoff R.M.
      • McClure C.
      • et al.
      Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project.
      The Women's Ischemia Syndrome Evaluation study emphasized that microvascular ischemia was associated with the signs and symptoms of ischemia in women with nonobstructive CAD.
      • Pepine C.J.
      • Anderson R.D.
      • Sharaf B.L.
      • et al.
      Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study.
      Symptomatic women with established endothelial dysfunction should be offered medical therapy directed at improving established risk factors and endothelial function. Noninvasive endothelial function testing in sex-specific assessment could provide additional benefit in preventing future cardiac events.
      • Suwaidi J.A.
      • Hamasaki S.
      • Higano S.T.
      • Nishimura R.A.
      • Holmes Jr., D.R.
      • Lerman A.
      Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.
      Although women might not have traditional risk factors for cardiovascular disease, further investigation into their clinical and medical history can elucidate risk factors that predispose them to cardiovascular disease. Conditions that are highly prevalent among women can contribute to accelerated atherosclerosis by inducing and promoting endothelial dysfunction. These conditions include preeclampsia, polycystic ovarian syndrome (PCOS), age at menopause, presence of inflammatory disorders, anemia, hyperuricemia, and stress-induced cardiomyopathy.

      Effect of Menopause on Endothelial Function

      As women age and reach menopause, hormonal changes can play a role in overall vascular health. Postmenopausal women have a greater than 3-fold risk of atherosclerosis when compared with premenopausal women, even after adjustment for age and other potential confounders; however, this theory remains controversial because several randomized controlled trials have suggested otherwise, and it could be attributed to age according to some theories.
      • Witteman J.C.
      • Grobbee D.E.
      • Kok F.J.
      • Hofman A.
      • Valkenburg H.A.
      Increased risk of atherosclerosis in women after the menopause.
      • Moreau K.L.
      • Hildreth K.L.
      • Meditz A.L.
      • Deane K.D.
      • Kohrt W.M.
      Endothelial function is impaired across the stages of the menopause transition in healthy women.
      The decline in endothelial function starts in the early menopause or early menopausal transition and increases after menopause or any period of prolonged estrogen deficiency, although it is naturally difficult to separate postmenopausal status from age, as these two risk factors go hand in hand.
      • Moreau K.L.
      • Hildreth K.L.
      • Meditz A.L.
      • Deane K.D.
      • Kohrt W.M.
      Endothelial function is impaired across the stages of the menopause transition in healthy women.
      • Bechlioulis A.
      • Kalantaridou S.N.
      • Naka K.K.
      • et al.
      Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes.
      Signs of endothelial dysfunction precede the appearance of plaques in the carotid arteries. Vascular health and aging in women is dependent on the hormonal status, and it can be detected by assessing endothelial function, as endothelial function can serve as marker of vascular aging.
      • Yildiz O.
      Vascular smooth muscle and endothelial functions in aging.
      This suggestion is supported by data showing that women who have undergone ovariectomy have reduced endothelial dependent dilation.
      • Pinto S.
      • Virdis A.
      • Ghiadoni L.
      • et al.
      Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women.
      • Virdis A.
      • Ghiadoni L.
      • Pinto S.
      • et al.
      Mechanisms responsible for endothelial dysfunction associated with acute estrogen deprivation in normotensive women.
      Women transitioning through menopause should be screened with noninvasive assessment of endothelial function for early risk stratification in addition to traditional comprehensive laboratory assessment, to manage and screen for vascular disease that might otherwise go undetected.
      Vasomotor symptoms could be related to oxidative stress and adverse cardiovascular disease (CVD) risk profile.
      • van der Schouw Y.T.
      • Grobbee D.E.
      Menopausal complaints, oestrogens, and heart disease risk: an explanation for discrepant findings on the benefits of post-menopausal hormone therapy.
      Severe menopausal symptoms have been associated with hypertension, elevated total cholesterol levels, and increased CVD events compared with female patients with no or few symptoms.
      • Gast G.C.
      • Grobbee D.E.
      • Pop V.J.
      • et al.
      Menopausal complaints are associated with cardiovascular risk factors.
      • Gast G.C.
      • Pop V.J.
      • Samsioe G.N.
      • et al.
      Vasomotor menopausal symptoms are associated with increased risk of coronary heart disease.
      Several studies have suggested that subclinical atherosclerosis is more prevalent in female patients with severe vasomotor symptoms.
      • Thurston R.C.
      • Sutton-Tyrrell K.
      • Everson-Rose S.A.
      • Hess R.
      • Matthews K.A.
      Hot flashes and subclinical cardiovascular disease: findings from the Study of Women’s Health Across the Nation Heart Study.
      • Thurston R.C.
      • Sutton-Tyrrell K.
      • Everson-Rose S.A.
      • Hess R.
      • Powell L.H.
      • Matthews K.A.
      Hot flashes and carotid intima media thickness among midlife women.
      Menopausal vasomotor symptoms are associated with increased sympathetic and decreased parasympathetic function,
      • Thurston R.C.
      • Christie I.C.
      • Matthews K.A.
      Hot flashes and cardiac vagal control during women's daily lives.
      • Hoikkala H.
      • Haapalahti P.
      • Viitasalo M.
      • et al.
      Association between vasomotor hot flashes and heart rate variability in recently postmenopausal women.
      which could enhance the risk of cardiovascular events. This increased risk could be important during a hot flush episode, particularly in women who are prone to severe arrhythmia.
      • Hoikkala H.
      • Haapalahti P.
      • Viitasalo M.
      • et al.
      Association between vasomotor hot flashes and heart rate variability in recently postmenopausal women.
      • Buber J.
      • Mathew J.
      • Moss A.J.
      • et al.
      Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2.
      Vasomotor symptoms are also exacerbated by an increase in insulin resistance and inflammatory factors derived from visceral adipose tissue, which has increased activity after menopause. In addition, there remains the need for further investigation to better understand the role of timing of hormonal replacement therapy in women who have reached menopause, as there are some data that support the effect of timing on the role of hormonal therapy in modulating cardiovascular risk.
      • Thurston R.C.
      • El Khoudary S.R.
      • Sutton-Tyrrell K.
      • et al.
      Vasomotor symptoms and insulin resistance in the study of women’s health across the nation.

