Feature | Cardiovascular Disease in Women: From Maternal Health to Menopause
It seems the cardiology world is at an inflection point in women's heart health where the specific issues for women are increasingly being researched, discussed and (hopefully) addressed and managed.
Perhaps the most salient change, one many feel is long overdue, is that women's health across the spectrum – crucially including the reproductive period and menopause transition – is increasingly recognized as a unique topic deserving of funding, research and focused management.
Women's heart health got top billing at ACC.23/WCC, with a Keynote and sessions devoted to the influence of menstrual and reproductive histories on the development of cardiovascular disease. Here are highlights from the Keynote and a handful of these sessions.
Keynote: Toward Precision Prevention of CVD in Women
"We need to stop ignoring overt cardiovascular and cardiometabolic risk in young adults and effect a paradigm shift from the arbitrary focus on 10-year risk to a lifetime risk horizon," said Michael C. Honigberg, MD, MPP, FACC, in his Douglas P. Zipes Distinguished Awardee Keynote. He is a preventive cardiologist and physician-scientist at Massachusetts General Hospital and an assistant professor at Harvard Medical School.
"Historically, we've assumed that young patients are at low risk of cardiovascular disease on the basis of being young. And we especially assume that about female patients," he said, citing the recent Women in Cardiovascular Disease Commission report in the Lancet on reducing the global burden of cardiovascular disease in women by 2030, which stated it is "understudied, under-recognized, under-diagnosed and undertreated."
Also needed is a better understanding of the sex-specific mechanisms in the pathophysiology and natural history of cardiovascular disease. The few data available indicate that myocardial infarction (MI) and cardiovascular mortality are increasing among young women.
"We've increasingly come to appreciate that reproductive history reveals or influences later life risk of cardiovascular disease in multiple respects, spanning earlier or late age of menarche, menstrual irregularity and polycystic ovary syndrome, infertility, adverse pregnancy outcomes, parity, breastfeeding, and various aspects of the menopause transition," said Honigberg.
Pregnancy and CVD
Recent U.S. data indicate that 15% of childbearing women experience a hypertensive complication in at least one pregnancy. On a global scale, hypertensive disorders of pregnancy (HDPs) are a leading cause of maternal and fetal morbidity and mortality.
The term HDPs covers a spectrum of pregnancy complications, including gestational hypertension, preeclampsia, HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome and eclampsia. Some also include chronic hypertension before pregnancy.
The pathophysiology of preeclampsia begins early in gestation with impaired trophoblast invasion of the uterine wall and abnormal remodeling of the maternal spiral arteries. Later in gestation, this leads to placental malperfusion and placental hypoxia, which in turn leads to an imbalance and an excess in circulating maternal anti-angiogenic factors such as sFlt-1. These anti-angiogenic factors antagonize the endothelium and lead to the syndrome of maternal systemic endothelial dysfunction that characterizes preeclampsia.
The few data available indicate that myocardial infarction and cardiovascular mortality are increasing among young women.
– Michael C. Honigberg, MD, MPP, FACC
Clinical risk factors for preeclampsia include pre-pregnancy chronic hypertension, obesity, diabetes and autoimmune disease. "But most women who experience these conditions don't have overt pre-pregnancy risk factors. Indeed, nulliparity confers the highest population attributable risk," noted Honigberg.
Evidence-based prevention of preeclampsia in 2023 includes low-dose aspirin beginning after 12 weeks' gestation, aimed at preventing preterm preeclampsia. Data from the CHAP trial at ACC.22 showed that treating chronic hypertension in pregnancy to a target <140/90 mm Hg improves birth outcomes and reduces the rate of preeclampsia with severe features.
Randomized evidence also supports the possibility that metformin may decrease the risk of preeclampsia in pregnant persons with obesity without diabetes. Observational data suggest weight loss before conception may help prevent preeclampsia, but this has not been tested prospectively.
The prevalence of HDP and chronic hypertension in pregnancy is increasing. "It's not entirely surprising, therefore, that these cardiometabolic factors in pregnancy and afterward lead to a syndrome of accelerated cardiovascular aging in these women," said Honigberg.
Using UK Biobank data, Honigberg, et al., found that women with a history of hypertension in pregnancy had an 80% increased risk for incident coronary heart disease, 70% increased risk of incident heart failure, "and to our great surprise, also increased risks of aortic stenosis and mitral regurgitation, leading us to hypothesize that this is really a syndrome of pan-accelerated cardiovascular aging in this population."
