Harvard Heart Letter

Beyond the bulge: A new look at heart disease in women

Heart disease with arteries that appear to be free of cholesterol-filled bulges isn't a contradiction in terms. Up to 3 million American women — and some men — may have this "new" form of heart disease.

If a "standard approach" to identifying and diagnosing heart disease exists, it goes something like this: You notice pain or tightness in your chest when climbing stairs or lugging groceries into the house. Your doctor sends you for an exercise stress test. As you walk on the treadmill, the electrocardiogram shows that part of your heart isn't getting enough oxygenated blood. Next stop: angiography. This special x-ray shows that cholesterol-filled plaque has narrowed one of your coronary arteries by 75% or more. Treatment follows.

This sequence, it turns out, doesn't work nearly as well in women who have chest pain, shortness of breath, unusual fatigue, or other signs of reduced blood flow to part of the heart as it does in men. Many women don't have the strength or endurance to complete an exercise stress test. And a whopping half or more of women who have alarming stress tests have what look to be clear coronary arteries on an angiogram.

In the past, such women were told not to worry; this wasn't really dangerous heart disease. Relatively few were counseled to start the same kinds of therapies as men with heart disease: lowering cholesterol and blood pressure, taking aspirin and other medications. Ongoing work from a study of women with chest pain is replacing this with a more urgent message: There's a stealth form of heart disease that doesn't show up on angiograms, and it might be just as bad for you as the traditional type.

This fundamentally different form of heart disease is as common and as costly as all female-specific cancers combined, affecting as many as 3 million American women. Its newly minted name, coronary microvascular disease, reflects new thinking and, we hope, new directions in recognizing and treating heart disease.

Such advances are sorely needed. Doctors have traditionally used a one-size-fits-all approach to identifying and diagnosing heart disease — an approach based largely on how it affects men. In this view, women often lack the "classic" signs of reduced blood flow to part of the heart, a condition known as ischemia. They have "false-positive" stress tests — an alarming stress test but clear arteries on an angiogram — nearly five times as often as men.

This is gradually giving way to the realization that ischemia can have different causes and different effects in women and men. Nudging this slow process forward is groundbreaking research from the ongoing Women's Ischemia Syndrome Evaluation (WISE) study.

"Classic" angina

The traditional explanation for the development of chest pain starts with LDL (bad) cholesterol. Here and there inside arteries, LDL particles work their way into the endothelium, the inner lining of an artery. White blood cells migrate to these deposits as if responding to an infection and gorge on LDL particles. Over time, as the cycle is repeated, the pus-like mixture of LDL and dead and dying white blood cells expands and bulges into the artery. Cardiologists call this bulge a plaque. It's almost like a pimple forming on the inside of the artery.

The more a plaque pushes into the interior space of the blood vessel, the less room there is for blood flow. When this happens in an artery that nourishes the heart (a coronary artery), the vessel may not be able to supply its section of heart muscle with enough blood when there's an extra demand for oxygen and fuel — say, during exercise or a stressful argument. Pain or pressure in or around the chest is one of the heart's responses to ischemia.

Two routes to heart disease

The classic explanation for reduced blood flow (ischemia) to part of the heart muscle revolves around cholesterol-filled plaque. As it bulges into the interior space of a coronary artery, the space available for blood flow shrinks. Yet it is also possible for plaque to limit blood flow by growing evenly around the artery, or bulging outward. On an angiogram, this looks like an open artery. Plaque formation in arteries too small to be seen on an angiogram, or problems with their ability to relax and increase blood flow, can also cause ischemia.

New explanations

But chest pain or pressure can't always be traced to a bulging plaque. Between 50% and 60% of women, and about 20% of men, have chest pain or other symptoms when they are active or stressed even though an angiogram shows no plaques big enough to limit blood flow through the coronary arteries.

This condition was once called cardiac syndrome X, a name that reflects its mysterious origins. It has been attributed to spasms of the coronary arteries, heightened sensitivity to pain in and around the heart, or problems with small arteries that can't be seen on an angiogram. It has even been written off as the manifestation of psychological problems.

To get a better handle on the origins and effects of chest pain, researchers started the WISE study back in 1996. They are tracking nearly 1,000 women who had chest pain or other symptoms of a blocked coronary artery but whose angiograms showed no plaques large enough to limit blood flow. Some eye-opening results were presented in a special supplement to the Feb. 7, 2006, Journal of the American College of Cardiology.

Greater hazard. Women with chest pain and clear arteries were once told that coronary microvascular syndrome, though aggravating, isn't really harmful. It is. Data from WISE and other studies show that women with this condition continue to have symptoms that disrupt their lives, undergo repeated tests, and often end up in the emergency room or hospital. They are at greater risk for a subsequent heart attack or stroke, and have a poorer quality of life.