      Polycystic Ovary Syndrome and Endothelial Function

      Polycystic ovary syndrome (PCOS) is a complex disorder characterized by oligomenorrhea, amenorrhea, hyperandrogenism, and polycystic appearance of the ovaries. It is the most common hormonal imbalance among women of reproductive age, affecting up to 10% of women. Endothelial dysfunction has been shown to be prevalent among women with PCOS, independent of obesity, age, and other risk factors.
      • Sprung V.S.
      • Cuthbertson D.J.
      • Pugh C.J.
      • et al.
      Nitric oxide-mediated cutaneous microvascular function is impaired in polycystic ovary syndrome but can be improved by exercise training.
      • Sprung V.S.
      • Jones H.
      • Pugh C.J.
      • et al.
      Endothelial dysfunction in hyperandrogenic polycystic ovary syndrome is not explained by either obesity or ectopic fat deposition.
      • Sorensen M.B.
      • Franks S.
      • Robertson C.
      • Pennell D.J.
      • Collins P.
      Severe endothelial dysfunction in young women with polycystic ovary syndrome is only partially explained by known cardiovascular risk factors.
      • Madnani N.
      • Khan K.
      • Chauhan P.
      • Parmar G.
      Polycystic ovarian syndrome.
      The mechanism responsible for this association is not known, although many studies suggest a direct vascular effect. Reduced nitric oxide bioavailability and hyperandrogenism are both potential contributing etiologies.
      • Lees C.
      • Jurkovic D.
      • Zaidi J.
      • Campbell S.
      Unexpected effect of a nitric oxide donor on uterine artery Doppler velocimetry in oligomenorrheic women with polycystic ovaries.
      The hyperandrogenic state has been associated with reduced endothelium and smooth muscle–dependent vasodilatation and vascular constriction with loss of nitric oxide dependent relaxation in the rat model.
      • Sara L.
      • Nadasy G.L.
      • Antal P.
      • et al.
      Pharmacological reactivity of resistance vessels in a rat PCOS model - vascular effects of parallel vitamin D₃ treatment.
      Over time, such hormonal imbalance can play a significant role in impairing vascular function and accelerating vascular aging.
      From a clinical standpoint, when evaluating female patients for cardiovascular risk, it is important to consider a history of PCOS and inquire about irregular menses. Because obesity is prevalent in patients with PCOS, weight loss should be integral to risk factor management. We suggest that patients with PCOS should undergo noninvasive assessment of endothelial function and the results can be used to guide therapy. Adequate treatment of PCOS early could play a role in reducing associating cardiovascular morbidity as a woman ages.

      Endothelial Function in Pregnancy: Effects of Gestational Hypertension and Diabetes

      Pregnancy is a stress-factor that might pose an intense challenge to the cardiovascular system (Figure 2). During normal pregnancy, several metabolic factors are temporarily increased, such as insulin resistance, lipid levels, and coagulation and inflammatory factors.
      • Yarde F.
      • Maas A.H.
      • Franx A.
      • et al.
      Serum AMH levels in women with a history of preeclampsia suggest a role for vascular factors in ovarian aging.
      • Visser S.
      • Hermes W.
      • Ket J.C.
      • et al.
      Systematic review and metaanalysis on nonclassic cardiovascular biomarkers after hypertensive pregnancy disorders.
      • Steegers E.A.
      • von D.P.
      • Duvekot J.J.
      • Pijnenborg R.
      Pre-eclampsia.
      In women who develop hypertensive pregnancy disorders or gestational diabetes mellitus, this physiologic response is altered, leading to vascular endothelial dysfunction in both the uterine and maternal circulation. Preeclampsia represents a severe form of hypertension in pregnancy that occurs after 20 weeks of gestation; it can lead to fetal growth retardation, intrauterine death, and metabolic, vascular, and thrombotic complications in the mother (HELLP-syndrome).
      • Steegers E.A.
      • von D.P.
      • Duvekot J.J.
      • Pijnenborg R.
      Pre-eclampsia.
      • Cartwright J.E.
      • Fraser R.
      • Leslie K.
      • Wallace A.E.
      • James J.L.
      Remodelling at the maternal-fetal interface: relevance to human pregnancy disorders.
      In developed countries, hypertensive pregnancy disorders (affecting 10% of all pregnancies) are the leading cause of maternal mortality, accounting for 16% of maternal deaths. Insufficient placentation can be caused by genetic, immunologic, vascular, and environmental factors, and it has many pathophysiologic mechanisms with concomitant release of biomarkers in common with the initial process of atherosclerosis. After experiencing hypertensive pregnancy disorders, women may also have earlier ovarian aging as a sign of impaired vascular health.
      • Yarde F.
      • Maas A.H.
      • Franx A.
      • et al.
      Serum AMH levels in women with a history of preeclampsia suggest a role for vascular factors in ovarian aging.
      Women with previous hypertensive pregnancy disorders have enhanced sympathetic nervous activity associated with more disabling vasomotor symptoms.
      • Collen A.C.
      • Manhem K.
      • Sverrisdottir Y.B.
      Sympathetic nerve activity in women 40 years after a hypertensive pregnancy.
      • Drost J.T.
      • van der Schouw Y.T.
      • Herber-Gast G.C.
      • Maas A.H.
      More vasomotor symptoms in menopause among women with a history of hypertensive pregnancy diseases compared with women with normotensive pregnancies.
      Figure thumbnail gr2
      Figure 2Identifying pregnancy as a stressor can increase awareness and identify an opportunity to institute chronic disease prevention. A, Women at high risk of future cardiovascular disease are identifiable during pregnancy, at which point subclinical vascular risk may become clinically evident. B, The risk revealed by pregnancy can be used to target high-risk women for screening and early intervention by lifestyle modification and treatment, altering their chronic disease trajectories as they enter middle age. Adapted with permission from Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ. 2002;325(7356):157-160.
      • Sattar N.
      • Greer I.A.
      Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening?.
      The retrospective Cardiovascular Health After Maternal Placental Syndromes (CHAMPS) study, which included 1.03 million healthy women, demonstrated that CVD occurring at least 90 days after the delivery was twice as common (hazard ratio, 2.0) in women who had any gestational complication.
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      A metaanalysis of 43 studies demonstrated that women with a history of preeclampsia had a 2-fold increased risk of both ischemic heart disease and cerebrovascular disease and a 4-fold increased risk of developing hypertension.
      • Bellamy L.
      • Casas J.P.
      • Hingorani A.D.
      • Williams D.J.
      Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
      The risk of chronic hypertension was found to be related to the severity of preeclampsia. After early preeclampsia, more than 40% of women clinically manifest hypertension before the age of 40 years.
      • Drost J.T.
      • Arpaci G.
      • Ottervanger J.P.
      • et al.
      Cardiovascular risk factors in women 10 years post early preeclampsia: the Preeclampsia Risk EValuation in FEMales study (PREVFEM).
      Other CVD risk factors, such as obesity, insulin resistance, and endothelial dysfunction, are also frequently present within several years after hypertensive pregnancies.
      • Sibai B.M.
      • el-Nazer A.
      • Gonzalez-Ruiz A.
      Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis.
      • He S.
      • Silveira A.
      • Hamsten A.
      • Blomback M.
      • Bremme K.
      Haemostatic, endothelial and lipoprotein parameters and blood pressure levels in women with a history of preeclampsia.
      • Chambers J.C.
      • Fusi L.
      • Malik I.S.
      • Haskard D.O.
      • De S.M.
      • Kooner J.S.
      Association of maternal endothelial dysfunction with preeclampsia.
      These data suggest the prolonged effect that the state of preeclampsia might have on overall vascular health. When assessing women for cardiovascular risk, it is important to be aware of such risk factors that might have contributed to premature aging of the vasculature. Gestational diabetes mellitus occurs in 2% to 10% of pregnancies and confers a 4- to 7-fold higher risk of future type II diabetes and the development of the metabolic syndrome in midlife.
      • Bellamy L.
      • Casas J.P.
      • Hingorani A.D.
      • Williams D.
      Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis.
      • Noussitou P.
      • Monbaron D.
      • Vial Y.
      • Gaillard R.C.
      • Ruiz J.
      Gestational diabetes mellitus and the risk of metabolic syndrome: a population-based study in Lausanne, Switzerland.
      These patients also have a higher risk of CAD, myocardial infarction, and stroke.
      • Gunderson E.P.
      • Chiang V.
      • Pletcher M.J.
      • et al.
      History of gestational diabetes mellitus and future risk of atherosclerosis in mid-life: the Coronary Artery Risk Development in Young Adults study.
      Signs of subclinical atherosclerosis were already present before the onset of overt diabetes mellitus or the metabolic syndrome. Women with gestational diabetes mellitus also have a 1.5-fold greater likelihood to develop hypertensive pregnancy disorders compared with women without gestational diabetes mellitus.
      • Bryson C.L.
      • Ioannou G.N.
      • Rulyak S.J.
      • Critchlow C.
      Association between gestational diabetes and pregnancy-induced hypertension.
      Endothelial dysfunction is thought to be one of the mechanisms linking preeclampsia and gestational diabetes mellitus to the development of cardiovascular disease.
      • Rao R.
      • Sen S.
      • Han B.
      • Ramadoss S.
      • Chaudhuri G.
      Gestational diabetes, preeclampsia and cytokine release: similarities and differences in endothelial cell function.
      • Wikström A.K.
      • Stephansson O.
      • Cnattingius S.
      Previous preeclampsia and risks of adverse outcomes in subsequent nonpreeclamptic pregnancies.
      Studies have suggested that vascular injury can predispose to the beginning of the atherosclerotic process in patients with history of preeclampsia.
      • Chambers J.C.
      • Fusi L.
      • Malik I.S.
      • Haskard D.O.
      • De S.M.
      • Kooner J.S.
      Association of maternal endothelial dysfunction with preeclampsia.
      • Agatisa P.K.
      • Ness R.B.
      • Roberts J.M.
      • Costantino J.P.
      • Kuller L.H.
      • McLaughlin M.K.
      Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk.
      Similarly, gestational diabetes mellitus is also a marker of abnormal vascular function. Maternal vascular endothelial dysfunction is thought to contribute to the high incidence of CVD seen in women with a history of gestational diabetes.
      • Knock G.A.
      • McCarthy A.L.
      • Lowy C.
      • Poston L.
      Association of gestational diabetes with abnormal maternal vascular endothelial function.
      Studies in mice have suggested long-term impairment of endothelial function in animals with previous gestational diabetes.
      • Stanley J.L.
      • Cheung C.C.
      • Rueda-Clausen C.F.
      • Sankaralingam S.
      • Baker P.N.
      • Davidge S.T.
      Effect of gestational diabetes on maternal artery function.
      Pregnancy-related disorders offer a unique opportunity for increasing the awareness of increased cardiovascular risk and promoting early preventive cardiovascular measures, and have therefore been incorporated in the 2011 American Heart Association guidelines prevention in women and the 2014 American Heart Association guidelines on stroke prevention.
      • Mosca L.
      • Benjamin E.J.
      • Berra K.
      • et al.
      Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the American Heart Association.
      • Bushnell C.
      • McCullough L.D.
      • Awad I.A.
      • et al.
      Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association.
      Adherence to a healthy lifestyle and regular measures of CVD risk factors are of primary importance, also reinforcing the importance of an increasing role for self-monitoring involving modern e-Health information. It is thus apparent that pregnancy-related conditions such as preeclampsia and gestational diabetes mellitus are associated with an increased risk of future endothelial dysfunction with advancing age. Although the underlying etiology is less understood, it is important to consider this closely when evaluating these patients, as such risk factors might call for early assessment and risk factor modification to prevent future cardiovascular morbidity and mortality.

