Heart disease has long been the leading killer of adults, but beyond that stark fact, men and women diverge.
From differences at the cellular level of the heart to circulatory structure to symptoms of distress and treatment, researchers are finding new manifestations of gender differences in cardiovascular disease.
Heart attacks look different in women than in stereotypically chest-clutching men, sending more diffuse pain shooting through the jaw, neck, arm, back, stomach, and more, all in ways that don’t scream “call 911.” Even where in the body a heart attack blocks blood flow is different: Microvessels in women get jammed, but it’s the larger arteries in men that starve the heart of oxygen.
The number and function of muscle cells in the heart differ, too. Women’s hearts have more cardiomyocytes than men, and their fuel tends to be more fatty acids as opposed to the sugars that male muscle cells prefer to burn, new research reveals.
All these differences have implications for diagnosis and treatment of cardiovascular disease.
Yet it is not lost on researchers that the nuances of women’s physiology have taken decades to be uncovered, and that now, any research on gender differences faces special scrutiny or roadblocks by the Trump administration.
“I think part of the reason, perhaps, that we don’t have the studies in sex differences or cardiovascular disease in women is because there aren’t enough women researchers and women in leadership,” said Esther Kim, chair of cardiovascular medicine at Wake Forest University School of Medicine and leader of an American Heart Association writing group that earlier this month issued a scientific statement on sex differences in peripheral vascular disease.
That statement has long been in the works.
“This was not some sort of rush job in response to the current administration at all. It’s unfortunate that we have to think about things like that even when this goes out,” she said. “But, you know, it’s science. Women deserve better and women deserve more.”
At a moment when research into women’s health is under threat in the United States as a casualty of outlawed diversity efforts, learning more about the basic biology and the clinical outcomes of disease takes on more urgency.
“Sex and gender should not just be a niche specialist area of science, but something that all scientists who study animals or humans or cells have to consider,” Madeline Wood Alexander, a Ph.D. student at the University of Toronto and Sunnybrook Research Institute whose paper was recently published in a special issue of Science Advances exploring women’s health. “In the current political climate, we need to be doing better, and to be a good scientist is to consider all of the factors that contribute to health and disease outcomes. And really, the bare minimum is considering sex differences in 50% of the population that has been historically understudied.”
Studying that half of the population means unraveling societal influences as well as more basic variations under the microscope that may exist along with broader influences.
“When we think about male-female differences in, for example, heart disease, we can quite rightly focus on things like access to care and differences in symptoms and issues of health equity,” said David Page, member of the Whitehead Institute for Biomedical Research and MIT professor of biology. “I don’t mean to deny the relevance of any of those. I mean to add another consideration: There can exist fundamental biochemical or molecular differences between male and female cells of the same type and tissues of the same type prior to any disease process.”
Vascular variance
Evidence has built in recent years of significant gender differences in how vascular diseases strike the blood vessels, from risk factors to diagnosis, treatment, and outcomes. The need to better recognize those variations led to the new American Heart Association guidelines delineating what is and isn’t the same in diseases cropping up in the peripheral arteries, including the aorta and its branch vessels.
TV commercials hammer us about heart attacks and strokes, said Kim, who is also director of the Center for Women’s Cardiovascular Health at Atrium Health in Charlotte, N.C. But few ads talk about aneurysm rupture (when a weakened blood vessel bursts open) or claudication (the cramping leg pain caused by narrowed arteries).
It’s worse for women looking for a solution to their vascular pain. Some examples:
Peripheral vascular disease: “Patients may present in a, quote, atypical manner, compared to the man,” said Kim. “It’s not the classic leg pain when you walk that goes away with rest that we learn in medical school. It could be pain at rest. It could be pain that occurs with exertion, but we can work through it. And that may be different than in men.”
If their subtle or “atypical” symptoms are missed or diagnosed only after a delay, women can miss out on treatment and fare worse, only able to walk more slowly and for shorter distances. In another disparity, a Black woman’s lifetime risk of 27.6% is higher than a white woman’s risk of 19%, yet chances are lower for a Black woman to receive recommended treatment, the AHA determined in 2024.
Diseases affecting the aorta: It’s the largest artery in the body and the one that delivers blood from the heart to the body. For aortic diseases, women are diagnosed later in life and at a more severe stage of disease. While estrogen protects the aorta from aneurysms, when one occurs it’s more severe than in men. Ruptures are three times more likely in women with an aneurysm the same size as a man’s.
If a woman is treated with a minimally invasive procedure, her chances of dying or having a stroke are higher. Screening guidelines for aortic aneurysms recommend lower repair thresholds for women than for men, but these thresholds may not fully reflect women’s unique risk factors, the AHA statement says.