The risks are even more augmented in women who experience recurrent hypertension in pregnancy, or whose first hypertensive complication is so severe they don't have more children.
It has been hypothesized that heart failure with preserved ejection (HFpEF) is the predominant phenotype of heart failure in this population, owing to the overlapping cardiometabolic risk profile between the hypertensive disorders and HFpEF. Support for this comes from two studies in 2021 showing an approximately twofold higher risk of HFpEF in women with a history of preeclampsia. While there was an increase in heart failure with reduced ejection fraction (HFrEF), it was less marked.
How Might Preeclampsia Accelerate CVD?
The progression from preeclampsia to chronic hypertension explains about two-thirds of the excess risk of coronary disease and about half the risk of HF, according to a causal mediation analysis of UK Biobank data conducted by Honigberg's team.
Cardio-Ovary: CV Risk Markers
Cardiovascular disease remains the leading cause of death in women and myocardial infarction is on the rise in women under age 45, both indicating that more attention needs to be paid to younger women who were once thought to be universally low risk. This starts with working towards a better understanding of female-specific factors related to menarche, hormones and pregnancy, plus obtaining a routine and comprehensive assessment of reproductive history in all female patients as part of standard cardiovascular risk assessment, said Erin D. Michos, MD, FACC, at ACC.23/WCC.
Women with menarche before age 12 tend to have worse cardiometabolic health in middle age, with higher waist circumference and body mass index (BMI), and more hypertension, hyperlipidemia and diabetes. In fact, there is a clear U-shaped relationship between menarche age and cardiovascular risk (after adjustment), with both early and late menarche (after age 16) associated with increased risk of cardiovascular disease later in life. "Very few cardiologists ever ask their patients about their onset of menarche, but should, said Michos."
Further along, polycystic ovary syndrome (PCOS), which affects one in 10 women, also increases cardiovascular risk. PCOS is the most common cause of infertility and subfertility and the most common antecedent cause (after obesity and family history) of type 2 diabetes in reproductive age women. It is also associated with anxiety, depression, obesity, endometrial cancer and liver disease.
In women with PCOS, there is a threefold increased risk for type 2 diabetes and up to a twofold increased risk for cardiovascular disease. In a meta-analysis, women with PCOS (average age, 40 years) were twofold more likely to have incident coronary calcium compared to BMI-matched controls, an increase driven in part by cardiometabolic risk factors. Interestingly, once a woman has made it to age 50 free of cardiovascular disease, having a history of PCOS doesn't seem to carry excess risk.
Women with PCOS are also at increased risk of cardiovascular complications during pregnancy and delivery, including preeclampsia and gestational diabetes, but also HF and peripartum cardiomyopathy. Monitoring during pregnancy is needed to evaluate for potential cardiovascular complications.
Cardiologists have a role in the management of PCOS in terms of helping these women attain an optimal heart-healthy lifestyle, as well as manage their cardiovascular risk. Oral contraceptives are first-line therapy that address both androgen excess and irregular menstrual cycles. Spironolactone can be added for its antiandrogen effects. These women should also be considered for insulin sensitizers, like metformin, and for weight management with GLP-1 receptor agonists, or an SGLT2 inhibitor if they have diabetes. Statin therapy is indicated if their LDL-C is high and a coronary artery calcium score might be helpful to better classify risk after age 40.
Lau, et al., found that infertility is associated with future HFpEF, but not HFrEF. Many women with infertility are using assisted reproductive technology (ART) to help achieve pregnancy, which also has been associated with some risk. This is not to say that ART should be avoided, but rather to increase awareness that these women may be at increased cardiovascular risk and should be helped to optimize their cardiovascular health before, during and after pregnancy.
And finally, in the Nurses' Health Study, spontaneous pregnancy loss was associated with a 21% increased risk of cardiovascular disease after adjusting for risk factors. As well, parity, or the number of live births, has been associated with later cardiovascular disease. More than five live births were associated with worse cardiometabolic health later in life in the MESA study, possibly linked to increased androgens. Breastfeeding is possibly protective against cardiovascular disease, but this comes from observational data that could be confounded.
Further work by his group, using Mendelian randomization, found significant genetic associations between both systolic and diastolic blood pressure as well as body mass index with the risk of HDPs. This finding has been replicated several times.
