Welcome. I'm Dr. Erin Nikos. I'm a professor in medicine in the Division of Cardiology at Johns Hopkins University, and I'm our director of our Women's Health Program. I'm really pleased to participate in this American College of Cardiology Educational Program about hypertension in women. And I'm going to be focusing on the role of menopause. These are my disclosures. The learning objectives for this program is I'm going to discuss the prevalence of hypertension throughout the women's life course with a focus on the menopause transition. I'm going to explain the pathophysiology and overlapping relationships between menopausal symptoms and hypertension. And I'm going to talk about cardiovascular risk assessment at the time of menopause with regards to cardiovascular risk reduction and hypertension management. So hypertension is very prevalent in the aging woman. This is data from NHANES, U.S. data, and we see by the time a woman reaches 60 years or older, 71% of women have hypertension. So it's a very common comorbidity. Now, hypertension is a risk factor for cardiovascular disease in both men and women. But actually, hypertension confers a greater relative risk in women compared to men. This is data from the U.K. Biobank looking at risk of blood pressure, myocardial infarction. You can see for women who have elevated blood pressure versus those without hypertension, there's a 64% increased risk of MI where elevated blood pressure was not a risk in men. Then when we go to stage 1 hypertension, it's about a 90% increased risk of MI in women compared to a 29% increase in men. And stage 2 hypertension, a 2.5-fold increased risk of myocardial infarction in women compared to 1.7-fold in men. So it's important for both men and women, but it confers a greater risk in women. Additionally, the cardiovascular risk associated with blood pressure occurs at lower blood pressure levels in women compared to men. So if you look here at cardiovascular disease, women are here in the red. You can see the risk of CVD even starts in blood pressures in the normal range and in the pre-hypertension range, and then for there's a dose response, but each increasing blood pressure group after that confers a greater relative risk of CVD in women compared to their male counterparts. Therefore, hypertension is a major risk factor of cardiovascular disease and a really important target for prevention. Now, here is some data about the blood pressure trajectories throughout the life course in women versus men. So in younger adults under the age of 60, on average women actually have a lower systolic blood pressure compared to their male counterparts. But after midlife, around the time of a menopause transition, women on average have higher blood pressures than men. So if you look at the change from baseline over the life course, women are on a steeper blood pressure trajectory throughout their life course compared to men, and this may be why cardiovascular disease presents differently in women compared to men. Now, this rise in systolic blood pressure with aging is mainly caused by an increase in vascular stiffness of the great arteries in combination with atherosclerotic changes in the vessel wall. But systolic blood pressure rises more steeply in the aging women compared to aging men, and this may be related to hormonal changes that occur at the menopause transition. Now, this slide depicts female-specific risk factors for hypertension across the life course. In women of reproductive age, there's issues related to fibromuscular dysplasia, FMD, which is more prevalent in women, autoimmune diseases, which are more prevalent in women, the use of oral contraceptives, infertility treatment, polycystic ovary syndrome, and premature ovarian insufficiency. Additionally, hypertensive disorders of pregnancy, increased cardiovascular risk, and then post-menopause, which I'll be focusing on in this talk, there's a drop in estradiol, and women have a relatively more androgenic state. So, this higher androgen sex hormone profile, as well as the influence of hormone replacement therapy, influences women's risk of hypertension after menopause. Now, menopause is not a disease. It's a normal life transition that all women who live long enough will experience. The average age of menopause is 51. But there are some notable metabolic changes that occur at the menopause transition. Even if there's no change in weight on the scale, there's a redistribution of body fat, where there's an increase of adipose deposition in the abdomen and abdomen cavity, so this visceral fat, this can lead to a more atherogenic lipid profile. With increase in triglycerides and LDL cholesterol, women become more insulin-resistant after menopause, can have more endothelial dysfunction, an increase in blood pressure, an increase in sympathetic tone. This slide depicts this in a little bit more detail. So, with menopause, there is a decline in estradiol and antimalarian hormone, AMH, and then