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Part I. Inflammation and Heart Disease

Looking Beyond Cholesterol

Cardiovascular disease (CVD) continues to be the leading cause of death for Americans. We've learned that smoking, elevated serum cholesterol levels, hypertension, and diabetes place people at greatly increased risk of heart disease and sudden cardiac death. But for many of the 250,000 people who succumb each year from sudden cardiac death, cholesterol - now the main focus of prevention efforts - is simply not a factor. Cholesterol screening fails to identify about 50% of those who have heart attacks in the US, because their total cholesterol is either normal or only slightly elevated (1). And that fact has led researchers on a decade-long search to find new factors that can help predict who is at risk for heart disease and stroke.

C-Reactive Protein: Emerging Risk Factor

The most important new risk factor to emerge is C-reactive protein (CRP), a protein produced in the liver and released into the blood stream when inflammation is present (2). High levels of this protein may explain why some people with low cholesterol develop heart disease, or why strict adherence to a cholesterol-lowering diet sometimes fails to prevent serious heart problem. In fact, an estimated 25-30 million people fall into the low cholesterol/high CRP category. In the ongoing Physicians' Health Study of 22,000 men, only CRP was predictive of those who suffered sudden cardiac deaths over 17 years of follow-up (3). For some women, too, CRP appears to be a better predictor of stroke, heart attack and other signs of CVD than low-density lipoprotein or LDL, the "bad" cholesterol (4).

Inflammation and CVD

There's been a major shift in thinking about atherosclerosis - the gradual process where hardened cholesterol substances called plaque, cause clogged and narrowed arteries. Once thought to be simply a disease where too much cholesterol is stored in artery walls, it's now widely accepted that inflammation is central to every aspect of the atherosclerotic process, from its initiation, to its progression, to the rupture of plaque. We now know that local inflammation helps trigger heart attack or stroke by making plaque less stable and therefore more likely to rupture and generate artery-blocking clots. People with elevated CRP either have plaques that are more inflamed, or they have a more easily triggered inflammatory response that makes their plaques more prone to rupture.

The CRP Test

CRP is measured by a simple inexpensive blood test. The best results are obtained through two separate tests that are done at least two weeks apart, with their results averaged. Experts from the Center for Disease Control and Prevention (CDC) and the American Heart Association (AHA) concluded in 2002 that people considered to be at "intermediate" risk of a heart attack, stroke, or other CVD event, should be tested for CRP. Those with CRP with levels of one milligram per liter (1 mg/L) or more should be treated aggressively to bring their levels down. Intermediate risk is defined as people with a 10-20% chance of developing CHD within 10 years, based on age, total cholesterol level, smoking status, systolic blood pressure (the upper number), and level of protective HDL.

The CDC and AHA don't recommend CRP testing for those at low risk of CHD, or for those at high risk either. High risk people are those who are already having symptoms or signs of trouble and should already be getting aggressive treatment. The rationale for not testing low risk people (younger aged, non-smokers with low total cholesterol and high HDL), is that a high CRP reading (over 3) wouldn't change their official recommended course of treatment - dietary and lifestyle changes.

Most clinicians look at blood cholesterol as an indication of how much plaque is likely to be in the arteries, while CRP signals how likely that plaque is to rupture and release dangerous plaque-containing clots into the blood stream. It's important to remember that one test doesn't replace the other, and both cholesterol and CRP screening have value.

References

1. Castelli WP. Lipids, risk factors and ischaemic heart disease. Atherosclerosis 124:S1-9, 1996.
2. Hackam DG and Anand SS. Emerging risk factors for artherosclerotic vascular disease: A critical review of the evidence. JAMA 290:932-40, 2003.
3. Albert CM et al. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 105(22):2595-9, 2002.
4. Ridker PM et al. Comparison of C-reactive protein and low density lipoprotein cholesterol levels in the prediction of first CVD events. N Eng J Med 347:1557-65, 2002.
5. Sesso HD et al. C-reactive protein and the risk of developing hypertension. JAMA 290:3000-2, 2003.