A genome-wide association study conducted in Honigberg's lab – the first of its kind for gestational hypertension – revealed a strong association between 18 locations in the genome and gestational hypertension and/or preeclampsia, with genome-wide statistical significance. Most of the locations were novel.
The pathways and processes they identified include angiogenesis, "which fits with what we know about the biology of preeclampsia," he noted, along with immune dysregulation, renal glomerular function, natriuretic peptide signaling, hormonal signaling and vascular tone, and trophoblast development and maintenance. The natriuretic peptide signaling could yield insights into shared genetic risk between hypertensive pregnancy complications and genetic predispositions of HF.
Is Preeclampsia Causal For CVD?
Genetic analyses also can provide insights into whether preeclampsia is a cause or a marker for cardiovascular disease.
A phenome-wide association study from Honigberg's lab found a "very, very strong genetic association" between the genetic risk of preeclampsia and risk of hypertension, along with ischemic heart disease, HF, diabetes and dyslipidemia.
Perhaps the best evidence so far connecting preeclampsia and accelerated vascular aging and disease comes from a study by Biwer, et al., published this year.1 In a mouse model of preeclampsia exposed to the anti-angiogenic factor, sFlt-1, they found enhanced smooth muscle cell mineralocorticoid receptor in response to pro-hypertensive stimuli like a salt load, as well as increased microvascular constriction in the mesenteric vasculature. "This is by far the most compelling evidence today if there is indeed a causal effect of this transient exposure to later life cardiovascular disease. And it comports with some analyses we did using the UK Biobank database leveraging machine learning," said Honigberg.
CHIPping Away at the Genetics of the Early Menopause-CVD Link
Recognizing that estrogen deficiency does not explain everything happening in menopause, Honigberg's group has looked to human genetics to better understand premature and early age menopause. This led them to CHIP, or 'clonal hematopoiesis of indeterminate potential.'
If premature menopause was a sort of syndrome of genomic instability, they wondered, are there genomic conditions that might be linked to it and to cardiovascular disease?
CHIP is an age-related hematologic condition characterized by the expansion of hematopoietic cells harboring mutations associated with the future development of leukemia, resulting in the selection and expansion of a genetically distinct subpopulation of blood cells. It's defined as a prevalence of these acquired mutations in ≥2% of circulating white blood cells (variant allele fraction ≥2%). The genes most commonly mutated in clonal hematopoiesis are the epigenetic regulators DNMT3A, TET2, and ASXL1.
CHIP is common, detectable in otherwise healthy people through next-generation sequencing of blood DNA in up to 10% of adults >70 years and nearly 20% of adults >90 years. It's been linked to increased risk for hematological cancers, coronary artery disease, heart failure, stroke, chronic obstructive pulmonary disease, osteoporosis and all-cause mortality.
"CHIP is something you're going to be hearing a lot more about in the coming years, so this is one to pay attention to," said Honigberg.
Unsurprisingly, CHIP is associated with an 11-fold risk of blood cancer (but only an absolute risk of <1% per year given the rarity of blood cancers). More important to cardiologists is that CHIP is associated with a 1.5- to twofold risk of coronary heart disease and a fourfold risk of early onset MI.
"Mouse experiments strongly support a causal relationship for accelerated or aggravated atherosclerosis in individuals with CHIP. And CHIP-directed precision therapeutics targeting inflammatory pathways are currently in development as we believe that inflammation primarily mediates this relationship."
Menopause Transitions and Hormone Replacement
With rising life expectancies, most women today will spend up to 40% of their lives in menopause – a time of accelerating cardiovascular disease risk, said Emily S. Lau, MD, MPH, FACC, at ACC.23/WCC. Greater awareness of this risk is needed among patients and cardiovascular clinicians, as well as more aggressive management of risk factors in peri- and postmenopausal women.
During the menopause transition, a number of adverse changes in cardiometabolic health occur that are linked to subclinical cardiovascular disease, including changes in several lipid and lipoprotein measures, and changes in body composition, including a sharp increase in visceral adipose tissue.
Low levels of ovarian estrogen have long been hypothesized to explain these adverse changes in cardiometabolic health, a hypothesis challenged by the landmark WHI and HERS trials, which showed that administration of estrogen therapy for both the primary and secondary prevention of cardiovascular disease did not reduce cardiovascular events. In fact, paradoxically, cardiovascular events increased in the WHI study.
