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Heart disease is not gender neutral, according to findings from the Women’s Ischemia Syndrome Evaluation (WISE) study, the landmark investigation into ischemic heart disease in women. Discoveries from the WISE study suggest that many women have coronary microvascular dysfunction that is not detected by standard diagnostic procedures and therefore goes unrecognized and untreated. Heart attacks are less likely to occur in premenopausal women than in age-matched men, a benefit attributed to estrogen. But doctors also assumed that when women developed heart disease that it was atherosclerotic plaque restricting blood flow in the coronaries. Consequently, procedures to diagnose and treat heart disease were biased on research conduced in male-only studies. |
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In the 1970s, the National Institutes of Health launched the Coronary Artery Surgery Study to evaluate this standard protocol. It was the first major heart study to include women, who made up about a quarter of the 25,000 participants. The findings were baffling: A woman with a positive stress test was 4.5 times more likely than a man with a positive stress test to have an angiogram showing no blockages. The researchers took this to mean that stress testing was unreliable in women. They also concluded that women had a much lower incidence of coronary artery disease than men. The cause of the women’s chest pain was left unexplored. The next few decades saw major advances in the diagnosis and treatment of coronary artery disease. The cardiovascular death rate declined steadily—but only in men. Women had angioplasties and bypasses, but they didn’t do as well as their male counterparts. More of them suffered heart attacks or heart failure after treatment. Even women whose coronary arteries were clear continued to develop and die from ischemic heart disease (IHD). By 2000, heart disease was claiming 60,000 more women than men every year. |
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In 1996, the NIH decided that these gender disparities couldn’t be ignored any longer. Not only were more women dying of heart disease, but female heart patients required longer hospital stays and incurred higher medical bills than males. |
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The WISE study was designed to answer three questions: 1. How does IHD develop in women without arterial blockages? 2. Would some other cardiac imaging method provide better clues to IHD in such women? 3. What role do estrogen and other female hormones play? The researchers enrolled nearly 1,000 women who had chronic chest pain severe enough to warrant coronary angiography. The women were interviewed about their chest pain, quality of life, and history of depression. They underwent laboratory tests for cardiac risk factors and traditional diagnostic procedures, including stress testing and coronary angiography. But they also received some newer tests, including intravascular ultrasound (IVUS), which evaluates the motion and structure of the blood vessel wall. Women with blocked coronary arteries had angioplasty or bypass. All the participants were monitored for at least a year for ongoing chest pain, heart attack, or stroke. How The EndoPAT Test Works |
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As expected, many symptomatic women with positive stress tests had negative angiograms. But many of these women also had abnormal results on vascular function tests. Their coronary arteries and smaller vessels feeding the heart muscle didn’t dilate properly and thus couldn’t accommodate increased blood flow, indicating vascular dysfunction. Vascular dysfunction occurred both in women with clear arteries and in those with obvious coronary artery narrowing. Moreover, it was not a problem of the large coronary arteries alone, but involved stiffening of the network of smaller vessels that also nourish the heart. This condition has since been called coronary microvascular dysfunction, or microvessel disease, and is sometimes referred to as Syndrome X. |
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To some cardiologists, the discovery of widespread microvessel disease helped explain why so many women with IHD were misdiagnosed and undertreated: The standard protocol identified only coronary artery obstructions. Microvessel disease could also help explain why so few women have the classic crushing chest pain that signals coronary artery disease. Instead, they feel diffuse discomfort, exhaustion, or shortness of breath under stress or even during daily routines—symptoms that are nonspecific and less dramatic than those that herald a blockage caused by a blood clot. As vessels lose their resilience, blood flow is reduced, and the heart muscle, deprived of oxygen, gradually dies, resulting in heart failure. The WISE data may also explain why women who undergo angioplasty and bypass surgery don’t fare as well as men. These women may have both coronary artery disease and unrecognized microvessel disease. In such cases, opening the arteries isn’t sufficient. |