there's a relative increase in testosterone and follicular stimulating hormone, FSH. And these metabolic changes include increases in weight, in fat mass, in the abdomen cavity, insulin resistance, dyslipidemia, blood pressure, atherosclerosis, like carotid intermedial thickness, and the vasomotor symptoms and decrease in fat-free mass and insulin sensitivity. There's a decrease in energy expenditure, and this impacts both vascular and cardiac health, as well as an impairment in sleep health and in bone health in women after the menopause transition. Now, there's been a little bit of a debate whether there is a menopause or ovarian effect on blood pressure, or whether it's just all due to an aging effect. So, data from the SWAN study, the Study of Women's Health Across the Nation, which enrolled women in the perimenopausal period and followed them long-term, showed that on average, blood pressure rose linearly, consistent with an aging effect. However, a deeper dive into this data suggested that not all women have similar blood pressure trajectories. There were some women who actually had a steeper increase in blood pressure in their reproductive years, and then sort of plateaued after menopause. Again, the average was just a linear increase that seemed to correlate with aging. But in about 35% of women, there was this accelerated increase in systolic blood pressure that occurred after menopause. And this was particularly seen in women who had early menopause and more significant vasomotor symptoms. So, this is another study from SWAN looking at arterial stiffness as measured from the carotid femoral pulse wave velocity. And we see that in this one-year period, around the final menstrual period, there is an increase in arterial stiffness, this vascular stiffness that occurs around menopause. Now, there was racial disparities where actually black women started to have increase in arterial stiffness even in the years leading up to menopause. But all women had this relative increase around the menopause transition. And so, this interval period within one year of the final menstrual period is a critical period for women when vascular functional alterations occur that can increase their risk of having hypertension. Now, vasomotor symptoms are experienced by 75% of women transitioning through menopause, although most women don't seek help for them. But about 25% of women, this can even be prolonged, lasting more than five years. Now, vasomotor symptoms are not necessarily benign. There's been data suggesting that women who have more frequent and more persistent vasomotor symptoms, this has been associated with increased cardiovascular risk, including incident hypertension. So, this is, again, data from that SWAN study of women who weren't menopause at baseline. But women who had more frequent vasomotor symptoms at baseline, it was associated with actually having a higher blood pressure at baseline and more prevalent hypertension. But among women without baseline hypertension, more frequent vasomotor symptoms was associated with a 39% increased risk of developing either prehypertension or hypertension, even after adjusting for comorbidities like age and body mass index. So, having very frequent or persistent vasomotor symptoms can be a marker of sympathetic, you know, instability that can hallmark an increased risk of developing hypertension. The same thing was seen for cardiovascular events from the same cohort, that women with more frequent vasomotor symptoms more than six days out of a two-week period, even after adjusting for traditional risk factors, they had a 51% increased risk of having a subsequent cardiovascular event over 22 years of follow-up. We also saw that women who had persistent vasomotor symptoms lasting more than five years had an 80% increased risk of a subsequent cardiovascular event. Now, this may not necessarily be causal. It may not be that vasomotor symptoms are causing a cardiovascular event, but that women who are experiencing vasomotor symptoms, this may be a marker of a higher risk woman who's also at risk for cardiovascular disease. And that's why it's so important that we talk to women about their menopause, you know, the age of onset of menopause, and whether they were experiencing vasomotor symptoms as part of comprehensive risk assessment, because if we don't ask this information, we'd be missing some key details about their cardiovascular risk. But I think very few clinicians outside of GYN, you know, certainly very few cardiologists ask women about their vasomotor symptoms, and I would encourage you to do so. Now, in addition to that, this is data from another study, a population-based study showing that women who had more severe vasomotor symptoms also had more atherosclerosis as measured on a coronary CT angiogram, that even in adjusted models, including this fully adjusted model, that women with severe vasomotor symptoms or severe symptoms lasting more than five years, they were much