Carotid artery disease: That’s the blood vessel snaking up your neck to the brain. When its walls are blocked by fatty plaque, it can lead to a stroke, but treatment options and outcomes are different for men and women. Preeclampsia, which is dangerously high blood pressure during pregnancy, as well as older age at menopause and estrogen therapy are risk factors for women. But studies have shown that men have bleeding with these fatty deposits at higher rates than women, elevating the stroke risk for men.
Vasculitis: An autoimmune disease that causes inflammation in the blood vessels, vasculitis has different types with different effects at different ages. Like other autoimmune diseases, it occurs more frequently in women. Some types have higher mortality rates in women as well as more treatment challenges.
Zooming in on chromosomes
Page’s research goes right to the heart of sex differences: our X and Y chromosomes, plus their underappreciated “inactive” versions. Some sex differences are biologically hard-wired, and Page would argue that male-female differences in health and disease will ultimately find their origins in the sex chromosomes.
While X and Y chromosomes may matter the most in the reproductive organs, their activity diverges elsewhere in the body. We all learned in science class that males have one X and one Y chromosome while females have two X chromosomes. It’s been assumed that the Y is less important and the second X, called Xi, is inactive.
Not so. That Xi has to be prepared to support pregnancy.
And both X chromosomes matter in the heart. For starters, there are proportionally more cardiomyocytes — what Page calls the hardest-working cells in the body — in the female heart compared to male hearts. During pregnancy, the heart works 50% harder to keep blood circulating.
Pumping is important not only in pregnancy but also in end-stage heart disease. Page calls heart failure an energy crisis: The heart is pumping inefficiently and can’t generate enough energy to meet the body’s needs.
Heart failure plays out differently, too. Men are diagnosed with the disorder much more frequently and die more often and earlier than women. Page led a team that discovered male and female hearts have a basic biochemical difference in their power source.
“We’re essentially reporting that in the central engine room, the female cardiomyocytes prefer to burn fatty acids a bit more than do male cardiomyocytes, which might be a little more inclined to burning sugar,” he said about a research paper published in February in Circulation. “So it’s as if we’re pointing to a difference in the fuel mix.”
That difference could potentially lead to better prevention and treatment for all patients.
Zooming out to post-operative care
In October, researchers reported on a phenomenon known as “failure to rescue,” when a patient dies from complications after surgery that might have been averted if recognized and treated. Differences between male and female patients may explain why women are less likely to survive high-risk cardiovascular surgery than men, the JAMA Surgery paper concluded.
After four common but serious procedures — abdominal aortic aneurysm repair, coronary artery bypass surgery, or aortic or mitral valve replacements — female patients later developed complications at the same rate as men. But these women were more likely to die within 30 days than men with the same serious post-op problems.
“I do suspect that one of the key reasons is that the diagnostic algorithms in the treatment for their complications are the same for men and women, but they should not be the same,” said Mario Gaudino, a cardiothoracic surgeon at Weill Cornell Medicine and NewYork-Presbyterian Hospital who studies cardiac surgery outcomes and who was not involved in the study.
Other experts traced the disparate outcomes back to whether a woman was diagnosed late in her disease. Being smaller with smaller blood vessels could make surgery take more time and recovery more difficult.
What now?
The American Heart Association’s Kim takes the long view as she calls for more attention to the women-aren’t-just-small-men conundrum.
“Before you fix something, you have to figure out what the problem is and the scope of the problem,” she said.
In that spirit, she zeroed in on three areas of need in her field. One is medical education. In cardiology training, new M.D.s don’t learn as much about vascular disease as cardiac disease. “We’ll know how to order stress tests, echos, EKGs, etc., but we’re also supposed to know how to interpret an ankle brachial index,” which compares blood pressure in the ankle to blood pressure in the arm in order to detect blockages in the legs.
Another gap is inclusion of women in clinical trials testing devices designed to repair vascular problems.
“We definitely have different anatomy. Our vessels are smaller. Women tend to present with more severe disease,” Kim said. “In these device trials, including in aneurysm trials, we’ve shown that compared to the prevalence, women are underrepresented.”
Then there’s screening of patients to spot trouble early enough to treat it — and determining if that’s the best course.
“For aneurysmal disease in particular, there’s still a little bit of clarification that needs to come in regards to when should a woman get an aneurysm fixed,” she said about the size of the aneurysm. “Because we tend to be shorter, our aortas are smaller. Should we really wait until 5 and a half centimeters? You know, my aorta is a lot smaller than Shaquille O’Neal’s.”
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