      Menarche and Menopause and Endothelial Function

      Age and hormonal levels at a specific age can also play a role in development or acceleration of CVD. Conflicting data exist regarding the correlation of age at menarche and CVD risk.
      • Charalampopoulos D.
      • McLoughlin A.
      • Elks C.E.
      • Ong K.K.
      Age at menarche and risks of all-cause and cardiovascular death: a systematic review and meta-analysis.
      • Lakshman R.
      • Forouhi N.G.
      • Sharp S.J.
      • et al.
      Early age at menarche associated with cardiovascular disease and mortality.
      • Mueller N.T.
      • Odegaard A.O.
      • Gross M.D.
      • Koh W.P.
      • Yuan J.M.
      • Pereira M.A.
      Age at menarche and cardiovascular disease mortality in Singaporean Chinese women: the Singapore Chinese Health Study.
      Genetic factors, obesity, and smoking are related to the onset of menarche and CVD risk.
      • Carty C.L.
      • Spencer K.L.
      • Setiawan V.W.
      • et al.
      Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.
      • Kivimäki M.
      • Lawlor D.A.
      • Smith G.D.
      • et al.
      Association of age at menarche with cardiovascular risk factors, vascular structure, and function in adulthood: the Cardiovascular Risk in Young Finns study.
      Worldwide, a decline in age of menarche is observed that is primarily attributed to deterioration in lifestyle factors and environmental toxic agents.
      • Hulsegge G.
      • Picavet H.S.
      • Blokstra A.
      • et al.
      Today’s adult generations are less healthy than their predecessors: generation shifts in metabolic risk factors: the Doetinchem Cohort Study.
      • McDowell M.A.
      • Brody D.J.
      • Hughes J.P.
      Has age at menarche changed? Results from the National Health and Nutrition Examination Survey (NHANES) 1999-2004.
      The magnitude and clinical significance of age at menarche for CVD risk assessment is still undetermined.
      The average age of menopause is approximately 51 years, and premature menopause (< 40 years), either natural or surgical, has been associated with an elevated risk of CVD.
      • van der Schouw Y.T.
      • van der Graaf Y.
      • Steyerberg E.W.
      • Eijkemans J.C.
      • Banga J.D.
      Age at menopause as a risk factor for cardiovascular mortality.
      • Ossewaarde M.E.
      • Bots M.L.
      • Verbeek A.L.
      • et al.
      Age at menopause, cause-specific mortality and total life expectancy.
      • Løkkegaard E.
      • Jovanovic Z.
      • Heitmann B.L.
      • Keiding N.
      • Ottesen B.
      • Pedersen A.T.
      The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy.
      • Atsma F.
      • Bartelink M.L.
      • Grobbee D.E.
      • van der Schouw Y.T.
      Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis.
      Because of the high proportion of Western women using oral contraceptives and hormonal uterine devices throughout menopause transition, the exact age of menopause is difficult to establish. Approximately 1% of women age 40 years receive a diagnosis of spontaneous primary ovarian insufficiency (POI).
      • de Villiers T.J.
      • Pines A.
      • Panay N.
      • et al.
      Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health.
      Women with POI are at increased risk for impaired endothelial function and earlier onset of ischemic heart disease.
      • Atsma F.
      • Bartelink M.L.
      • Grobbee D.E.
      • van der Schouw Y.T.
      Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis.
      • Kalantaridou S.N.
      • Naka K.K.
      • Papanikolaou E.
      • et al.
      Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy.
      It has been suggested that early-onset vascular dysfunction may be a crucial determinant of menopausal age, either through direct effects on the ovarian vasculature or effects on the endocrine system.
      • Kok H.S.
      • van Asselt K.M.
      • van der Schouw Y.T.
      • et al.
      Heart disease risk determines menopausal age rather than the reverse.
      • Matthews K.A.
      • Crawford S.L.
      • Chae C.U.
      • et al.
      Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition?.
      It is thus unclear whether vascular aging is a result of hormonal risk factors or a cause of these. This will be important to further investigate management for these patients. Still, data suggest that early risk factors could have a role in inducing vascular damage and thus adversely affect overall vascular health.
      Interestingly, women who have had a prophylactic bilateral oophorectomy before the age of 40 also have an increased risk for CVD.
      • Løkkegaard E.
      • Jovanovic Z.
      • Heitmann B.L.
      • Keiding N.
      • Ottesen B.
      • Pedersen A.T.
      The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy.
      • Parker W.H.
      • Broder M.S.
      • Chang E.
      • et al.
      Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study.
      Although long-term follow-up data are relatively scarce, a recent metaanalysis showed that POI is associated with a modest increased risk for ischemic heart disease (hazard ratio, 1.61; 95% CI, 1.22-2.12), but not for stroke.
      • Roeters van Lennep J.E.
      • Heida K.Y.
      • Bots M.L.
      • Hoek A.
      collaborators of the Dutch Multidisciplinary Guideline Development Group on Cardiovascular Risk Management after Reproductive Disorders
      Cardiovascular disease risk in women with premature ovarian insufficiency: a systematic review and meta-analysis.
      In the current guidelines of the International Menopause Society, systemic hormone replacement therapy is recommended in women with POI, at least until the average estimated age of natural menopause.
      • de Villiers T.J.
      • Gass M.L.
      • Haines C.J.
      • et al.
      Global Consensus Statement on menopausal hormone therapy.
      • Baber R.J.
      • Panay N.
      • Fenton A.
      • Group I.W.
      2016 IMS Recommendations on women's midlife health and menopause hormone therapy.
      Appropriate use of hormonal therapy in this younger patient population is therefore an important consideration.
      BRCA1/2 mutation carriers have an elevated risk of developing breast cancer and ovarian cancer at a relatively young age. Risk-reducing salpingo-oophorectomy (RRSO) is an established strategy to reduce the risk of ovarian cancer. It is recommended that this surgery be performed during the age of 35-40 years (BRCA1) or 40-45 years (BRCA2), resulting in an early and abrupt menopause.
      • Rebbeck T.R.
      • Kauff N.D.
      • Domchek S.M.
      Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.
      Although temporary use of hormone therapy is not contraindicated in BRCA-patients without previous breast cancer, its use is hampered by the increased susceptibility and fear of breast cancer.
