Women Have Been Misled About Heart Disease

Women's unique heart health needs can no longer be ignored

Photo by Debby Hudson on Unsplash

A few years ago, a midlife health coach posted on Instagram about an episode of chest pain that sent her to the ER. After doctors found no blockages, they sent her home.

In my message to her, I explained that the issue might stem from her microvascular system, which is often not associated with obstructive coronary artery disease. Doctors typically check for blockages in the large arteries, but frequently overlook the microvascular system.

I’m not sure if she followed up on this, but it boggles my mind that we still aren’t talking about the elephant in the living room in terms of women’s heart health.

Even prominent doctors, cardiologists, and menopause specialists are in the dark about how women are at increased risk ischemia with no obstructive coronary artery disease (INOCA).

In a 2023 survey of mostly women with INOCA, emergency rooms sent nearly 70% home without treatment, and even more (77.5%) were told their problem wasn’t cardiac related.

Cardiologists diagnosed less than 10% of women at their first visit, and most women visited three cardiologists before they found the problem. These poor women with INOCA lived with symptoms for at least a year before being diagnosed with half experiencing symptoms up to 10 years.

How did we get here? I’m glad you asked.

A man’s disease?

About a century ago, we learned about heart disease. Yet at the time, people considered it a man’s disease. In fact, a woman’s only role was to help the men in her life.

The American Heart Association themed a 1960s conference, “How can I help my husband cope with heart disease?”

When it came to women’s health, doctors focused on the parts under a bikini, a practice referred to as “bikini medicine.”

“It was, ‘Get a pap smear and a mammogram and you’re good,’” said Dr. Gina Lundberg, clinical director of the Emory Woman's Heart Center and a professor at Emory University School of Medicine in Atlanta, in this AHA article. “We left out all the things we were checking men for, like diabetes and cardiovascular disease. But between a woman’s breasts and her reproductive organs is her heart.”

Researchers only began studying how heart disease affects women in the mid-1980s, because the Framingham Heart Study showed sex-specific patterns and highlighted researchers’ previous oversight of women’s roles.

Although there were attempts to include more research for women, it wasn’t until a 2001 report from the Institute of Medicine called for a better understanding of how heart disease affects men and women differently that things changed.

The difference between men and women

Beginning early in life, females and males show significant difference in structure and function of both their hearts and blood vessels.

For instance, women have a smaller blood vessel diameter even after accounting for differences in body size, making them more vulnerable to endothelial dysfunction (cells that line blood vessels) and microvascular remodeling.

Even the way women develop plaque is different. Compared to men, women have more plaque stability, fewer cholesterol crystals, and less lesion calcification. This also means they exhibit more erosion vs eruption, even at younger ages.

Plaque erosion occurs with damage to the endothelial lining. This also ups the risk of stroke because it exposes underlying material like collagen which can trigger platelet activation and formation of clots.

It’s true that young and premenopausal women have an added boost from estrogen to dilate blood vessels via nitric oxide and lower oxidative stress. But this is only part of the story.

Longterm longitudinal studies (10-20 years) reveal a link between lower ovarian reserve measures and worse lipid profiles and cardiovascular risk.

Although ovarian aging can promote endothelial dysfunction, cardiovascular risk can also speed up ovarian aging.

The big picture tells us it’s the “accumulation of hormone mediated effects that begin in early adulthood, accelerate in midlife, and culminate in late life,” as this 2022 review in Circulation Research states.

This framework for considering ovarian aging effects of the cardiovascular system is aligned with the observed steadily progressing subclinical myocardial and vascular changes in aging women that begin their course decades prior to the menopausal transition and then, later on, further increase in rate of development.

Ji et al, 2022, Circulation Research

Types of coronary heart disease

Because men have been the primary focus of research and are more likely to develop obstructive coronary heart disease (CHD), most of the knowledge and training has centered on this condition.

This is when plaque forms on the lining of the coronary arteries, referred to as atherosclerosis.

When 50% or more of an artery is blocked, this is obstructive coronary artery disease. Non-obstructive coronary artery disease means less than 50% blockage.

Ischemia is the reduced blood supply to tissue. This can be because of atherosclerosis or reduced/blocked blood flow in micro vessels, referred to as coronary microvascular disease (CMD).

About 30-50% of women undergoing angiography because of heart-related symptoms don’t have obstructive coronary artery disease. But further testing reveals that 50-65% of them have CMD.

