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CRP has long been measured in clinical laboratories to monitor active infection. Traditional assays for CRP have a lower detection limit of 3-8 mg/L and, thus, are not sensitive enough to detect the low-end variations required for prediction of cardiovascular risk. High-sensitivity assays that overcome this limitation are now commercially available.

Although it is an acute-phase reactant, CRP exhibits a relatively low degree of intrain-dividual variability in clinically stable patients. Whether serial assessment of hsCRP provides incremental clinical benefit is uncertain. Consistent with cholesterol-screening guidelines, the Centers for Disease Control (CDC) and the American Heart Association (AHA) recommend the use of two hsCRP measures taken at least 2 wk apart with the average value used to estimate vascular risk (9). However, many physicians believe that a single measure is sufficient provided that a value of <10 mg/L is obtained. Because CRP levels increase sharply in response to major infections, trauma, or other acute conditions, levels above 10 mg/L should initially be disregarded and the test should be repeated when the patient has stabilized. If an elevated CRP level persists, especially in the presence of a high erythrocyte sedimentation rate, alternative sources of systemic inflammation such as rheumatoid arthritis, inflammatory bowel disease, or endocarditis should be considered. Nevertheless, recent analyses from the Women's Health Study suggest that chronically elevated CRP levels may indicate exceptionally high coronary risk (69).

CRP has other characteristics in addition to its relatively low long-term biological variability that render it suitable for use in clinical practice. CRP levels are not affected by food intake and exhibit little circadian variation. Thus, measurements can be made without regard for fasting status or time of day. CRP has a long plasma half-life of between 18 and 20 h, allowing accurate readings in fresh or frozen blood without the need for special collection procedures. Elevated CRP levels within the range detected by high-sensitivity assays have demonstrated specificity for vascular events. In the Women's Health Study, baseline hsCRP levels were not associated with the incidence of cancer (42). Similarly, in the Study of Osteoporotic Fractures, a population-based cohort of women age 65 yr and older, an elevated hsCRP level predicted cardiovascular mortality (hsCRP >3 vs <3 mg/L; adjusted RR: 8.0; 95% CI: 2.2-2.9) but was unrelated to mortality from noncardiovascular causes (RR: 0.92; 95% CI: 0.4-2.1) during 6 yr of follow-up (98).

Population norms for hsCRP are available, and there are currently no compelling data to support the use of gender-, age-, or race-specific guidelines, thus simplifying the application of clinical cut points. Ranges of <1, 1-3, and >3 mg/L, which correspond to approximate tertiles of the hsCRP distribution in healthy US adults, are recommended for classification of individuals into lower-, moderate-, and higher-cardiovascular-risk groups in primary prevention (Fig. 9) (9,99). However, although this simple trichotomy is useful for primary care practice, it should be recognized that patients with the lowest hsCRP levels (<0.5 mg/L) are at very low cardiovascular risk and those with persistent marked elevations in hsCRP (>10 mg/L) are at very high risk (69).

The cost of hsCRP screening is comparable with that of standard cholesterol evaluation and is less than that of alternative screening approaches such as EBCT or magnetic resonance imaging. hsCRP screening appears to yield tangible benefits in terms of years of life saved and cost-to-benefit ratios (100). For these reasons, the inclusion of hsCRP testing in routine physical examinations is gaining popularity.

10 mg/L

Low Risk

Moderate Risk

High Risk

Acute Phase Response Ignore Value, Repeat Test in 3 weeks

Fig. 9. Clinical application of hsCRP levels for cardiovascular screening: levels of hsCRP of <1, 1-3, and >3 mg/L correspond to low-, moderate-, and high-risk groups. (Reproduced from ref. 125.)

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