      • Arts-de Jong M.
      • Maas A.H.
      • Massuger L.F.
      • Hoogerbrugge N.
      • de Hullu J.A.
      BRCA1/2 mutation carriers are potentially at higher cardiovascular risk.
      The decision to use hormone therapy after RRSO should be based on individual quality of life issues and not on life expectancy. Others advise consideration of the use of hormone therapy use in BRCA1/2 mutation carriers without prior breast cancer after RRSO to the age of natural menopause, and especially in women who have had risk-reducing mastectomy.
      • Finch A.
      • Evans G.
      • Narod S.A.
      BRCA carriers, prophylactic salpingo-oophorectomy and menopause: clinical management considerations and recommendations.
      BRCA1/2 mutation carriers could have excess mortality unrelated to cancerous causes.
      • Mai P.L.
      • Chatterjee N.
      • Hartge P.
      • et al.
      Potential excess mortality in BRCA1/2 mutation carriers beyond breast, ovarian, prostate, and pancreatic cancers, and melanoma.
      Whether the potential harmful effects of an early surgically induced menopause in BRCA1/2 mutation carriers translates to endothelial dysfunction and increased CVD risk is still unknown; however, recent evidence suggests a potential excess CVD risk.
      • Arts-de Jong M.
      • Maas A.H.
      • Massuger L.F.
      • Hoogerbrugge N.
      • de Hullu J.A.
      BRCA1/2 mutation carriers are potentially at higher cardiovascular risk.
      Preclinical research shows that BRCA1 is basally expressed in endothelial cells and is a modulator of endothelial cell apoptosis, endothelial dysfunction, and potentially atherogenesis.
      • Singh K.K.
      • Shukla P.C.
      • Quan A.
      • et al.
      BRCA1 is a novel target to improve endothelial dysfunction and retard atherosclerosis.
      After a diagnosis of breast cancer, women with BRCA1/2 mutation have an excess risk of diabetes, particularly in overweight patients. In addition, breast cancer therapies including chemotherapy and radiation each are associated with increased cardiovascular risk as well.
      • Bordeleau L.
      • Lipscombe L.
      • Lubinski J.
      • et al.
      Diabetes and breast cancer among women with BRCA1 and BRCA2 mutations.
      Future research might reveal whether basal mechanisms involving BRCA genes influence the cardiovascular system and disease processes, and the role of immunomodulating therapies with limited cardiovascular risk profile. At present, however, it is still unclear whether these findings translate to increased CVD risk in women with BRCA1/2 mutations or what role therapy plays in this association. Further investigation is necessary to determine the interactions among age, CVD risk, and BRCA1/2 mutations and the role of novel chemotherapy agents and radiation protocols to better manage these patients while minimizing cardiovascular risk.

      Hormonal Therapy and Vascular Function

      There are substantial data to suggest that estrogen plays a role in triggering the release of nitric oxide through estrogen receptors, thus improving overall endothelial function. It is also important to consider the effects of hormonal therapy on vascular function. In a double-blinded randomized controlled trial conducted by Hurtado et al,
      • Hurtado R.
      • Celani M.
      • Geber S.
      Effect of short-term estrogen therapy on endothelial function: a double-blinded, randomized, controlled trial.
      the effect of conjugated equine estrogens versus placebo was studied in 64 women. Authors found that administration of estrogen for 28 days had a significant effect in improving flow-mediated dilation of the brachial artery, a marker of vascular nitric oxide–dependent dilatation.
      • Hurtado R.
      • Celani M.
      • Geber S.
      Effect of short-term estrogen therapy on endothelial function: a double-blinded, randomized, controlled trial.
      A separate study by Moreau et al
      • Moreau K.L.
      • Stauffer B.L.
      • Kohrt W.M.
      • Seals D.R.
      Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women.
      exploring the effect of endurance training on endothelial function in women treated with estrogen therapy and found that estrogen status could have a role in modulating improvements in endothelial function with endurance training in postmenopausal women. There are limited data to suggest an improvement in endothelial vascular function with the use of estrogen replacement. This limitation stems from the underlying pathophysiology and that reduced estrogen is associated with a variety of factors that contribute to abnormal endothelial function, including reduced nitric oxide.
      • Moreau K.L.
      • Hildreth K.L.
      Vascular aging across the menopause transition in healthy women.
      The timing of administration of hormonal therapy in the postmenopausal period is an important consideration as well, and data have suggested that the potential benefits of estrogen are dependent on the timing of initiation relative to the onset of menopause. The timing hypothesis essentially suggests that estrogen has a time-dependent beneficial effect if administered early in menopause, because at this point a woman's arteries are likely to be relatively healthy. On the other hand, if started late in menopause, the estrogen may be less likely to have a beneficial effect because of the higher likelihood of atherosclerotic disease later in menopause.
      • Manson J.E.
      The ‘timing hypothesis’ for estrogen therapy in menopausal symptom management.
      • Bassuk S.S.
      • Manson J.E.
      The timing hypothesis: Do coronary risks of menopausal hormone therapy vary by age or time since menopause onset?.
      • Choi S.D.
      • Steinberg E.M.
      • Lee H.H.
      • Naftolin F.
      The Timing Hypothesis remains a valid explanation of differential cardioprotective effects of menopausal hormone treatment.
      In a study by Bassuk et al,
      • Bassuk S.S.
      • Manson J.E.
      The timing hypothesis: Do coronary risks of menopausal hormone therapy vary by age or time since menopause onset?.
      oral estradiol therapy administered within 6 years of menopause was associated with reduced atherosclerotic progression when compared with patients in whom estrogen was administered 10 or more years after menopause. Thus, it is possible that the presence of abnormal vascular endothelial function in the immediate postmenopausal period may be an indication to consider estrogen therapies; however, more investigation in the form of large studies is required to better understand both the role and timing of estrogen therapy in postmenopausal women with abnormal vascular endothelial function.

