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Tue 2 Aug 2005 04:00 AM

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C-reactive protein is adding fuel to the fire of coronary artery disease

|~||~||~|Heart disease is the leading cause of death in the United States; with the exception of 1918, it has held that dubious distinction every year since 1900. Nearly 2,600 Americans die of heart disease each day — that’s one death every 34 seconds. And that’s just the tip of the iceberg, since more than 64 million American adults have some form of cardiovascular disease; in some 13 million, the problem is coronary artery disease. In all, American men face a 49% lifetime risk of developing coronary artery disease beyond the age of 40.

Faced with a near epidemic of coronary artery disease, scientists have identified a series of factors that increase risk. As research continues, new risk factors have been discovered. It’s enabled doctors to devise new ways to prevent, diagnose, and treat heart disease. One of the newest risk factors is C-reactive protein (CRP); one of the oldest preventive tactics is exercise. Can this old standby help with the new worry?

Atherosclerosis or “atheroscleritis”
Coronary artery disease is a manifestation of atherosclerosis; in addition to heart attacks, the disease is responsible for most strokes, for many cases of kidney failure, and for peripheral artery disease that can lead to gangrene and amputations, usually in the legs and feet.

Atherosclerosis usually is translated as “hardening of the arteries,” but the disease is much more complex. Twentieth-century science taught us that the ancient Greek words that go into the name are surprisingly accurate: athere means porridge or gruel, and in atherosclerosis the middle layer of an artery becomes filled with soft, mushy material; only later does the artery develop sclerosis or stiffness and hardening. And 21st-century research now shows us that inflammation is also a crucial element of the disease. In time, that may give the disease a new name; since “itis” indicates inflammation, “atheroscleritis” would be a more accurate description.

By any name, the process starts when low-density lipoprotein cholesterol (LDL, the “bad” cholesterol) penetrates the wall of an artery. If all goes well, high-density lipoprotein cholesterol (HDL, “good” cholesterol) will reverse the process, carrying cholesterol out of the artery wall for eventual disposal by the liver. But if LDL accumulates in the artery wall, it becomes a target for oxygen free radicals, the high-energy molecules generated by the body’s metabolism. When free radicals bombard cholesterol, they turn it into oxidized LDL, much as they turn fat rancid.

Oxidized cholesterol gets atherosclerosis started. Until recently, doctors assumed that the fatty plaques of atherosclerosis were simply passive deposits of cholesterol, and that the largest plaques were the most dangerous. Neither assumption is correct. In fact, oxidized cholesterol triggers active inflammation in the artery wall. T-lymphocytes and macrophages, special white blood cells that are key components of the body’s immune system, leave the blood, migrate into the artery wall, and gobble up the oxidized LDL. When macrophages ingest bacteria and viruses, they kill the microbes, but in the case of cholesterol, the reverse is true: The lipid-laden macrophages enlarge to become foam cells, then rupture, releasing oxidized cholesterol into the artery wall where it can perpetuate the cycle of damage. In response to all the inflammation, smooth muscle cells in the artery wall enlarge and attempt to form a hard cap over the inflammatory plaque.

Large plaques with firm caps are serious: They narrow coronary arteries, reducing the flow of blood. Such plaques cause angina, the chest pain that develops when the heart muscle cannot get the oxygen-rich blood it needs. But these large, firm plaques don’t usually cause heart attacks. Instead, smaller, softer plaques are the culprits. They can rupture, triggering the formation of a blood clot or thrombus on the disrupted plaque’s surface. This instantly transforms a minor obstruction into a major one. It is the clot that finally blocks the artery, killing the heart muscle cells that depend on the artery to supply oxygen-rich blood. And similar blockages cause many strokes along with debilitating cases of peripheral artery disease.

What is CRP?
CRP is a key element of the acute phase response, the body’s reaction to any form of inflammation. In the past, doctors measured blood levels of CRP to help diagnose acute rheumatic fever. When rheumatic fever became uncommon, the test fell into disuse, but it’s now finding a new role in the diagnosis and management of coronary artery disease.
CRP is produced in the liver, so everybody has it in their blood. In healthy people, blood levels of CRP are very low, but they are boosted by any inflammation in any part of the body. Because CRP reflects the liver’s response to inflammation, it is a marker for inflammation. But does it also participate in inflammation? Does it add to the damage of coronary artery disease?

Scientists don’t know the answers, but many suspect that CRP may add fuel to the fire of atherosclerosis. Although it is made in the liver, CRP does find its way from the blood into atherosclerotic plaques. Research shows that the protein can bind to cholesterol, facilitating its uptake by macrophages, and it can also stimulate inflammation and promote clotting in its own right.

It’s far too early to say that lowering CRP levels will help, but there are a few hints that it may. For example, statin therapy, moderate alcohol consumption, and low-dose aspirin are all associated with a reduced risk of coronary artery disease, and studies find that they also lower CRP levels. It’s not clear if the drop in CRP is the horse or the cart, but it’s hopeful information. And in the case of cardiac patients, two major 2005 studies found that CRP levels predict risk even when statin therapy has reduced LDL cholesterol to very low levels.

