NEW CLUE TO AN OLD KILLER.

Inflammation & Heart Disease

For decades, researchers were stumped: Why do half of all heart attacks strike people with normal cholesterol levels?

Now a growing body of evidence indicates that it's not just the slow, steady build-up of plaque in the coronary arteries that cuts off blood to the heart muscle. It's also the rupture of a plaque that can set off the cascade of events that ends with a panicked call to 911.

When a clot forms on a ruptured plaque, the supply of blood and oxygen--could be completely choked off. Without oxygen, the heart muscle--and possibly its owner dies.

And plaques are more likely to rupture in people who have a strong "inflammatory response," says Harvard researcher Paul Ridker.

Q: What does a low level of inflammation throughout the body have to do with heart attacks?

A: Over the past 15 years, molecular biology has taught us that atherosclerosis--or hardening of the arteries--is very much an inflammatory disease, the same way that arthritis and lupus are inflammatory diseases.

The inflammatory process is a mechanism by which the immune system deals with injury--it's how the body repairs itself. We've learned that it's part and parcel of atherosclerosis, though we don't know exactly what injury triggers the inflammatory response. High blood cholesterol, infections, and tobacco smoke are just some of the possible causes.

Q: So inflammation and infection aren't the same thing?

A: No. It's possible that infection is driving this process, but infection is only one of many causes of inflammation. Finding the cause of the strong inflammatory response is the Holy Grail of this field.

And it may not be an infection at all. It's possible that atherosclerosis is nothing more than an inflammatory disease, just like arthritis. We don't ask what causes the inflammation of arthritis.

Q: But the inflammation that leads to heart disease doesn't cause pain like it does with arthritis?

A: No. We're talking about an extremely low level of inflammation--so low that the person has no symptoms and isn't sick. Until recently, we couldn't even detect the inflammation with a blood test.

Q: How does inflammation lead to a heart attack?

A: Once an injury in the wall of an artery has occurred, the immune system sends cells to repair it. Over time, a "plaque" made of immune cells, cholesterol, and muscle cells forms, with a fibrous "cap" separating it from the blood.

Some of these plaques are more vulnerable, or unstable, than others. Vulnerable plaques are more likely to rupture. If they do, a blood clot forms at the rupture site, and that can cut off the flow of blood. If that blood was on its way to the heart muscle, the person has a heart attack. If the blood was on its way to the brain, the person has a stroke.

Q: And whether the plaque ruptures depends on inflammation?

A: Yes. The immune system mounts an inflammatory response that starts to degrade the cap. The more the cap degrades, the more likely it is to rupture.

PREDICTING A HEART ATTACK

Q: Why is the link between inflammation and heart disease a breakthrough?

A: The idea that atherosclerosis involves a great deal more than just high cholesterol is very important to physicians and their patients. It's a real revolution in our understanding of the disease. We now know that measuring inflammation--which we can do with a simple blood test--may help physicians determine who among their patients is more prone to have a heart attack.

Q: What role does cholesterol play?

A: Cholesterol levels tell you how much plaque is building up in your arteries. But the inflammatory process tells you how vulnerable those plaques are.

That's why we began measuring markers of inflammation. We wanted to see if they could help us better predict who will have a heart attack. One marker--high-sensitivity C-reactive protein, or hs-CRP--seems to be the best predictor.

We found that if you take healthy, middle-aged men or women and measure their hs-CRP levels, you can do a very good job of predicting who will go on to have a heart attack or stroke.

More importantly, the combination of the hs-CRP test with cholesterol screening provides a much better way of predicting who is more likely to get a heart attack than does cholesterol screening alone. And it's inexpensive. The hs-CRP test should cost around $25 to $35, about as much as getting your cholesterol checked.

Q: So some people have a stronger inflammatory response?

A: Yes. Some of us have an enhanced ability to deal with injury, and those people tend to have higher levels of hs-CRP. Unfortunately, they also tend to develop more unstable plaques. Those who don't have this enhanced propensity tend to get stable plaques, which are less likely to rupture and cause a heart attack.

And that may explain some patients who have always puzzled us. I have a patient with severe atherosclerosis but he's still alive ten or 12 years later. My guess is that's because he has high cholesterol but not a strong inflammatory response. Some patients can have a tremendous amount of blockage in their arteries, but the blockages never rupture.

On the other hand, other patients can have a fairly small blockage in an artery, yet it ruptures. I had a 40-year-old with one little plaque blocking only 40 to 50 percent of his artery, but he had a heart attack. That's probably because he had both high cholesterol and a strong inflammatory response.

Q: Is inflammation linked to other diseases?

A: It's also a risk factor for stroke and peripheral vascular disease, which are caused by atherosclerosis in areas other than the heart.

Q: Do we still need to worry about cholesterol?

A: Yes. Lowering your cholesterol remains critically important, but you have to remember that half of all heart attacks occur in people who do not have high cholesterol. Within that group, those who have high hs-CRP turn out to have substantial risk. So it's putting these two kinds of markers together that gives us the best handle on cardiovascular risk [see "The Risk of High hs-CRP"].

