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Heart disease in women

Yale Medicine Magazine, Spring 2024 (Issue 172) Women's Health Special Report
by Rachel Tompa, PhD


How bias compounds sex-linked biological differences.

In the 1960s, doctors in the United States sounded the alarm that heart attacks were on the rise.

That is, heart attacks in American men were on the rise. Something was going on with women too, but it wasn’t as clear-cut. Like men, more women were having cardiac symptoms, but many of these cases didn’t look like a “typical” (that is, a man’s) heart attack—the women’s arteries were clear.

Doctors puzzled over this phenomenon. In 1973, it was dubbed “cardiac syndrome X”—a term that would stand for several decades, to be replaced only recently with more descriptive diagnoses. Cardiac syndrome X referred to the fact that many people, mostly women, were having symptoms identical to those of a standard heart attack but with no evidence of blockages in their coronary arteries.

Arterial blockages are still the most common cause of heart attacks in both women and men, but we now know that heart attacks without arterial blockages can happen—80% of these kinds of attacks occur in women, and they’re just as dangerous (or possibly more so) as attacks involving the arteries. But at the time, doctors believed that cardiac syndrome X was benign; they would often send patients home without treatment.

“The field was calling it [cardiac] syndrome X because we had no name for what women experienced when they had the same cardiac symptoms as men, just without blockages,” says Samit Shah, MD, PhD, assistant professor of cardiovascular medicine and director of the VA Connecticut Cardiac Catheterization Laboratory. “It’s so vague and nondescriptive and, to the patient, really not a helpful diagnosis.”

While cardiac syndrome X is a real biological phenomenon, brushing it off as benign was a societal response, akin to the many other documented instances of understudied or undertreated health conditions in women. Today, effective treatments exist for heart disease, including the forms available to women, and researchers know a lot more about the biological and societal factors that increase women’s risk of heart disease. But getting the message to the public and clinicians is the sticking point. Despite the fact that heart disease is the number one killer of women, there’s a persistent misconception, even among many medical professionals, that women rarely have heart attacks.

“Women don’t receive as aggressive heart care as men do, and that is a significant problem,” says Lisa Freed, MD, assistant professor of cardiovascular medicine and director of the Women’s Heart and Vascular Program. For instance, doctors are less likely to recommend statins—a class of cholesterol-lowering drugs—to women than to men with the same cardiovascular risk profile. Women also refuse statins and other life-saving treatments more often than men do, in part out of fear that these medications haven’t been thoroughly tested on women. “You shouldn’t undertreat yourself, and you shouldn’t let anyone undertreat you. That’s been a long-standing story in women’s health, and it’s something that I work against every day,” says Freed.

Waning estrogen

While women of any age can and do have heart attacks, higher levels of estrogen before menopause help protect against plaque formation and blockages. Estrogen raises HDL cholesterol, lowers LDL cholesterol, and keeps artery walls flexible. After menopause, when estrogen levels wane, those protective effects disappear. Even though some research has shown that women who take estrogen (hormone therapy) closer to the onset of menopause may have a lower risk of developing cardiovascular disease, those findings have not been consistently demonstrated in other trials. Recommendations from the American College of Cardiology state, “At this time, there is no role for menopausal hormone therapy (MHT) for cardiovascular disease prevention.” To address menopausal symptoms with the use of MHT, the American College of Cardiology, the American Heart Association, and the North American Menopause Society support an individualized risk assessment for women contemplating MHT, rather than an absolute recommendation.

Other risk factors

There are many other sex-linked risk factors for heart disease, according to the American College of Cardiology, some of which can influence disease risk even decades after the fact. Polycystic ovarian syndrome (PCOS), which affects 6% to 12% of U.S. women of reproductive age, is tied to a higher risk of heart attacks, perhaps due to the syndrome’s effects on sex hormones. Women make up nearly 80% of patients with autoimmune disorders—conditions that are themselves often linked to heart disease. The leading cause of death among women with lupus is cardiovascular disease, and rheumatoid arthritis nearly doubles a woman’s risk of heart attack. Endometriosis, an under-diagnosed condition that affects at least 10% of women, increases the risk of heart disease and stroke. Mental disorders like post-traumatic stress disorder (PTSD) and depression—both more common in women than in men—also increase the risk.

Adverse events during pregnancy like preeclampsia, a pregnancy-related form of hypertension, increase the risk of heart disease even decades after giving birth. So too does gestational diabetes, as well as certain kinds of pregnancy loss related to blood flow disorders or dysfunctions of the endothelium, the thin tissue that lines blood vessels and organs.

While current guidelines from the American College of Obstetrics and Gynecology state that anyone with preeclampsia should visit a cardiologist soon after delivery, that doesn’t always happen—women are often so busy with a new baby that even regular post-partum checkups fall by the wayside, says Erica Spatz, MD, MHS, associate professor of cardiology, associate professor of epidemiology (chronic diseases), and director of the Preventive Cardiovascular Health Program. Because high blood pressure is tied to so many other adverse health outcomes, Spatz and her colleagues are looking for new ways to reach those at risk, including newly post-partum women.

Spatz is part of a study at Yale, led by Rafael Pérez-Escamilla, PhD, professor of public health (social and behavioral sciences), and Heather Lipkind, MD, MS, of Weill Cornell Medicine, that recruits women with preeclampsia in hospital delivery wards, giving them blood pressure cuffs for home use to transmit data to the study coordinators.