more likely to have coronary atherosclerosis. So, again, vasomotor symptoms can be a marker of a higher risk woman. So, in men, you know, there is an andropause where men lose testosterone about 1 to 2% per year over their life course, but women have this acute hormone change that men do not with acute loss of estradiol with the final menstrual period. Now, the postmenopausal ovary is still metabolically active. It still is making testosterone even out to 10 years after menopause. And so, there's a relative, you know, increase in androgens, a relative increased androgen state after menopause with the loss of estradiol. And that can influence cardiovascular risk. Certainly, women in the reproductive years who have polycystic ovary syndrome, a condition that's associated with hyperandrogenism, they have increased cardiovascular risk. And so, a lot of my research work has been focusing on sex hormone levels in postmenopausal women. And this is some of my studies from the multi-ethnic study of atherosclerosis where we looked at sex hormone levels in postmenopausal women. And we showed that postmenopausal women who had higher testosterone levels, you know, even after adjusting for cardiovascular risk factors, they had increased concentric remodeling over 10 years of follow-up. So, they had increased mass-volume ratio, meaning that their hearts were getting thicker and stiffer, which can be an imaging precursor to heart failure with preserved ejection fraction. We also showed in the same cohort that postmenopausal women with higher testosterone levels had decreased compliance. They had decreased distensibility, you know, more stiffness of their aorta. We also showed that women with higher testosterone levels had impaired brachial reactivity, a marker of endothelial function. So, with higher testosterone levels, they had a decrease in flow-mediated dilation. We also showed that women with higher androgen levels after menopause had more coronary atherosclerosis. They had increased coronary artery calcium progression by 26% compared to women with lower testosterone levels. And in the final study, we actually looked at events. We showed that postmenopausal women with higher testosterone relative to estradiol, even after adjusting for traditional risk factors like age and hypertension, they had increased risk for subsequent cardiovascular events, including coronary events and heart failure events. So, getting into the pathophysiology, there is this vicious cycle between hyperandrogenism and cardiovascular risk that both we see in PCOS, in reproductive years, and perhaps in the postmenopause years. Now, sympathetic overactivity is associated with abdominal visceral fat. And we know that sympathetic activity is higher in postmenopausal women compared to age-matched men, especially in women who are overweight. They have more impact of obesity than their male counterparts. And so, hyperandrogenism can lead to insulin resistance. Of course, weight gain that can occur after menopause can lead to insulin resistance. This leads to hyperinsulinemia, which then can confer arterial stiffness, sodium retention, and that increased blood pressure. Hyperandrogenism may do this as well. And this may be, you know, the mechanisms of the hypertension risk increasing after menopause. So, you have a vicious cycle of endocrine and metabolic abnormalities that are exacerbated by weight gain that leads to aggravating clinical symptoms and increased cardiovascular risk in women with hyperandrogenism. This slide depicts some of that pathophysiology of how the decline in estrogen at menopause can influence blood pressure. So, we know that androgens increase blood pressure by activating the renin-angiotensin-aldosterone system. And there's a relatively increase in androgen levels post-menopause. And so, thus, there is a relative activation of RAS and higher renin levels in the post-menopausal woman. And this can lead to increase in vasoconstrictors, such as angiotensin 2, endothelial 1, and catecholamines that can up blood pressure. Post-menopausal women also have higher salt sensitivity. They're more sensitive to the influence of salt on blood pressure. As mentioned, they have increased insulin resistance, higher sympathetic activity. Estradiol is associated, can lead to vasodilatation through a nitric oxide effect. And so, post-menopause, with the loss of estrogen, there is reduced vascular nitric oxide availability. And then, the increased weight that we talked about. So, the pre-menopausal cardiovascular effects of estrogen may be in part from this renin-angiotensin-aldosterone system inhibition. Now, this slide kind of depicts what I was just talking about, about sex differences in the development of arterial dysfunction and cardiac complications. And the red arrows indicate mechanisms that are enhanced in females compared to men. So, there's an aging effect on artery stiffness. But this, again, is greater impact in women compared to men. And this can