WHAT TO DO

Q: What can people do if they have high hs-CRP?

A: You do what anyone would do to cut their risk of heart disease. You eat a diet that's low in saturated fat and cholesterol, you lose weight, you exercise, you control your blood pressure, you stop smoking.

Beyond that, we've learned that aspirin reduces inflammation. We've also been able to show that cholesterol-lowering drugs like pravastatin reduce hs-CRP levels.

Q: Only aspirin, not ibuprofen or acetaminophen?

A: As far as we know, only aspirin has this effect. And low doses of aspirin--81 mg a day--seem to be enough.

Q: Isn't that data on men only?

A: Yes. We don't have any direct data on aspirin in women. But the data on pravastatin come from both men and women.

Q: Do we know how aspirin prevents heart attacks?

A: Aspirin reduces the ability of platelets to clump and form a blood clot. That's its main mechanism of preventing a heart attack. However, aspirin is more effective if you have high hs-CRP. That tells us that in addition to its ability to prevent blood clots, aspirin seems to have an anti-inflammatory effect.

Q: Should people check with a doctor before taking aspirin on a daily basis?

A: Yes. Like any drug, aspirin has a risk-to-benefit ratio that can only be determined by a discussion with your physician.

If people have bleeding tendencies or an increased risk for ulcers, the risks of taking aspirin may outweigh the benefits.

Q: How did researchers learn that statin drugs lower hs-CRP?

A: The statin story is very interesting. Our findings about hs-CRP help explain some past observations about statins that were puzzling. First, we know that even among people with low LDL ["bad"] cholesterol levels, say about 130 milligrams per deciliter, those who take statins have a lower risk of heart disease than those who don't.

Second, statins reduce the risk of stroke, even though high LDL cholesterol is not a very potent risk factor for stroke. We've shown that the higher a person's inflammatory response measured by hs-CRP, the higher his or her risk of stroke.

Both of those observations suggest that statins lower the risk of heart attack and stroke by doing something other than simply lowering LDL cholesterol.

Q: Any clue what statins do?

A: We have intriguing studies showing that if you feed laboratory animals a diet that raises their LDL and then give them statin drugs, the inflammatory cells start to get leached out of the plaque. That means less inflammation and a lower risk of heart attack.

And that fits with the results of the Cholesterol and Recurrent Events (CARE) trial, which was designed to see whether pravastatin could lower the risk of a second heart attack. There was a 54 percent reduced risk in people who had high hs-CRP, and only a 20 to 25 percent reduced risk in people who had lower hs-CRP.

Q: Should everyone be on statin drugs?

A: No. We know from two large clinical trials that even among people who have never had a heart attack, going on statin drugs reduces the risk of having a heart attack or stroke. But treating healthy people is a very expensive undertaking.

Screening for both cholesterol and hs-CRP may tell us who is truly at high risk. Therefore, the cost-to-benefit ratio might be significantly better for people who haven't had a heart attack or stroke, but who have high hs-CRP. In contrast, almost everybody who's already had a heart attack or stroke should take statins and aspirin.

Q: How does diet affect hs-CRP?

A: Obesity, which is a major risk factor for heart attacks, heightens the inflammatory response. Overweight and obese people tend to have higher levels of hs-CRP than people who are normal-weight. That may be one reason why obesity contributes to a heart attack.

Q: Does weight loss lower hs-CRP?

A: We don't know yet, but we do know that fat cells produce something called interleukin-6, which, in turn, produces hs-CRP. So there's a logical explanation for why losing weight might reduce levels of hs-CRP.

Q: Does hs-CRP rise steadily as weight increases?

A: No, the increase in the inflammatory response is much steeper than the rise in weight.

Q: Can gaining an extra ten or 20 pounds raise hs-CRP?

A: Yes. The problem is substantial even among ordinary overweight people. You don't have to be obese.

Q: What else affects hs-CRP?

A: Cigarette smoking drives it up and exercise reduces it. We're doing a study to evaluate diet's impact on hs-CRP. We're looking at saturated fat, cholesterol, fish, alcohol, and other components of the diet, but we don't have the answers yet.

Q: Do a person's genes affect his or her hs-CRP level?

A: Probably. There may even be some evolutionary benefit of having a strong inflammatory response. This is an area of active research.

Q: Is the hs-CRP test also used to diagnose arthritis?

A: No. There's a difference between an hs-CRP test and an ordinary CRP test.

The standard CRP test isn't sensitive enough to detect the low levels of inflammation needed to predict a heart attack. It's designed to distinguish people who have severe arthritis from those who don't. The high-sensitivity CRP test allows us to measure low levels of inflammation with tremendous fidelity.

The good news is that this inflammation can be measured many years in advance of the first heart attack or stroke. So you have lots of time to recognize the problem and prevent cardiovascular disease.

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Paul Ridker is the director of the Center for Cardiovascular Disease Prevention and a member of the Divisions of Cardiology and Preventive Medicine at Brigham and Women's Hospital and Harvard Medical School. He spoke with NAH's Bonnie Liebman.