“Hypertension is the most modifiable risk factor for heart disease,” Spatz says. “We’ve been trying to flip the script, and not wait for people to come in for care but reach them where they are.”

Better diagnoses

Even if a woman with cardiac symptoms seeks care, accurate diagnoses and treatments can still be hard to obtain. Shah is working to bring better diagnoses to patients with what was formerly called cardiac syndrome X and is now described as ischemia/angina with no obstructive coronary arteries (INOCA/ANOCA). Two related but different conditions, coronary microvascular disease and coronary vasospasm, can both result in heart attacks without blockages in the coronary arteries; both of these conditions are also much more common in women. The prevalence of these conditions in women partially explains why women’s heart attack symptoms are different from those that men experience, Shah says. Chest pain or pressure is by far the leading symptom of a heart attack in both men and women, but women are also more likely to experience less recognized symptoms, like nausea or pain in the jaw or back. These symptoms can sometimes occur without chest pain in women.

In microvascular disease, small blood vessels that feed the heart don’t work as they should, either due to problems in the vessel lining or damage to the vessels themselves, which can decrease blood flow. In vasospasm, the vessels spontaneously narrow when they should open, shutting off blood flow to the heart—this may result from problems in the blood vessel lining or from genetic factors. Vasospasm can cause chest pain or other cardiac symptoms at rest because the spasms happen at random, while arterial blockages and microvascular disease tend to trigger symptoms during exertion.

It’s not clear why these conditions are so much more common in women, but their risk factors are similar to those for other kinds of heart disease, including smoking, high cholesterol, and diabetes. Heart attacks resulting from these syndromes are just as dangerous as an attack due to arterial blockage. These vascular disorders require different treatments; but luckily, effective treatments exist. Accurate diagnoses, however, have lagged behind.

In work presented at the 2023 American Heart Association’s annual meeting, Shah and his colleagues showed that coronary function testing, a cutting-edge set of methods that can diagnose and distinguish microvascular disease and vasospasm, resulted in correct diagnoses more often than the standard-of-care testing—coronary angiography, which images only the arteries. The methods include dosing a patient with the neurotransmitter acetylcholine, which induces spasms in someone who has coronary vasospasm and inserting tiny wires into blood vessels to check for decreased blood flow. Patients who received accurate diagnoses were also more likely to change medication, receiving more individualized treatment. Shah is now leading a multisite trial to evaluate these diagnostic methods in more patients, as well as to better understand the risk factors for these disorders and patient outcomes.

In another project, Shah and his colleagues conducted detailed interviews of women who have cardiac symptoms without blockages. Many less recognized symptoms of heart attacks, such as nausea, dizziness, or arm pain, are not captured in standard screenings, Shah says, but a better understanding of symptoms in women could help doctors detect unrecognized heart disease.

Shah sees physicians’ lack of awareness as a huge stumbling block to women’s heart health, especially in the conditions that he treats. His study also found that for patients without an arterial blockage, their average time from onset of symptoms to an accurate diagnosis was a startling 6.5 years.

“Even if all the tests are normal, take your patient who has new-onset cardiac symptoms seriously,” he says. “We have to figure out what the diagnosis is. It’s not in their head.”

A troubling trend

While heart disease risk rises in postmenopausal women, heart disease is also a leading cause of death in adult women younger than 65. Even though heart attacks have been declining in many groups over the past few decades, the decline in younger women has been minimal. And perhaps most concerning, women under 55 who have a heart attack are more likely to die from it than are young men. This could be due to lack of awareness—women are more likely to dismiss symptoms of a heart attack or may not recognize subtler symptoms, such as unexplained jaw pain or extreme fatigue, and may not seek treatment until symptoms become more severe. Additionally, when younger women arrive at the hospital, their wait time to be evaluated is, on average, about 10 minutes longer than that of younger men. And with heart attacks, every minute counts to prevent permanent damage.

A team of Yale researchers is studying what happens to these women after their heart attacks—and why their outcomes might be different from those of men. A recent study from the group showed that women 55 and younger have twice the rate of rehospitalization after a heart attack as young men. Many biological factors were similar in the men and women in the study, but several social factors differed. The women in the study with poor outcomes not only had higher rates of depression, but also were more affected by health inequity issues, such as lower income and education levels, than their male counterparts. They also had higher rates of disorders that raise the risk of heart disease, like diabetes and hypertension.

“It turns out that psychosocial factors such as stress, depression, [lack of] social support, whether they can get to the hospital to access health care, all these factors are impacting the outcome of young women,” says Yuan Lu, ScD, assistant professor of medicine (cardiology), and one of the leaders of the cardiac outcomes study. “This has not been a main focus of research in the past, but now we really need to think about tailored intervention for these women. We need to raise awareness that young women with heart attacks have worse outcomes than men, and that their clinical and social risk factors may be different from those of men, so clinicians need to pay special attention to these characteristics.”

As in the study providing home monitoring to women with preeclampsia, Lu and Spatz think strides can be made through community outreach. Spatz is leading a new multicenter study partnering with community organizations in Black, Hispanic, and low-income communities to address hypertension in both men and women, pairing community health workers and remote blood pressure monitoring so that people can participate in the study without disrupting their normal routines.

“The idea is to meet people in spaces they feel comfortable in, that they already trust,” Spatz says. “We think that this is going to be effective for women—especially women who may not have otherwise come to the clinic or attended to their health if they weren’t part of this program.”

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