      Practice Recommendations

      Vascular endothelial function is a risk factor for progressive atherosclerotic disease; if recognized early, it can play a role in risk stratification and cardiovascular risk prevention. There remains substantial controversy regarding the role of noninvasive vascular function testing to guide further management of cardiovascular health. Although additional investigation is required to better understand treatment and management of abnormal endothelial function, it is important to institute aggressive lifestyle modification and risk factor management based on the results of abnormal endothelial function testing. Although risk factor management typically involves management of specific risk factors, an abnormal endothelial function test provides a comprehensive assessment of overall cardiovascular risk, and it is a marker of subclinical atherosclerosis. As a result, a provider can tailor therapies more aggressively rather than simply basing antihypertensive, lifestyle, and statin regimens on single laboratory values.
      We call for noninvasive vascular function testing using MRI, positron emission tomography, or venous plethysmography in all women to establish a baseline vascular health assessment during the early perimenopausal period. Although further investigation is needed in this regard to separate normal aging from pathologic endothelial dysfunction, baseline measurements of peripheral endothelial function in conjunction with the presence of traditional and nontraditional risk factors can help to alert both the patient and provider to the increased risk of cardiovascular disease and help to address this early. Such early vascular health screening can help to identify a systemic process that is not isolated to individual risk factors and could motivate the patient to address the underlying risk factors with appropriate lifestyle changes and medication. Furthermore, noninvasive vascular function testing can be used to assess the effects of such lifestyle and medical interventions to help guide therapy further. The results of peripheral endothelial function should be taken in conjunction with other traditional and nontraditional risk factors and a risk stratification strategy and appropriate therapies should be used accordingly. We recommend aggressive risk factor screening during this time as well. This screening is inclusive of but not limited to traditional risk factor profiles, including the lipid profile, blood pressure measurements, and novel risk factors including inflammatory markers such as C-reactive protein and uric acid and lipoprotein(a). Asymptomatic women with endothelial dysfunction should be managed with appropriate control of hypertension, hyperlipidemia, and exercise programs. In addition to screening, noninvasive vascular screening has a role in women who have symptomatic known coronary artery disease as well. Although vascular function testing results will likely be abnormal in patients with known obstructive coronary artery disease, baseline testing can again serve as a marker against which to measure response to treatment or lifestyle modifications. Further investigation studying the role of serial vascular function testing is required to better understand this phenomenon and its potential role in the management of patients.
      Thus, this field requires additional large studies to better assess the role of noninvasive vascular screening in management of women with nonobstructive and obstructive coronary artery disease. The information provided is often a marker of underlying systemic vascular health and an important precursor to atherosclerotic disease; therefore, routine testing of vascular function and surveillance has the potential to guide treatments. We look forward to large cohort studies to better understand the role of this noninvasive testing to help guide further management. Currently, our recommendation is that providers begin to use such noninvasive testing, whether it be positron emission tomography, MRI, or plethysmography in conjunction with traditional risk factor screening in all perimenopausal women to better understand the systemic nature of a patient's vascular heath profile and to help guide therapy by performing serial measurements every 1 to 2 years. The vascular function assessment will give the provider a snapshot of the overall cardiovascular risk profile and vascular function as opposed to individual risk factors such as lipid profile or hemoglobin A1c, which is a component of the patient's overall cardiovascular risk. The assessment of vascular function provides a measurement of subclinical atherosclerosis which may differ from patient to patient, but within the same patient can be used to guide appropriative cardiovascular risk prevention strategies. As increased research is conducted in this field, our approach to the use of such tests will continue to become more sophisticated.

      Conclusion

      Cardiovascular disease is the leading cause of morbidity and mortality in women. We suggest the need to develop novel paradigms that can improve cardiovascular risk assessment and management in women, which might lead to improved cardiovascular outcomes. A wealth of clinical data exist, but additional preclinical studies in female animal models could play a role in elucidating unknowns in this field. Specifically, the role of both traditional and novel biomarkers, noninvasive assessment of vascular function testing and hormonal factors in predicting cardiovascular events in women will help to guide preventive management in this patient population. Management of these patients should include traditional therapies including weight loss, regular physical activity and a healthy diet, but in addition, more aggressive risk factor modulation might be necessary, depending on an individual's comprehensive risk profile. We suggest further research and evaluation of these areas in an attempt to improve the cardiovascular health of women.