As stated earlier, INOCA is the term most often used to describe these patients. Men are not exempt from this. For instance, according to one study, about 50% of women with INOCA had CMD while 30% of men did.

For years, doctors considered INOCA benign until studies like the WISE study (Women’s Ischemia Syndrome Evaluation) revealed major risks. This prospective cohort comprised 936 symptomatic women who underwent coronary angiography to evaluate symptoms and signs of ischemia.

Researchers followed women (average age of 58) for 10 years. A stunning 20% of the women died, with most of them (13%) having INOCA. Compare that to 2.8% mortality rate in age-matched control women.

INOCA can lead to heart attack (MINOCA) through a blockage of the micro vessels or microvascular spasms. And this is one of the reasons why heart attack symptoms differ between woman and men.

Chest pain affects both men and women; however, women also tend to experience fatigue, anxiety, shortness of breath, nausea, vomiting, upset stomach, and pain in the shoulder, back, or arm.

The heart, brain & body connection

It’s bad enough the toll INOCA takes and is under-recognized, but it’s more far-reaching than that.

Grasping the consequences requires understanding CMD. The micro vessels including arterioles and capillaries are smaller (<500 um diameter) than other major blood vessels. Because they control vascular resistance, we call them “resistance arteries”.

This means when everything is going right and there’s increased demand, the vessels dilate (by secreting nitric oxide), playing a key role in blood flow throughout the circulatory system, including the heart. When they can’t dilate fully, there’s a problem.

Not just in the heart, but also and brain.

That’s because the heart and brain share similar anatomy with arteries that divide into a tiny network, regulating blood flow. When this becomes compromised in the brain, it is referred to as cerebrovascular small vessel disease (CSVD). We also know that CMD and CSVD have been linked.

According to a 2023 review study, CSVD is responsible for 45% of dementias and 25% of ischemic strokes. And guess who gets dementia more often? Women!

What makes matters worse is that CMD is the breeding ground for other diseases found more frequently in women. Besides CSVD, there’s heart failure with preserved ejection fraction, Takotsubo cardiomyopathy, pulmonary arterial hypertension (PAH), endothelial dysfunction in diabetes, diabetic cardiomyopathy, rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis.

This starts earlier than we think with adverse pregnancy outcomes like pre-eclampsia, autoimmune disorders, thyroid dysfunction, and PCOS all linked to CMD.

Not only that, in a 2017 study in Menopause, women age 40-53 with more frequent hot flashes had poorer endothelial health, the primary cause of CMD.

“Hot flashes are not just a nuisance,” said Dr JoAnn Pinkerton, former executive director of the North American Menopause Society on Contemporary Clinic. “They have been linked to cardiovascular, bone, and brain health. In this study, physiologically measured hot flashes appear linked to cardiovascular changes occurring early during the menopause transition.”

To learn more about endothelial health, read The Game-Changing One Health Principle for Women Over 40

Diagnosis and treatment

Recent studies, including WISE and CorMicA (Coronary Microvascular Angina), led to the inclusion of INOCA in the 2021 chest pain guidelines. FINALLY!

According to the guidelines, high-risk populations are women, people with hypertension, diabetes, and insulin resistance.

Invasive testing such as cardiac catheterization with acetylcholine, is a class 2A recommendation that can also diagnose microvascular spasm.

Beyond invasive functional testing, the 2021 US chest pain INOCA guidelines recommend PET scanning, cardiac MRI, and stress echocardiography.

There is substantive evidence that testing focusing on documentation of coronary or microvascular flow abnormalities can aid in the diagnosis of microvascular angina, and abundant evidence supports that the addition of flow alterations improves risk stratification.

- 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain

But just because there are guidelines doesn’t mean everyone is following them. The INOCA survey showed doctors informed most women that their chest pain was non-cardiac and also conducted noninvasive testing on them.

“These findings are particularly bothersome and underscore the importance of educating the community of physicians caring for patients with chest pain,” said Jacqueline E. Tamis-Holland, MD from Mount Sinai Morningside Hospital, New York, NY, in this piece on tctMD. “If all cardiologists and internal medicine doctors recognized this syndrome, then patients may receive a proper diagnosis and treatment earlier in their clinical course. Until then, many patients will continue to go undiagnosed.”