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How and why does coronary microvascular syndrome develop? Inflammation is a prime suspect. Not only is inflammation implicated in atherosclerosis, but it’s also at the heart of inflammatory disorders, such as autoimmune diseases, which are far more common in women than in men. The WISE researchers, led by Noel Bairey Merz, M.D. of Cedars-Sinai Medical Center in Los Angeles, reported that three proteins associated with inflammation—C-reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A (SAA)—were particularly important. Dr. Bairey Merz has an EndoPAT and has been advising Itamar Medical over the years on heart-related medical issues. |
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Compared to women with low levels of these proteins, women with the highest levels were at much greater risk for a coronary event or death within five years—even though they were only slightly more likely to have coronary artery blockages. This led to the idea that inflammatory markers could help assess microvessel disease in women. Autopsy studies support this approach. They show that women who die of heart attacks often have a pathology different from that of their male counterparts. In men, plaque tends to form in isolated accumulations that push into the lumen or burrow into the artery wall. In women, plaque is more likely to be deposited uniformly around the inside of the vessel—the possible handiwork of chronic inflammation. When inflammatory substances course chronically through the bloodstream, they strip away cells that line the blood vessels, creating an ideal bed for cholesterol-laden plaque. The plaque gave these women’s vessels stiff interior walls that tended not to rupture under stress, which is a common characteristic of the male heart attack, but to erode. Efforts to repair the erosion perpetuate the inflammatory cycle and spur the formation of tiny blood clots, a possible trigger for heart attacks resulting from microvessel disease. |
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Inflammation isn’t the only cause of coronary microvascular dysfunction. The WISE researchers looked at the classic cardiovascular risk factors and found that all the usual suspects—genes, high LDL cholesterol, low HDL cholesterol, high triglycerides, elevated blood sugar, hypertension, sedentary lifestyle, and obesity—were implicated. They uncovered some other risk factors as well, including these: Premenopausal high blood pressure. Hypertension, particularly in younger women, is a major risk factor for IHD. It damages the cells lining the coronary vessels, which attracts immune cells that trigger and feed inflammation. Anemia. The WISE study determined that cardiovascular outcomes are worse for anemic women than for women with normal hemoglobin levels. Anemia leaves fewer red blood cells to supply the heart muscle with oxygen. Polycystic ovarian syndrome (PCOS). Women with PCOS have many components of the metabolic syndrome along with erratic levels of circulating estrogen. Estrogen may dampen inflammation, so when too little is available, the risk of heart disease may rise, especially in premenopausal women. |
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What’s The Wisdom For Us? |
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The WISE investigators are developing a new protocol for screening women for heart disease, but it may be years before this process is completed. Meanwhile, here are some things your female patients can do now to reduce their risk for microvessel disease. |
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Live heart-healthfully. Take the same steps to prevent coronary artery disease: Get regular exercise; maintain a healthy weight; don’t smoke; and keep cholesterol levels in balance, glucose in check, and blood pressure under control. Pay attention to symptoms. Certain seemingly unrelated symptoms — fatigue, depression, shortness of breath — could be preludes to a serious cardiac event. Encourage women to seek medical help for these symptoms. What's Your EndoScore? |
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Talk To Your Patients And Reassess Risks |
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If you have a patient at high risk for or have symptoms of heart disease, such as unexplained fatigue or shortness of breath, discuss the WISE findings with your patients. You may want to reevaluate their care, especially if they’ve had a “false-positive” stress test. |
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Even if your patients are not at risk for coronary artery disease, the chance of an early cardiac event might be elevated by microvessel disease. EndoPAT can play an important role here. The odds are higher for African American women, who tend to suffer heart attacks at an earlier age than whites, and premenopausal women with inflammatory disorders, autoimmune diseases, or low estrogen levels. If you have patients in any of these groups, encourage them to do all they can to reduce their lifestyle risk factors. Dr. Near You |
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