lead to the increased pulse pressure, decreased diastolic blood pressure. And women have increased risk of having left ventricular hypertrophy, that concentric remodeling, and heart failure with preserved ejection fraction. Where men are more likely to have eccentric hypertrophy and heart failure with reduced ejection fraction. Additionally, those are the menopause-related changes I've been discussing. The activation of the renin-angiotensin-aldosterone system, an increase in sympathetic nervous system, the decrease in nitric oxide that leads to increased vascular resistance, microcirculation damage that could impact both kidney health and brain health. As well as, of course, the cardiovascular health. Now, unfortunately, estrogen replacement therapy at menopause does not reverse all this. It's not been shown to be cardioprotective or should not be used for the purposes of cardiovascular disease protection. But it does improve menopausal symptoms. And it's an important strategy for addressing those vasomotor symptoms, those hot flashes and night sweats. But if one's going to use hormone therapy, the dose and duration and formulation matters. In particular, studies such as this, which was from a large administrative data from Canada, showed that oral estrogen hormone therapy was associated with increased risk of hypertension compared to the transdermal estrogen or vaginal estrogens. And we can see this across all the age groups post-menopause that oral estrogen has significantly increased risk of hypertension compared to transdermal estrogen. So, if systemic hormone therapy is being considered, the preference is to use transdermal estrogen to use the lowest dose needed to control symptoms for the shortest duration. Because we do see, even with all the different types of preparations, that the longer a woman's been on estrogen therapy, the increased risk of hypertension. Similar to there's concern with blood pressure elevation with oral contraceptives in women in reproductive years. And so, oral estrogens, we also have to be careful about blood pressure and would be contraindicated in a woman who has uncontrolled hypertension. So, our current approach to menopausal hormone therapy, again, we're not using it for cardiovascular disease prevention, but one should have a cardiovascular risk assessment prior to starting hormone therapy. Generally, hormone therapy is appropriate if a woman's within 10 years of her final menstrual cycle under the age of 60 and actually having vasomotor symptoms. Because that's the indication is to treat vasomotor symptoms. Now, if a woman meets all that and is at low risk, you know, gets a green light for hormone therapy. But hormone therapy is not recommended in women who have established cardiovascular disease, a prior heart attack or stroke, a prior breast or endometrial cancer, who's had a phenothromobolic event, like a pulmonary embolism or a DVT, or uncontrolled hypertension, or if a woman's more than age 60 or more than 10 years out from menopause or very high cardiovascular risk, hormone therapy is not recommended. Now, many women fall in this intermediate group who might have one or two risk factors, such as maybe controlled hypertension or controlled dyslipidemia. And in these situations, it's part of shared decision making, understanding a woman's symptoms from her menopausal symptoms and her cardiovascular risk to come up with a decision about hormone therapy. And if cardiovascular risk is uncertain, sometimes I will get an imaging test like a coronary artery calcium score to help guide risk stratification. So, in conclusion, menopause plays a key role in the lives of women midlife. A woman might spend 40% of her life in menopause. Systolic blood pressure rises more steeply in aging women compared with men, and this may be related to hormone changes during menopause. The decline in estrogen levels around menopause causes an upregulation on the renin-angiotensin-aldosterone system with an increase in plasma renin activity. The decline in estrogen-androgen ratio dilutes or impairs the vasorelaxant effect of estrogens on the vessel wall and promotes the production of vasoconstrictor factors like endothelin. Vasomotor symptoms are associated with increased risk of hypertension and cardiovascular disease. So, ask about that as part of risk assessment, but that doesn't mean that treating with hormone therapy will reduce this risk. If considering hormone therapy, you know, again, it's important that we assess the cardiovascular risk of a woman transitioning through menopause and having menopausal symptoms, prioritizing the treatment of lifestyle factors, treatment of hypertension as a priority, and lipids, and then considering hormone therapy for management of symptoms if a woman is otherwise at low cardiovascular risk. Thank you for your time and for participating in this educational activity.

hypertension

menopause

cardiovascular risk

hormonal changes

estrogen

lifestyle changes