      References

        • Shaw L.J.
        • Bugiardini R.
        • Merz C.N.
        Women and ischemic heart disease: evolving knowledge.
        J Am Coll Cardiol. 2009; 54: 1561-1575
        • Maas A.H.
        • van der Schouw Y.T.
        • Regitz-Zagrosek V.
        • et al.
        Red alert for women's heart: the urgent need for more research and knowledge on cardiovascular disease in women: proceedings of the workshop held in Brussels on gender differences in cardiovascular disease, 29 September 2010.
        Eur Heart J. 2011; 32: 1362-1368
        • Lerman A.
        • Sopko G.
        Women and cardiovascular heart disease: clinical implications from the Women's Ischemia Syndrome Evaluation (WISE) Study. Are we smarter?.
        J Am Coll Cardiol. 2006; 47: S59-S62
        • Bell S.P.
        • Saraf A.A.
        Epidemiology of multimorbidity in older adults with cardiovascular disease.
        Clin Geriatr Med. 2016; 32: 215-226
        • Lee P.Y.
        • Alexander K.P.
        • Hammill B.G.
        • Pasquali S.K.
        • Peterson E.D.
        Representation of elderly persons and women in published randomized trials of acute coronary syndromes.
        JAMA. 2001; 286: 708-713
        • Jespersen L.
        • Hvelplund A.
        • Abildstrom S.Z.
        • et al.
        Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events.
        Eur Heart J. 2012; 33: 734-744
        • Suwaidi J.A.
        • Hamasaki S.
        • Higano S.T.
        • Nishimura R.A.
        • Holmes Jr., D.R.
        • Lerman A.
        Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.
        Circulation. 2000; 101: 948-954
        • Ohman E.M.
        Chronic stable angina.
        N Engl J Med. 2016; 375: 293
        • Lanza G.A.
        • Crea F.
        Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management.
        Circulation. 2010; 121: 2317-2325
        • Baeyens N.
        • Bandyopadhyay C.
        • Coon B.G.
        • Yun S.
        • Schwartz M.A.
        Endothelial fluid shear stress sensing in vascular health and disease.
        J Clin Invest. 2016; 126: 821-828
        • Lian B.Q.
        • Keaney Jr., J.F.
        Predicting ischemic heart disease in women: the value of endothelial function.
        J Am Coll Cardiol. 2010; 55: 1697-1699
        • Creager M.A.
        • Cooke J.P.
        • Mendelsohn M.E.
        • et al.
        Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans.
        J Clin Invest. 1990; 86: 228-234
        • Hamasaki S.
        • Al S.J.
        • Higano S.T.
        • Miyauchi K.
        • Holmes Jr., D.R.
        • Lerman A.
        Attenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hypertrophy.
        J Am Coll Cardiol. 2000; 35: 1654-1660
        • Taddei S.
        • Virdis A.
        • Mattei P.
        • et al.
        Aging and endothelial function in normotensive subjects and patients with essential hypertension.
        Circulation. 1995; 91: 1981-1987
        • Mieno S.
        • Boodhwani M.
        • Clements R.T.
        • et al.
        Aging is associated with an impaired coronary microvascular response to vascular endothelial growth factor in patients.
        J Thorac Cardiovasc Surg. 2006; 132: 1348-1355
        • Shimbo D.
        • Grahame-Clarke C.
        • Miyake Y.
        • et al.
        The association between endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort.
        Atherosclerosis. 2007; 192: 197-203
        • Gepner A.D.
        • Korcarz C.E.
        • Colangelo L.A.
        • et al.
        Longitudinal effects of a decade of aging on carotid artery stiffness: the multiethnic study of atherosclerosis.
        Stroke. 2014; 45: 48-53
        • Hasdai D.
        • Lerman A.
        The assessment of endothelial function in the cardiac catheterization laboratory in patients with risk factors for atherosclerotic coronary artery disease.
        Herz. 1999; 24: 544-547
        • Flammer A.J.
        • Anderson T.
        • Celermajer D.S.
        • et al.
        The assessment of endothelial function: from research into clinical practice.
        Circulation. 2012; 126: 753-767
        • Anderson T.J.
        • Uehata A.
        • Gerhard M.D.
        • et al.
        Close relation of endothelial function in the human coronary and peripheral circulations.
        J Am Coll Cardiol. 1995; 26: 1235-1241
        • Bonetti P.O.
        • Pumper G.M.
        • Higano S.T.
        • Holmes D.R.
        • Kuvin J.T.
        • Lerman A.
        Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia.
        J Am Coll Cardiol. 2004; 44: 2137-2141
        • Donato A.J.
        • Gano L.B.
        • Eskurza I.
        • et al.
        Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase.
        Am J Physiol Heart Circ Physiol. 2009; 297: H425-H432
        • Laurent S.
        • Marais L.
        • Boutouyrie P.
        The noninvasive assessment of vascular aging.
        Can J Cardiol. 2016; 32: 669-679
        • Bortolotto L.A.
        • Blacher J.
        • Kondo T.
        • Takazawa K.
        • Safar M.E.
        Assessment of vascular aging and atherosclerosis in hypertensive subjects: second derivative of photoplethysmogram versus pulse wave velocity.
        Am J Hypertens. 2000; 13: 165-171
        • Nilsson P.M.
        • Boutouyrie P.
        • Laurent S.
        Vascular aging: a tale of EVA and ADAM in cardiovascular risk assessment and prevention.
        Hypertension. 2009; 54: 3-10
        • Bugiardini R.
        • Bairey Merz C.N.
        Angina with “normal” coronary arteries: a changing philosophy.
        JAMA. 2005; 293: 477-484
        • Matsuzawa Y.
        • Sugiyama S.
        • Sugamura K.
        • et al.
        Digital assessment of endothelial function and ischemic heart disease in women.
        J Am Coll Cardiol. 2010; 55: 1688-1696
        • Gulati M.
        • Cooper-DeHoff R.M.
        • McClure C.
        • et al.
        Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project.
        Arch Intern Med. 2009; 169: 843-850
        • Pepine C.J.
        • Anderson R.D.
        • Sharaf B.L.
        • et al.
        Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study.
        J Am Coll Cardiol. 2010; 55: 2825-2832
        • Witteman J.C.
        • Grobbee D.E.
        • Kok F.J.
        • Hofman A.
        • Valkenburg H.A.
        Increased risk of atherosclerosis in women after the menopause.
        BMJ. 1989; 298: 642-644
        • Moreau K.L.
        • Hildreth K.L.
        • Meditz A.L.
        • Deane K.D.
        • Kohrt W.M.
        Endothelial function is impaired across the stages of the menopause transition in healthy women.
        J Clin Endocrinol Metab. 2012; 97: 4692-4700
        • Bechlioulis A.
        • Kalantaridou S.N.
        • Naka K.K.
        • et al.
        Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes.
        J Clin Endocrinol Metab. 2010; 95: 1199-1206
        • Yildiz O.
        Vascular smooth muscle and endothelial functions in aging.
        Ann N Y Acad Sci. 2007; 1100: 353-360
        • Pinto S.
        • Virdis A.
        • Ghiadoni L.
        • et al.
        Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women.
        Hypertension. 1997; 29: 268-273
        • Virdis A.
        • Ghiadoni L.
        • Pinto S.
        • et al.
        Mechanisms responsible for endothelial dysfunction associated with acute estrogen deprivation in normotensive women.
        Circulation. 2000; 101: 2258-2263
        • van der Schouw Y.T.
        • Grobbee D.E.
        Menopausal complaints, oestrogens, and heart disease risk: an explanation for discrepant findings on the benefits of post-menopausal hormone therapy.
        Eur Heart J. 2005; 26: 1358-1361
        • Gast G.C.
        • Grobbee D.E.
        • Pop V.J.
        • et al.
