Towards better screening of CV risk Paul Ridker MD Associate Professor of Medicine Division of Preventive Medicine and Cardiovascular Diseases Harvard Medical School Boston, MA

Standard CRP tests designed to detect clinical information cannot predict cardiovascular event rates hs-CRP tests can detect C-reactive protein levels far below the lower sensitivity limits of standard clinical assay can predict cardiovascular event rates High-sensitivity C-reactive protein tests CRP vs hs-CRP

Factors affecting the propensity of plaques to rupture  lipids  the inflammatory process  the inflammation itself Determining vulnerability Ross R. N Engl J Med 1999;340(2): Plaques Atherogenesis and atherothrombosis are as much inflammatory disorders as lipid disorders.

Half of all individuals that have MI or stroke do not have abnormalities of lipid function. For specific markers of inflammation, hs-CRP turns out to be the most clinically useful in determining who is truly at risk for future heart attacks and stroke in currently healthy populations of men and women. Markers of inflammation The clinical picture

NIH-funded study  large-scale prospective cohort  designed to determine a variety of issues in women's health, including the fundamental determinants of cardiovascular events Enhancing screening for cardiovascular disease Women's Health Study Ridker PM, et al. N Engl J Med 2000; 342(12):

study of healthy middle-aged men experimental assay for hs-CRP used Results the higher the level of C-reactive protein, the higher the risk of having either a myocardial infarction or a stroke CRP levels and risk of MI or stroke Ridker PM, et al. Circulation 1998;97(20): Physicians’ Health Study

Markers measured Women's Health Study Ridker PM, et al. N Engl J Med 2000; 342(12): different putative markers of risk were simultaneously measured in the same baseline blood sample using a commercial assay. hs-CRP serum amyloid A ICAM 1 interleukin-6 total cholesterol LDL cholesterol HDL cholesterol apolipoprotein A-I apolipoprotein B-100 Lp(a) ratio of total cholesterol to HDL homocysteine

The single strongest predictor of future risk of heart attack and stroke was hs-CRP, not lipid level. Women with the higher levels of the hs-CRP were at nearly 4.5 times increased risk of having a future heart attack or stroke. LDL cholesterol levels only had a predictive value of about 2.2 (this marker is potentially better than lipid screening). Homocysteine and Lp(a) values were marginal at best. Homocysteine was a significant predictor of risk but much less predictive than the inflammatory markers. Results for otherwise healthy women Women's Health Study Ridker PM, et al. N Engl J Med 2000; 342(12):

hs-CRP greatly increases the predictive value of standard lipid screening. With lipid and the inflammatory process data, predicting future vascular events is much more accurate. Additive effects of CRP Women's Health Study Ridker PM, et al. N Engl J Med 2000; 342(12):

Subgroup Only women with LDL cholesterol of 130 mg/dL (3.37 mmol/L) or less were included. hs-CRP levels and risk hs-CRP levels were associated with a 4-fold increase in risk. Low levels of cholesterol may not mean low risk if there is an enhanced propensity to inflammatory response. Women with a propensity to plaque rupture may be a high-risk subgroup. CRP and normal lipid levels Women's Health Study Ridker PM, et al. N Engl J Med 2000; 342(12):

The CARE trial (Cholesterol and Recurrent Events) showed that people randomly allocated to pravastatin therapy had significantly lower CRP levels than those allocated to placebo. The magnitude of risk reduction associated with pravastatin was greatest among those who had the inflammatory response. Research is being done to determine if the combination of lipid screening and hs-CRP testing will identify truly high-risk patients who will benefit from statin therapy. Statins and CRP levels Ridker PM, et al. Circulation ;100(3): CARE trial

Still at high risk  people with low CRP levels but high lipid levels  people with high CRP levels but low lipid levels High CRP levels are never good CARE trial Ridker PM, et al. Circulation ;100(3): People with low lipid levels and low CRP levels were the lowest-risk group. People with high lipid levels and high CRP level were the highest-risk group.

hs-CRP testing is limited to people who might otherwise be screened for cholesterol. NHANES research group Population studies found fairly broad ranges of CRP levels, even in younger patients. This suggests that the inflammatory process may well be present in our teens and 20s. This is not surprising, because we know that atherosclerosis is a chronic lifelong disease and the inflammatory process is predicting events 8, 10, 12 years down the road. CRP in younger people Ford ES, et al. Arterioscler Thromb Vasc Biol 2000;20(4): NHANES data

CRP is a very nonspecific marker of inflammation. Infections and trauma drive CRP levels up well into the clinical range. But, hs-CRP testing detects very low-grade levels in healthy patients. Still, in clinical practice, CRP levels should be measured 2 to 3 weeks after an acute infection. Differentiating inflammations Ridker PM, et al. Circulation 2000;101:1767 Physicians’ Health Study

CRP is elevated in obese patients. Body Mass Index and obesity are determinants of CRP levels. But hs-CRP is predictive among lean and heavy individuals. Meditation through the pro-inflammatory response may be one of the mechanisms that make obesity so destructive in terms of vascular function. CRP and obesity Physicians’ Health Study Ridker PM, et al. Circulation 2000;101:1767

CRP is likely a downstream marker of a much more sophisticated process, with no direct vascular effects. There may be a systemic, low-grade inflammatory response. There may be a population distribution, where some people have more inflammatory response, some less. The inflammatory response in our 50s and 60s may lead to increased vulnerability of plaques. CRP levels Mediator or marker?

 ICAM-1, one of the adhesion molecules involved in the adhesion and transmigration of macrophages and monocytes across the endothelium  interleukin-6, one of the primary drivers of CRP production  serum amyloid A, another hepatically derived acute-phase reactant Markers associated with increased risk Women's Health Study Ridker PM, et al. N Engl J Med 2000; 342(12):

Because other markers and/or upstream modulators predict risk, CRP is probably a marker. The single strongest clinical predictor is the hs-CRP, likely because it gives a downstream overview of the whole process. Measuring IL-6 or ICAM 1 is difficult in a clinical setting. Advantages of hs-CRP  it is a very hardy protein  there is very little degradation  it can be handled like a typical outpatient analyte  it is very stable  it is easy to measure CRP: probably a marker Women's Health Study Ridker PM, et al. N Engl J Med 2000; 342(12):

Ongoing research Data for hs-CRP Unstable angina Attilio Maseri's Italian group Liuzzo G, et al. N Engl J Med 1994; 331(7): Morrow DA, et al. J Am Coll Cardiol 1998; 31(7): Acute coronary syndromes TIMI investigators Toss H, et al. Circulation 1997; 96(12): European studies from the FRISC investigators

These inflammatory markers might be used as a method of targeting therapy or as a method of providing entire new avenues of therapy. If this inflammatory response is profoundly involved in the acute coronary syndromes and in changing that plaque from stable to unstable, we might have an impact on the inflammatory component as well as the thrombotic component in clinical trials. Potential uses The future of hs-CRP