And what about treatments? There are none except to give statins and ACE inhibitors, which help quality of life but lack of evidence on outcomes. Researchers are looking into treatment options.

What about hormone therapy?

The assumption has always been that because estrogen helps large blood vessels dilate, it has the same effect in the microvasculature; however, limited research suggests this may not always hold true, particularly for women with compromised function.

While some older studies examined hormone therapy’s effect on the microvasculature, it isn’t a common area of research. In fact, the KEEPS trial which compared CEE oral estrogen to transdermal estradiol measured CIMT, a measure of atherosclerosis.

Ughh!

I keep coming back to the research being done at the Freed lab.

Flow mediated dilation is used to measure nitric-oxide driven dilation in large arteries but not small arteries or arterioles. In fact, unlike large arteries, arterioles can switch from nitric oxide to hydrogen peroxide (H202) for vasodilation.

Prolonged H2O2 can create a proinflammatory and pro-thrombotic environment, which affects the one health principle for midlife women.

Estrogen use in post-menopausal women has been shown to maintain or improve arteriole blood flow, but only in those free of risk factors. What gives?

In its first-of-its kind study published in 2023, Freed and colleagues used isolated human arterioles and found that females (30-78 years old) exposed to 100nM of estrogen–considered an elevated dose–revealed a switch from NO to H202 in all the arterioles.

The women with coronary artery disease showed a trend toward reduced microvascular blood flow. But in cis males, there was a significant reduction.

I interviewed the lead researcher, Julie Freed, about this study and her work on the microvascular system. And her lab plans to do more studies to get answers, since this work is very preliminary.

I can’t help but wonder if problems in the micro vessels—something rarely checked — puts women at more risk on certain types or doses of hormone therapy.

Is a similar process observed in women experiencing preeclampsia during pregnancy’s hormonal surge?

Summary

Half of women with chest pain are found to have ischemia with no obstructive coronary artery disease (INOCA). However, they are often misdiagnosed or dismissed because heart disease was historically seen as a man's issue, with more targeted research on women only beginning in the 2000s.

INOCA is typically caused by coronary microvascular disease (CMD), which affects smaller heart vessels and is linked to higher risks of heart attacks and mortality in women. Symptoms, such as fatigue, nausea, and shortness of breath, differ from men’s, and women’s smaller blood vessels make them more prone to endothelial dysfunction and microvascular issues.

Women are also more likely to experience plaque erosion, increasing stroke risk. CMD can affect the brain, leading to conditions like cerebrovascular small vessel disease (CSVD), which raises the risk of dementia and ischemic strokes. It is also linked to other women-centric diseases like heart failure with preserved ejection fraction, autoimmune disorders, and pre-eclampsia. Estrogen’s impact on microvascular health remains debated, as it may not benefit women with preexisting issues.

The 2021 chest pain guidelines now include INOCA, recommending invasive, MRI, PET scans, and stress echocardiography tests. Despite this, many women are still misdiagnosed due to a lack of awareness, and treatment options like statins and ACE inhibitors lack solid evidence for CMD outcomes.

Where are all the experts?

I can’t help but wonder why menopause specialists and cardiologists - with their gigantic platforms - aren’t talking about this.

I just got an email about heart disease from Mary Claire Haver’s The Pause. No mention of CMD and special risk to women.

Jen Gunter had on cardiologist Danielle Belardo to discuss statins in women’s health and no mention of CMD. The focus? Atherosclerotic vascular disease.

Statins ARE Recommended for Women

Not even Peter Attia, who often covers a vast range of co-morbidities with regard to heart disease. (I could’ve missed it but a google search brought nothing up).

With menopause receiving increased attention, specialists, including the Menopause Society, have a crucial role in raising awareness of INOCA in women and advocating for more research into risk reduction, treatments, and optimized hormone therapy.

Not to mention the oh-so-important link to brain health and hot flashes as a cardiovascular risk factor.

And coronary calcium score is not the sole answer because it does not detect CMD, only plaque build up in the large arteries.

One thing is for sure, women deserve much better than they are getting and it’s time everyone catches up to their unique heart and vascular health needs. Twenty five years of examining the heart health needs of women is a blink of an eye in medical years.

The narrative that women are protected of heart disease until menopause - where hormones save the day - has lots of holes in it. We need more research and we need it now. Lives literally depend on it.