It's now understood the story is more complicated. The cardiovascular effects of menopausal hormone therapy (MHT) appear to be influenced by the timing of initiation. When initiated earlier, <10 years post menopause and <60 years old, MHT appears to reduce coronary heart disease risk by roughly 50% and all-cause mortality by 30%. In contrast, in older women farther out from menopause, MHT appears to have no effect on coronary heart disease or all-cause mortality.
Two randomized trials have tested this so-called 'timing hypothesis' by examining the effect of MHT on subclinical cardiovascular disease in younger postmenopausal women. In the KEEPS trial, no significant increase in carotid intimate media thickness (CIMT) was seen with MHT when given to women less than three years postmenopause. In ELITE, low-dose oral estradiol reduced CIMT progression in women less than six years postmenopause, but not in women who were >10 years postmenopause.
Even with this newer data, HRT is only prescribed to about 3-4% of peri- and postmenopausal women in the U.S. today.
Lau's group looked at differences in 71 cardiovascular biomarkers between pre- and postmenopausal women and found that the profiles of postmenopausal women closely resemble those of men. Interestingly, administration of MHT rescued the premenopausal biomarker phenotype. In other words, the biomarker profile of postmenopausal women taking MHT looked more like that of premenopausal women.
Hormone Therapy in 2023
MHT is approved by the U.S. Food and Drug Administration for four indications: relief of vasomotor symptoms, prevention of osteoporosis, premature hypoestrogenism and vulvovaginal atrophy.
MHT usually consists of either estrogen alone for women without a uterus or estrogen plus progestin for women with an intact uterus. Oral and transdermal estrogen are considered systemic hormone therapy and have similar efficacy profiles, but the safety profile is somewhat superior with transdermal estrogen. Vaginal estrogen is minimally absorbed and primarily used for the local treatment of vulvovaginal atrophy.
The role of the cardiovascular clinician in prescribing MHT is to determine whether MHT is safe for an individual with one of the four approved indications. This requires assessing the number of years since menopause onset and 10-year ASCVD risk. For women <10 years postmenopause and at low ASCVD risk, MHT is considered to be quite safe, said Lau.
For women <10 years postmenopause with intermediate ASCVD risk, MHT is thought to be safe, but the transdermal formulation is recommended. And for women >10 years postmenopause and either low or intermediate ASCVD risk, consider other alternatives like SSRIs. However, if the patient has severe vasomotor symptoms, an individualized shared decision-making discussion is warranted. For women with high (>10%) ASCVD risk, avoiding MHT is recommended.
This belief, he added, received support from a recent post-hoc subgroup analysis from the CANTOS trial (testing canakinumab in secondary prevention patients with elevated C-reactive protein) which showed that in individuals who had TET2 CHIPs, specifically, the derived benefit from canakinumab treatment was markedly greater than in the overall population (hazard ratio, 0.38 vs. 0.86 overall and 0.93 in patients without CHIP).2
As it turns out, CHIP is more prevalent among women who experience premature menopause. Honigberg's group published an analysis in 2021 using the UK Biobank and Women's Health Initiative (WHI) database and showed that the overall pooled prevalence of CHIP was 8.8% among women with a history of premature menopause vs. 5.5% among women without (p<0.001).3
"In adjusted models where we stratified premature menopause by natural vs. surgical, we observed statistically significant increased odds of CHIP in women with natural or spontaneous premature menopause, but not surgical premature menopause," said Honigberg. "This was not what we expected and suggests there's something other than postmenopausal hormone deficiency driving this relationship. In fact, predilection to develop CHIP may be an upstream risk factor for both conditions."
They also showed that CHIP is an independent risk factor for incident coronary disease in this postmenopausal middle-aged population, with a hazard ratio of 1.52 across cohorts.
"Premature menopause represents an opportunity for early primordial and primary prevention and possibly also novel precision prevention strategies."
Moving the Needle on Women's Heart Health
"Preeclampsia and other HDPs are a 'red flag' of maternal CVD risk," said Honigberg. Chronic hypertension and accelerated microvascular aging are key mediators, but likely not the only mediators.
Scientific statements advise frequent monitoring of cardiovascular disease risk factors in the first year postpartum and transitioning to longitudinal primary care for women with HDPs, offering an opportunity for early prevention. Unfortunately, up to half of women with severe preeclampsia are lost to follow-up in the early postpartum period.