Measuring CRP
Healthy people have only tiny amounts of CRP in their blood; although a normal range has not yet been defined precisely, healthy levels are generally below 1 mg/L (milligram per litre). Intense inflammation, such as that found in acute rheumatic fever, pneumonia, or rheumatoid arthritis, can boost levels to 40 mg/L or more. When researchers first developed a test for CRP, they were interested in detecting widespread inflammation, so the test was only sensitive enough to measure rather high levels.||**|||~||~||~|The inflammation of coronary artery disease can be very harmful, even fatal, but it involves just a tiny area of the body. As a result, coronary inflammation produces only a slight elevation of CRP levels; it remains within the old “normal” range and is too low for the standard CRP blood test to detect.

Enter the high-sensitivity CRP test, which has allowed researchers to measure small changes in the protein. And because this test is reliable and relatively easy to perform, it is moving from the research arena to ordinary diagnostic labs.

Although CRP is the best current test for arterial inflammation, other acute-phase reactants are also being used to detect coronary artery inflammation. Examples include myeloperoxidase, tumor necrosis factor-alpha, fibrinogen, serum amyloid A protein, intracellular adhesion molecule-1, interleukin-6, and serum albumin. If nothing else, these many markers show that arterial inflammation is both active and complex.

Several investigations, including the Harvard-sponsored Physicians’ Health Study of some 21,000 men and the Women’s Health Study of some 28,000 women, suggest that CRP can predict heart disease before it is otherwise evident. Although the magnitude of risk varies from study to study, people with the highest CRP levels appear to be two to seven times more likely to develop cardiovascular disease than people with the lowest levels. In general, levels below 1 mg/L indicate low risk, levels between 1 and 3 mg/L moderate risk, and levels above 3 mg/L high risk. Similar relationships exist between CRP and both stroke and peripheral artery disease. It’s no surprise; like coronary artery disease, they are manifestations of atherosclerosis.

CRP in cardiac patients
CRP is one of the risk factors that can help determine if a healthy person is at risk of coronary artery disease (see table below). It’s an important determination, since people at high risk stand to benefit most from aggressive preventive measures, including both lifestyle changes (diet, exercise, weight control, tobacco avoidance, and possibly low-dose alcohol) and medications (aspirin and drugs for cholesterol, blood pressure, and diabetes if indicated). But people with angina or heart attacks know that they have coronary artery disease; their risk is 100%. Can CRP measurements help with their management?

Yes and no. Yes, because CRP levels can assist doctors in risk stratification; the higher the CRP, the greater the risk for a bad outcome, including recurrent heart attacks, restenosis (recurrent narrowing) of arteries that have been opened by angioplasty, and cardiac death. But since all patients with coronary artery disease deserve aggressive treatment, it’s not clear that knowing a person’s CRP level would change his therapy.

Exercise and CRP
Taking a statin drug or daily baby aspirin may lower a patient’s CRP level; men who can enjoy a drink or two without overdoing it may notice a similar drop. But can exercise also reduce CRP levels?

The first large study of the question was published in 2002. Using data gathered by the National Health and Nutrition Examination Survey III, Dr. Earl Ford evaluated exercise and CRP levels in 13,748 American adults. Even after taking account of other factors that might affect CRP levels (cholesterol, smoking, obesity, aspirin use, alcohol consumption, and diet), there was a clear link between physical activity and CRP. Compared to people who got little or no exercise, those who exercised at moderate levels were 15% less likely to have elevated CRP levels, while those who exercised vigorously enjoyed a 47% lower risk of having high CRPs.

As of 2005, 12 additional studies have reported that people who exercised regularly have lower CRP levels than couch potatoes. The studies included men and women, adults and (in one case) children. Another investigation reported a similar trend, but it did not meet the tough statistical tests for validity, and a study from Belgium was negative.

If exercise is linked to lower CRP levels in healthy people, can it have a similar effect in cardiac patients? A three-month study of 277 cardiac patients provided impressive evidence that it can. On average, exercise lowered CRP levels by 41%, and the benefit was independent of weight loss and statin therapy. And since the cardiac rehab study was a clinical trial, it provides evidence of a cause and effect relationship between exercise and CRP that the earlier observational studies cannot offer.

CRP is the best-studied inflammatory marker, but studies that have looked at other indicators of vascular inflammation report similar findings. Regular exercise appears to reduce the “itis” in “atheroscleritis.”

Not by CRP alone
Doctors are still learning when to measure CRP levels and how to use the information to guide therapy. But they don’t have to rely on CRP alone to determine cardiac risk. Instead, they evaluate a whole series of risk factors. Three of these indicators can’t be modified; increasing age, male gender, and a family history of coronary artery disease indicate increased vulnerability, but they come with the territory. Other risk factors, though, can — and should — be modified. The table opposite lists the major risk factors — and it shows that exercise has a beneficial effect on most of them.

CRP is but one of the many illustrations of how far scientists have come in understanding coronary artery disease and atherosclerosis. New progress is soon to follow, but you should not wait for new results to take advantage of these insights. As research moves forward, you should encourage your patients to move forward as well. Regular exercise will reduce their risk of heart disease, stroke, diabetes, obesity, high blood pressure, osteoporosis (“thin bones”), depression and anxiety, gallstones, colon cancer, benign prostatic hyperplasia, and erectile dysfunction. And it doesn’t take much to realise these benefits; a brisk 30- to 40-minute walk nearly every day will produce important gains.

Exercise is not a panacea, but it is the best bargain in prevention. Among other things, new research shows it can help douse the flames of atherosclerosis.

This article is provided courtesy of Harvard Medical International.
© 2005 President and Fellows of Harvard College||**||

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