Under the radar

A baffling new form of heart disease is on the rise in women. Undetectable on angiograms and inconclusive in stress tests, Healthcare Middle East explores coronary microvascular disease.

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By  Harvard Medical School Published  July 10, 2006

A baffling new form of heart disease is on the rise in women. Undetectable on angiograms and inconclusive in stress tests, Healthcare Middle East explores coronary microvascular disease.

If a standard approach to identifying and diagnosing heart disease exists, it goes something like this: a patient notices pain or tightness in her chest when climbing stairs or lugging groceries into the house. You send her for an exercise stress test. As she walks on the treadmill, the electrocardiogram shows that part of her heart isn’t getting enough oxygenated blood. Next stop: angiography. This shows that cholesterol-filled plaque, or atheroma, has narrowed one of her coronary arteries by 75% or more. Treatment follows.

Yet this sequence does not work nearly as well in women who have chest pain, shortness of breath, unusual fatigue, or other signs of reduced blood flow to the heart, as it does in men. Many women don’t have the strength or endurance to complete an exercise stress test. And more than half of women who produce alarming stress tests have what look to be clear coronary arteries on an angiogram.

In the past, these women were told not to worry. Few were encouraged to start the same kinds of therapies as men with heart disease, such as lowering cholesterol and blood pressure, taking aspirin and other medications. But
ongoing work from a study of women with chest pain is replacing this nonchalance 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 as the traditional type. This fundamentally different form of heart disease is as common and as costly as all female-specific cancers combined. Its newly minted name, coronary microvascular disease, reflects new thinking and, hopefully, new directions in recognising 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 ischemia. They have ‘false-positive’ stress tests (an alarming stress test but clear arteries on an angiogram) nearly five times as often as men. However, this
homogenous approach is gradually giving way to the realisation that reduced blood flow, or ischemia, can have different causes and 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 cholesterol. As is widely known, LDL particles work their way into the endothelium. 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, forming an atheromatous plaque. The more this plaque pushes into the interior space of the blood vessel, the less room there is for blood flow – a process called atherosclerosis. When this occurs in a coronary artery, the vessel may not be able to supply its section of heart muscle with enough blood when there’s an added demand, during exercise, for example. Pain or pressure in or around the chest is one of the heart’s responses to ischemia.

Unexplained pain
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 grasp of the origins and effects of chest pain, researchers started the WISE study back in 1996. The study is 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 obstruct blood flow. Some eye-opening results were presented in a special supplement to the 7 February 2006, Journal of the American College of Cardiology. Here are the main points:

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, such as 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 responds to plaque, high blood pressure, and other stresses may also
differ in women and men. Oestrogen 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 ‘At a glance’) can help determine who is a good candidate for an exercise stress test and who might require an alternative form of testing.

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 or pulse pressure was linked with higher chances of having significant coronary artery disease.

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

A word to the WISE
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.

Dr Elizabeth Nabel, director of the National Heart, Lung, and Blood Institute, in a statement about the WISE work, 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. 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 form 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, using medication 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 forms of lifestyle therapies that are recommended for people with blocked or narrowed coronary arteries. These include exercise, a good diet, and not smoking. 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 anaemia and possibly even oestrogen replacement may emerge as beneficial therapies.

The WISE study has raised more questions than it has answered. But one rule is crystal clear: if you a patient has chest pain or other worrisome symptoms when she exercises or is under stress, clean arteries don’t necessarily mean her heart is fine.

This article is provided courtesy of Harvard Medical International. © 2006 President and Fellows of Harvard College.

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