Later in life, cholesterol and primary prevention guidelines include preeclampsia and other adverse pregnancy outcomes as risk-enhancing factors in individuals at borderline and intermediate risk for atherosclerotic cardiovascular disease.
As a preventive cardiologist and researcher of women's heart health, Honigberg had several suggestions for moving the needle to advance their care.
"I think the selection of this topic and this talk for the Zipes Keynote represents a growing recognition in the field of cardiology that women's heart health is important, historically neglected and understudied, and we need to play catch up."
Along with the need to deepen mechanistic knowledge and more, he stated that a WHI study is needed of women of reproductive age. At a practical level, health promotion needs to move outside the clinic, recognizing that most patients, especially young ones, spend very little time there.
Importantly, teamwork is needed to move the needle. "We need engagement with our primary care colleagues, endocrinology colleagues and OB-GYN colleagues on this," said Honigberg.
The Reproductive Years: Impacting Future Cardiovascular Health
A woman's reproductive years may influence her future cardiovascular health, especially for those who experience pregnancy. Therefore, a very detailed maternal health history is needed for all women, expanding beyond the usual medical history, said Rachel M. Bond, MD, FACC, at ACC.23/WCC.
While a steady decline in cardiovascular death rates has been seen for women >65 years and slow but steady declines in those aged 55 to 65, the rates have not declined in women aged 25 to 54. Furthermore, 80% of one's health status is dictated by social determinants of health, including the social constructs of race and socioeconomic status. Accordingly, among women aged 25 to 54 years, women from Black and Latina communities experience the highest rates of cardiovascular disease and mortality.
Moreover, disparities in utilization of guideline-directed strategies and care across all forms of cardiovascular disease heavily impact these groups. And in this population, the evidence is limited to inform guideline-directed therapy because of the persistent underrepresentation of women in research trials, particularly minority women, women of reproductive age and women who are pregnant.
Every woman should be screened for their cardiometabolic risk during their reproductive years, targeting those at greatest risk.
– Rachel M. Bond, MD, FACC
Awareness that cardiovascular disease is the leading cause of death in women is lacking among women themselves. A 2009 survey conducted by the American Heart Association showed that 65% of women knew that heart disease was their greatest threat. By 2019, that figure had dropped to 44%, with the lowest awareness among women aged 25 to 34 who identified as either Latina or Black.
This lack of awareness extends to primary care and cardiovascular clinicians. Only 22% and 42%, respectively, report they are well prepared to assess cardiovascular disease risk. Only 39% of primary care clinicians make cardiovascular disease their top priority.
A key factor in poor cardiovascular outcomes in women is not understanding how the identification of sex-specific and female-predominant risk factors, including adverse pregnancy outcomes, can influence cardiovascular disease.
Pre-pregnancy cardiovascular health is associated with an increased risk of adverse pregnancy outcomes. Diabetes, smoking, overweight and obesity, being physically inactive, hypertension and dyslipidemia all put women at higher risk of maternal health complications. Additionally, pre-pregnancy counseling is scarce and about 45% of pregnancies are unintended or unplanned, so opportunities to intervene and optimize health prior to pregnancy are few, leaving women at greater risk for adverse outcomes like preeclampsia, which is the leading cause of maternal morbidity.
Adverse pregnancy outcomes impact cardiovascular disease years down the line. For example, gestational diabetes leads to a sevenfold greater risk of transitioning to diabetes – and increases the risk for cardiovascular disease by nearly twofold.
As a first step in combating all this, every woman should be screened for their cardiometabolic risk during their reproductive years, targeting those at greatest risk, that is, the more disenfranchised populations based on race and ethnic group.
Risk stratification enables early identification of sex-specific risk factors, and traditional risk factors that can be targeted for prevention. When estimating risk, Bond cautioned, be aware that guidelines consider adverse pregnancy outcomes as "risk enhancers," but that risk assessment tools like the ACC ASCVD Risk Estimator Plus app do not include these factors.
Research is needed to determine how to best stratify women who may have encountered an adverse pregnancy outcome beyond the standardized approach, including whether coronary artery calcium scoring should be offered to reclassify risk. Indeed, more research is needed overall about women and heart disease, which is exacting a greater toll on younger and younger women. Pregnancy is a window to a woman's future health that can no longer be ignored.
Elevated hs-cTnI Precedes Development of Preeclampsia
A multicenter observational study presented at ACC.23/WCC found that elevated levels of high-sensitivity cardiac troponin I (hs-cTnI) appear to precede and may predict the development of preeclampsia, a condition that complicates roughly 2-8% of all pregnancies and is a growing health problem.