        Menopausal complaints are associated with cardiovascular risk factors.
        Hypertension. 2008; 51: 1492-1498
        • Gast G.C.
        • Pop V.J.
        • Samsioe G.N.
        • et al.
        Vasomotor menopausal symptoms are associated with increased risk of coronary heart disease.
        Menopause. 2011; 18: 146-151
        • Thurston R.C.
        • Sutton-Tyrrell K.
        • Everson-Rose S.A.
        • Hess R.
        • Matthews K.A.
        Hot flashes and subclinical cardiovascular disease: findings from the Study of Women’s Health Across the Nation Heart Study.
        Circulation. 2008; 118: 1234-1240
        • Thurston R.C.
        • Sutton-Tyrrell K.
        • Everson-Rose S.A.
        • Hess R.
        • Powell L.H.
        • Matthews K.A.
        Hot flashes and carotid intima media thickness among midlife women.
        Menopause. 2011; 18: 352-358
        • Thurston R.C.
        • Christie I.C.
        • Matthews K.A.
        Hot flashes and cardiac vagal control during women's daily lives.
        Menopause. 2012; 19: 406-412
        • Hoikkala H.
        • Haapalahti P.
        • Viitasalo M.
        • et al.
        Association between vasomotor hot flashes and heart rate variability in recently postmenopausal women.
        Menopause. 2010; 17: 315-320
        • Buber J.
        • Mathew J.
        • Moss A.J.
        • et al.
        Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2.
        Circulation. 2011; 123: 2784-2791
        • Thurston R.C.
        • El Khoudary S.R.
        • Sutton-Tyrrell K.
        • et al.
        Vasomotor symptoms and insulin resistance in the study of women’s health across the nation.
        J Clin Endocrinol Metab. 2012; 97: 3487-3494
        • Sprung V.S.
        • Cuthbertson D.J.
        • Pugh C.J.
        • et al.
        Nitric oxide-mediated cutaneous microvascular function is impaired in polycystic ovary syndrome but can be improved by exercise training.
        J Physiol. 2013; 591: 1475-1487
        • Sprung V.S.
        • Jones H.
        • Pugh C.J.
        • et al.
        Endothelial dysfunction in hyperandrogenic polycystic ovary syndrome is not explained by either obesity or ectopic fat deposition.
        Clin Sci (Lond). 2014; 126: 67-74
        • Sorensen M.B.
        • Franks S.
        • Robertson C.
        • Pennell D.J.
        • Collins P.
        Severe endothelial dysfunction in young women with polycystic ovary syndrome is only partially explained by known cardiovascular risk factors.
        Clin Endocrinol (Oxf). 2006; 65: 655-659
        • Madnani N.
        • Khan K.
        • Chauhan P.
        • Parmar G.
        Polycystic ovarian syndrome.
        Indian J Dermatol Venereol Leprol. 2013; 79: 310-321
        • Lees C.
        • Jurkovic D.
        • Zaidi J.
        • Campbell S.
        Unexpected effect of a nitric oxide donor on uterine artery Doppler velocimetry in oligomenorrheic women with polycystic ovaries.
        Ultrasound Obstet Gynecol. 1998; 11: 129-132
        • Sara L.
        • Nadasy G.L.
        • Antal P.
        • et al.
        Pharmacological reactivity of resistance vessels in a rat PCOS model - vascular effects of parallel vitamin D₃ treatment.
        Gynecol Endocrinol. 2012; 28: 961-964
        • Sattar N.
        • Greer I.A.
        Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening?.
        BMJ. 2002; 325: 157-160
        • Yarde F.
        • Maas A.H.
        • Franx A.
        • et al.
        Serum AMH levels in women with a history of preeclampsia suggest a role for vascular factors in ovarian aging.
        J Clin Endocrinol. Metab. 2014; 99: 579-586
        • Visser S.
        • Hermes W.
        • Ket J.C.
        • et al.
        Systematic review and metaanalysis on nonclassic cardiovascular biomarkers after hypertensive pregnancy disorders.
        Am J Obstet Gynecol. 2014; 211: 373.e1-373.e9
        • Steegers E.A.
        • von D.P.
        • Duvekot J.J.
        • Pijnenborg R.
        Pre-eclampsia.
        Lancet. 2010; 376: 631-644
        • Cartwright J.E.
        • Fraser R.
        • Leslie K.
        • Wallace A.E.
        • James J.L.
        Remodelling at the maternal-fetal interface: relevance to human pregnancy disorders.
        Reproduction. 2010; 140: 803-813
        • Collen A.C.
        • Manhem K.
        • Sverrisdottir Y.B.
        Sympathetic nerve activity in women 40 years after a hypertensive pregnancy.
        J Hypertens. 2012; 30: 1203-1210
        • Drost J.T.
        • van der Schouw Y.T.
        • Herber-Gast G.C.
        • Maas A.H.
        More vasomotor symptoms in menopause among women with a history of hypertensive pregnancy diseases compared with women with normotensive pregnancies.
        Menopause. 2013; 20: 1006-1011
        • Ray J.G.
        • Vermeulen M.J.
        • Schull M.J.
        • Redelmeier D.A.
        Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
        Lancet. 2005; 366: 1797-1803
        • Bellamy L.
        • Casas J.P.
        • Hingorani A.D.
        • Williams D.J.
        Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
        BMJ. 2007; 335: 974
        • Drost J.T.
        • Arpaci G.
        • Ottervanger J.P.
        • et al.
        Cardiovascular risk factors in women 10 years post early preeclampsia: the Preeclampsia Risk EValuation in FEMales study (PREVFEM).
        Eur J Prev Cardiol. 2012; 19: 1138-1144
        • Sibai B.M.
        • el-Nazer A.
        • Gonzalez-Ruiz A.
        Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis.
        Am J Obstet Gynecol. 1986; 155: 1011-1016
        • He S.
        • Silveira A.
        • Hamsten A.
        • Blomback M.
        • Bremme K.
        Haemostatic, endothelial and lipoprotein parameters and blood pressure levels in women with a history of preeclampsia.
        Thromb Haemost. 1999; 81: 538-542
        • Chambers J.C.
        • Fusi L.
        • Malik I.S.
        • Haskard D.O.
        • De S.M.
        • Kooner J.S.
        Association of maternal endothelial dysfunction with preeclampsia.
        JAMA. 2001; 285: 1607-1612
        • Bellamy L.
        • Casas J.P.
        • Hingorani A.D.
        • Williams D.
        Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis.
        Lancet. 2009; 373: 1773-1779
        • Noussitou P.
        • Monbaron D.
        • Vial Y.
        • Gaillard R.C.
        • Ruiz J.
        Gestational diabetes mellitus and the risk of metabolic syndrome: a population-based study in Lausanne, Switzerland.
        Diabetes Metab. 2005; 31: 361-369
        • Gunderson E.P.
        • Chiang V.
        • Pletcher M.J.
        • et al.
        History of gestational diabetes mellitus and future risk of atherosclerosis in mid-life: the Coronary Artery Risk Development in Young Adults study.
        J Am Heart Assoc. 2014; 3e000490
        • Bryson C.L.
        • Ioannou G.N.
        • Rulyak S.J.
        • Critchlow C.
        Association between gestational diabetes and pregnancy-induced hypertension.
        Am J Epidemiol. 2003; 158: 1148-1153
        • Rao R.
        • Sen S.
        • Han B.
        • Ramadoss S.
        • Chaudhuri G.
        Gestational diabetes, preeclampsia and cytokine release: similarities and differences in endothelial cell function.
        Adv Exp Med Biol. 2014; 814: 69-75
        • Wikström A.K.
        • Stephansson O.
        • Cnattingius S.
        Previous preeclampsia and risks of adverse outcomes in subsequent nonpreeclamptic pregnancies.
        Am J Obstet Gynecol. 2011; 204: 148.e1-148.e6
        • Agatisa P.K.
        • Ness R.B.
        • Roberts J.M.
        • Costantino J.P.
        • Kuller L.H.
        • McLaughlin M.K.
        Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk.
        Am J Physiol Heart Circ Physiol. 2004; 286: H1389-H1393