Outward expansion. There's no physical law that says plaque must bulge inward. In many women and some men, plaque expands outward, away from blood flow. It can also uniformly thicken the entire artery wall, making it expand evenly inward or outward. Seen from the inside, which is what happens during angiography, the artery looks bulge-free and fine.

Size matters. Plaque can build up in coronary arteries that are too small to be seen on an angiogram. Problems in these smaller arteries could limit blood flow to the heart. This may be a bigger issue for women than men.

Endothelial function. How the endothelium (the lining of the coronary arteries) responds to plaque, high blood pressure, and other stresses may also differ in women and men. Estrogen may play an important role here. In some women with coronary microvascular syndrome, a malfunction in the endothelium prevents coronary arteries from opening up and delivering more blood to the heart when needed, which can cause ischemia.

Beyond the stress test. Some women don't have the strength to do a full exercise stress test. An incomplete one doesn't work the heart enough to yield truly useful results. This can be frustrating to someone seeking answers and can lead to other inconclusive tests. The WISE researchers show that answering simple questions about the ability to climb stairs, do housework, have sex, or other activities (see "Check your function") can help determine who is a good candidate for an exercise stress test and who might be better off with other tests.

Check your function

This questionnaire, called the Duke Activity Status Index, can help gauge who isn't well-suited for an exercise stress test. Circle the points for a question only if you can answer "Yes, with no difficulty." Add up the circled points. Scores of 4.7 or below indicate trouble functioning, as well as a greater burden of cardiovascular disease. Individuals with low scores may not get much useful information from an exercise stress test.

Activity

Points

Can you take care of yourself (eating, dressing, bathing, etc.)?

0.8

Can you walk around your house?

0.5

Can you walk a block or two on level ground?

0.8

Can you climb a flight of stairs or walk up a hill?

1.6

Can you run a short distance?

2.3

Can you do light work around the house (washing dishes, etc.)?

0.8

Can you do moderate work around the house (sweeping, carrying groceries, etc.)?

1.0

Can you do heavy work around the house (scrubbing floors, moving heavy furniture, etc.)?

2.3

Can you do yard work (raking leaves, pushing a mower, etc.)?

1.3

Can you have sexual relations?

1.5

Can you participate in moderate recreational activities (golf, dancing, etc.)?

1.7

Can you participate in strenuous sports (swimming, singles tennis, skiing, etc.)?

2.1

Early warning. High blood pressure isn't a good sign at any stage of life. But it seems to be especially ominous when it appears in a woman before menopause. In the WISE study, the early onset of high systolic (the top number of a blood pressure reading) or pulse pressure (the difference between the top and bottom numbers) was linked with higher chances of having significant coronary artery disease.

Anemia. In women with heart disease, low iron stores may further complicate matters. In the WISE study, 10% of women with anemia died over a three-year period, compared with 5% of those with normal iron levels. Women with anemia were also more likely to have had a heart attack or stroke or to develop heart failure.

WISE lessons

Much of what has emerged from the WISE study is grist for future research. Some of the findings, though, carry clear implications for women and their doctors.

We'll let Dr. Elizabeth Nabel, director of the National Heart, Lung, and Blood Institute, speak to the doctors. In a statement about the WISE work, she urged doctors to "think outside the box when it comes to the evaluation and diagnosis of heart disease in women." In other words, don't just rely on the angiogram. The WISE investigators suggest looking at the whole person and going beyond angiography when necessary.

What does the WISE study say to women? "If you have recurrent chest pain, clear arteries on an angiogram aren't the end of the line," says Dr. Paula A. Johnson, chief of the Division of Women's Health at Harvard-affiliated Brigham and Women's Hospital. "Tell your story to your doctor and don't give up until someone takes your symptoms seriously."

Exactly which tests might supplement or replace the standard exercise stress test and angiography isn't clear. The WISE investigators mentioned several possibilities. One is nuclear SPECT, a special kind of CT scan that tracks the movement of a radioactive tracer through the heart's arteries. It creates a clear, three-dimensional picture of the heart and coronary arteries. Another alternative or add-on is the pharmacologic stress test, which uses medications instead of exercise to make the heart work harder.

Coronary microvascular syndrome is so new that no one really knows how best to treat women and men who have it. According to the WISE team, a "prudent strategy" involves the same sorts of things that are recommended for people with blocked or narrowed coronary arteries. These include exercise, a good diet, and not smoking, for starters. Drug therapy aimed at controlling blood pressure and cholesterol and improving artery function would include a cholesterol-lowering statin, aspirin, and an ACE inhibitor. Iron for women with anemia and possibly even estrogen replacement could someday emerge as beneficial therapies.

The WISE study has raised more questions than it has answered. But it has made one thing crystal clear: If you have chest pain or other worrisome symptoms when you exercise or are under stress, clean arteries don't necessarily mean your heart and arteries are fine. If your doctor dismisses you or your symptoms, it's time to dismiss your doctor.