Dirk Westermann, MD, PhD, et al., pooled four international, prospective cohorts including 2,293 pregnant women and divided them according to gestational weeks (14, 22 and 29 weeks). The STAT hs-TnI ABBott Architect 12000 assay was used to test for hs-cTnI.
Overall, the prevalence of preeclampsia was 7.8% in the pooled cohort and 0.9% for severe early-onset preeclampsia (requiring delivery before 34 weeks). Using the NICE criteria, a priori risk was seen in 17.3%. cTnI was higher in patients who developed preeclampsia beginning from gestation week 14, compared with those who did not. The differences were statistically significant at weeks 14 and 22, but less apparent for week 28. Differences in cTnI were even more pronounced in patients who developed severe early-onset preeclampsia.
In the receiver operating characteristic curve analysis, the area under the curve (AUC) at 14 weeks was 0.72, rising to 0.77 at 22 weeks. For severe disease, the AUCs ranged from 0.82 to 0.91. Of note, negative predictive value, the biomarkers ability to rule out preeclampsia, was 100% in a group of women considered to be at high risk for the disease. Further study is needed to test whether troponins can be used to triage at-risk patients to preventive therapies.
Become A Part of ACC's Newest Member Section
ACC's Reproductive Health and Cardio-Obstetrics Member Section was created to respond to the public health crisis of maternal morbidity and mortality, say Natalie Ann Bello, MD, FACC, and Ki Park, MD, FACC, co-chairs of the Section, which had its inaugural meeting during ACC.23/WCC.
The Section's mission is to address identified needs and gaps across the domains of clinical care, education, training and mentorship, research and public policy. "A true team-based approach to improving patient care is needed," they say. "This Section will serve as a home to both cardiovascular specialists and noncardiology clinicians and promote collaborative efforts within the ACC as well as between other societies within the House of Medicine to improve cardiovascular outcomes related to reproductive health and cardio-obstetrics."
Click here to learn more and join.
ACC Anywhere Opens the Door to Learn More
Dive deeper into these sessions and more from ACC.23/WCC with ACC Anywhere, a comprehensive library of ACC's in-person and virtual courses. Visit ACC.org/ACCAnywhere to learn more and get started viewing presentations today.
This article was authored by Debra L. Beck, MSc.
- Biwer LA, Lu C, Ibarrola J, et al. Smooth muscle mineralocorticoid receptor promotes hypertension after preeclampsia. Circ Res 2023;132:674-89.
- Svensson EC, Madar A, Campbell CD, et al. TET2-driven clonal hematopoiesis and response to canakinumab: An exploratory analysis of the CANTOS trial. JAMA Cardiology 2022;7:521-28.
- Honigberg MC, Zekavat SM, Niroula A, et al. Premature menopause, clonal hematopoiesis, and coronary artery disease in postmenopausal women. Circulation 2021;143:410-23.
Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Valvular Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Genetic Arrhythmic Conditions, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension, Mitral Regurgitation
Keywords: ACC Publications, Cardiology Magazine, ACC Annual Scientific Session, ACC23, Cardiovascular Diseases, Menopause, Reproductive History, Cardiovascular System, Cardiology, Pregnancy, Menarche, Polycystic Ovary Syndrome, Cardiologists, Breast Feeding, Risk Factors, Hypertension, Menstruation Disturbances, Infertility, Infarction, Eclampsia, Pre-Eclampsia, HELLP Syndrome, Metformin, Mitral Valve Insufficiency, Hemolysis, Biological Specimen Banks, Stroke Volume, Stroke Volume, Trophoblasts, Hypertension, Pregnancy-Induced, Endothelium, Autoimmune Diseases, Coronary Disease, Liver, Acute Coronary Syndrome, Body Mass Index, Genome-Wide Association Study, Natriuretic Peptides, Heart Failure, Receptors, Mineralocorticoid, Metabolic Syndrome, Diabetes Mellitus, Myocytes, Smooth Muscle, Clonal Hematopoiesis, C-Reactive Protein, Alleles, Aneurysm, Prevalence, Coronary Artery Disease, Postmenopause, Menopause, Premature, Genomics, Atherosclerosis, Genomic Instability, Mutation, Inflammation, Osteoporosis, Pulmonary Disease, Chronic Obstructive
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