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.

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.

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."

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.

References

1. Biwer LA, Lu C, Ibarrola J, et al. Smooth muscle mineralocorticoid receptor promotes hypertension after preeclampsia. Circ Res 2023;132:674-89.
2. 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.
3. Honigberg MC, Zekavat SM, Niroula A, et al. Premature menopause, clonal hematopoiesis, and coronary artery disease in postmenopausal women. Circulation 2021;143:410-23.