Novel risk factors and cardiovascular risk prediction

Identifying asymptomatic individuals at high risk of developing a first cardiovascular disease (CVD) event is a critical issue in primary prevention. Although the use of global

From: Contemporary Cardiology: Cardiovascular Biomarkers: Pathophysiology and Disease Management Edited by: David A. Morrow © Humana Press Inc., Totowa, NJ

Lipoprotein(a) Homocysteine IL-6 TC

LDL-C slCAM-1 SAA Apo B TC:HDL-C hsCRP

Relative Risk of Future Cardiovascular Events Fig. 1. Head-to-head comparison ofvarious biomarkers in cardiovascular risk prediction. TC, total cholesterol; sICAM-1, soluble intercellular adhesion molecule type 1; SAA, serum amyloid A; Apo B, apolipoprotein B-100. (Adapted from ref. 10.)

prediction algorithms such as those derived from the Framingham Heart Study (1) greatly improves the assessment of heart disease risk in primary prevention settings, as many as 20% of all coronary events occur in the absence of any of the major classic vascular risk factors. In a recent analysis of more than 120,000 patients with coronary heart disease (CHD), 15% of the men and 19% ofthe women had no evidence ofhyperlipidemia, hypertension, diabetes, or smoking, and more than half had only one of these traditional risk factors (2). In another large population, between 85 and 95% of participants with CHD had at least one conventional risk factor, but so too did those participants without CHD, despite follow-up for as long as three decades (3). Because of the considerable need to improve risk detection, the identification of novel atherosclerotic risk factors has been a major goal of cardiovascular research in recent years (4,5).

In a recent monograph, we examined the evidence for high-sensitivity C-reactive protein (hsCRP) as a potential adjunct for cardiovascular risk prediction (6); this chapter updates and summarizes that detailed review. When evaluating a novel biomarker as a potential screening tool, clinicians should consider whether a standardized, reproducible, and cost-efficient assay for the biomarker exists; whether prospective data show that the biomarker consistently predicts future risk; and whether adding the biomarker to existing global risk prediction algorithms significantly improves prognostic ability. Clinicians should also weigh the relative magnitude of candidate biomarkers in terms of risk prediction. Application of these standards to a series of novel risk factors indicates that, to date, hsCRP is the most promising with respect to clinical utility (7-9). For example, in a direct comparison of the relative ability of various biomarkers, including lipid fractions, to predict future CVD (a combined end point of CHD death, nonfatal myocardial infarction [MI], stroke, and coronary revascularization) in the Women's Health Study, an 8-yr follow-up of28,000 middle-aged women, hsCRP emerged as the most powerful single predictor of cardiovascular risk (Fig. 1) (10). The same result was obtained for the outcome of periph-

Relative Risk of Future Cardiovascular Events Fig. 1. Head-to-head comparison ofvarious biomarkers in cardiovascular risk prediction. TC, total cholesterol; sICAM-1, soluble intercellular adhesion molecule type 1; SAA, serum amyloid A; Apo B, apolipoprotein B-100. (Adapted from ref. 10.)

CRP mediates LDL uptake by macrophages

Fig. 2. Mechanisms relating CRP to development and progression of atherothrombosis. eNOS, endothelial nitric oxide synthase. (Reproduced from ref. 110.)

eral arterial disease (11). Moreover, prediction models that incorporated hsCRP in addition to lipid profile were significantly better than models based on lipids alone—a not entirely unexpected finding given that 77% of cardiovascular events occurred among women with low-density lipoprotein cholesterol (LDL-C) levels of <160 mg/dL, and 46% occurred among those with LDL-C levels <130 mg/dL (12). Although other markers of inflammation, including cytokines such as interleukin (IL)-6 (13) and tumor necrosis factor-a (14); cell adhesion molecules such as soluble intercellular adhesion molecule-1 (15,16), P-selectin (17), and soluble CD40 ligand (18); macrophage inhibitory cytokine-1 (19); lipoprotein-associated phospholipase A2 (20,21); and white blood cell count (22) have also shown promise as markers of vascular risk, they each have analytic shortcomings that preclude their use in general clinical practice. For example, the half-life of several of these markers is too short for diagnostic testing in this setting, whereas the ability of others to predict risk in population-based studies after adjustment for traditional risk factors has been marginal (23,24).

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