        • Knock G.A.
        • McCarthy A.L.
        • Lowy C.
        • Poston L.
        Association of gestational diabetes with abnormal maternal vascular endothelial function.
        Br J Obstet Gynaecol. 1997; 104: 229-234
        • Stanley J.L.
        • Cheung C.C.
        • Rueda-Clausen C.F.
        • Sankaralingam S.
        • Baker P.N.
        • Davidge S.T.
        Effect of gestational diabetes on maternal artery function.
        Reprod Sci. 2011; 18: 342-352
        • Mosca L.
        • Benjamin E.J.
        • Berra K.
        • et al.
        Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the American Heart Association.
        Circulation. 2011; 123: 1243-1262
        • Bushnell C.
        • McCullough L.D.
        • Awad I.A.
        • et al.
        Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association.
        Stroke. 2014; 45: 1545-1588
        • Charalampopoulos D.
        • McLoughlin A.
        • Elks C.E.
        • Ong K.K.
        Age at menarche and risks of all-cause and cardiovascular death: a systematic review and meta-analysis.
        Am J Epidemiol. 2014; 180: 29-40
        • Lakshman R.
        • Forouhi N.G.
        • Sharp S.J.
        • et al.
        Early age at menarche associated with cardiovascular disease and mortality.
        J Clin Endocrinol Metab. 2009; 94: 4953-4960
        • Mueller N.T.
        • Odegaard A.O.
        • Gross M.D.
        • Koh W.P.
        • Yuan J.M.
        • Pereira M.A.
        Age at menarche and cardiovascular disease mortality in Singaporean Chinese women: the Singapore Chinese Health Study.
        Ann Epidemiol. 2012; 22: 717-722
        • Carty C.L.
        • Spencer K.L.
        • Setiawan V.W.
        • et al.
        Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.
        Hum Reprod. 2013; 28: 1695-1706
        • Kivimäki M.
        • Lawlor D.A.
        • Smith G.D.
        • et al.
        Association of age at menarche with cardiovascular risk factors, vascular structure, and function in adulthood: the Cardiovascular Risk in Young Finns study.
        Am J Clin Nutr. 2008; 87: 1876-1882
        • Hulsegge G.
        • Picavet H.S.
        • Blokstra A.
        • et al.
        Today’s adult generations are less healthy than their predecessors: generation shifts in metabolic risk factors: the Doetinchem Cohort Study.
        Eur J Prev Cardiol. 2014; 21: 1134-1144
        • McDowell M.A.
        • Brody D.J.
        • Hughes J.P.
        Has age at menarche changed? Results from the National Health and Nutrition Examination Survey (NHANES) 1999-2004.
        J Adolesc Health. 2007; 40: 227-231
        • van der Schouw Y.T.
        • van der Graaf Y.
        • Steyerberg E.W.
        • Eijkemans J.C.
        • Banga J.D.
        Age at menopause as a risk factor for cardiovascular mortality.
        Lancet. 1996; 347: 714-718
        • Ossewaarde M.E.
        • Bots M.L.
        • Verbeek A.L.
        • et al.
        Age at menopause, cause-specific mortality and total life expectancy.
        Epidemiology. 2005; 16: 556-562
        • Løkkegaard E.
        • Jovanovic Z.
        • Heitmann B.L.
        • Keiding N.
        • Ottesen B.
        • Pedersen A.T.
        The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy.
        Maturitas. 2006; 53: 226-233
        • Atsma F.
        • Bartelink M.L.
        • Grobbee D.E.
        • van der Schouw Y.T.
        Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis.
        Menopause. 2006; 13: 265-279
        • de Villiers T.J.
        • Pines A.
        • Panay N.
        • et al.
        Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health.
        Climacteric. 2013; 16: 316-337
        • Kalantaridou S.N.
        • Naka K.K.
        • Papanikolaou E.
        • et al.
        Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy.
        J Clin Endocrinol Metab. 2004; 89: 3907-3913
        • Kok H.S.
        • van Asselt K.M.
        • van der Schouw Y.T.
        • et al.
        Heart disease risk determines menopausal age rather than the reverse.
        J Am Coll Cardiol. 2006; 47: 1976-1983
        • Matthews K.A.
        • Crawford S.L.
        • Chae C.U.
        • et al.
        Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition?.
        J Am Coll Cardiol. 2009; 54: 2366-2373
        • Parker W.H.
        • Broder M.S.
        • Chang E.
        • et al.
        Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study.
        Obstet Gynecol. 2009; 113: 1027-1037
        • Roeters van Lennep J.E.
        • Heida K.Y.
        • Bots M.L.
        • Hoek A.
        • collaborators of the Dutch Multidisciplinary Guideline Development Group on Cardiovascular Risk Management after Reproductive Disorders
        Cardiovascular disease risk in women with premature ovarian insufficiency: a systematic review and meta-analysis.
        Eur J Prev Cardiol. 2016; 23: 178-186
        • de Villiers T.J.
        • Gass M.L.
        • Haines C.J.
        • et al.
        Global Consensus Statement on menopausal hormone therapy.
        Maturitas. 2013; 74: 391-392
        • Baber R.J.
        • Panay N.
        • Fenton A.
        • Group I.W.
        2016 IMS Recommendations on women's midlife health and menopause hormone therapy.
        Climacteric. 2016; 19: 109-150
        • Rebbeck T.R.
        • Kauff N.D.
        • Domchek S.M.
        Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.
        J Natl Cancer Inst. 2009; 101: 80-87
        • Arts-de Jong M.
        • Maas A.H.
        • Massuger L.F.
        • Hoogerbrugge N.
        • de Hullu J.A.
        BRCA1/2 mutation carriers are potentially at higher cardiovascular risk.
        Crit Rev Oncol Hematol. 2014; 91: 159-171
        • Finch A.
        • Evans G.
        • Narod S.A.
        BRCA carriers, prophylactic salpingo-oophorectomy and menopause: clinical management considerations and recommendations.
        Womens Health (Lond). 2012; 8: 543-555
        • Mai P.L.
        • Chatterjee N.
        • Hartge P.
        • et al.
        Potential excess mortality in BRCA1/2 mutation carriers beyond breast, ovarian, prostate, and pancreatic cancers, and melanoma.
        PLoS One. 2009; 4e4812
        • Singh K.K.
        • Shukla P.C.
        • Quan A.
        • et al.
        BRCA1 is a novel target to improve endothelial dysfunction and retard atherosclerosis.
        J Thorac Cardiovasc Surg. 2013; 146: 949-960.e944
        • Bordeleau L.
        • Lipscombe L.
        • Lubinski J.
        • et al.
        Diabetes and breast cancer among women with BRCA1 and BRCA2 mutations.
        Cancer. 2011; 117: 1812-1818
        • Hurtado R.
        • Celani M.
        • Geber S.
        Effect of short-term estrogen therapy on endothelial function: a double-blinded, randomized, controlled trial.
        Climacteric. 2016; 19: 448-451
        • Moreau K.L.
        • Stauffer B.L.
        • Kohrt W.M.
        • Seals D.R.
        Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women.
        J Clin Endocrinol Metab. 2013; 98: 4507-4515
        • Moreau K.L.
        • Hildreth K.L.
        Vascular aging across the menopause transition in healthy women.
        Adv Vasc Med. 2014; 2014
        • Manson J.E.
        The ‘timing hypothesis’ for estrogen therapy in menopausal symptom management.
        Womens Health (Lond). 2015; 11: 437-440
        • Bassuk S.S.
        • Manson J.E.
        The timing hypothesis: Do coronary risks of menopausal hormone therapy vary by age or time since menopause onset?.
        Metabolism. 2016; 65: 794-803
        • Choi S.D.
        • Steinberg E.M.
        • Lee H.H.
        • Naftolin F.
        The Timing Hypothesis remains a valid explanation of differential cardioprotective effects of menopausal hormone treatment.
        Menopause. 2011; 18: 230-236