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120 PA R T I I / Physiologic and Pathologic Responses
assay (ELISA); these assays are sensitive (being able to detect less rinogen levels increase along with many other well-established risk
than one 1/100 of the physiological concentration of each adhe- factors for CVD begs the possibility that associations may be
sion molecule) and 100% specific (no cross-reaction with other caused by confounding factors. Fibrinogen levels positively co-
serum components occurs). vary with age, plasma total cholesterol, LDL cholesterol and
Data from the Atherosclerosis Risk in Communities studies in- plasma triglycerides, obesity, smoking, hypertension, diabetes
dicates a five-fold increased risk of coronary heart disease (CHD) mellitus, and socioeconomic factors. 158,159
and a two-fold increased risk of carotid atherosclerosis between
the extreme quartiles of plasma ICAM-1 levels. 135 Analysis of High Sensitivity C-Reactive Protein
ICAM-1 levels in the Physicians’ Health Study (PHS) revealed a C-reactive protein (CRP) is a small protein complex produced by
1.6-fold increase risk of myocardial infarction in men with the liver in response to inflammatory stimuli. 107,160 The synthesis
ICAM-1 concentrations in the highest quartile compared with of CRP is stimulated by cytokines, primarily IL-6 released from
those in the lowest quartile. 136 Evidence from the ARIC study in- inflamed tissue. Levels of CRP can increase up to 1,000-fold dur-
dicates that E-selectin is more closely associated with carotid dis- ing acute inflammation. Recently, appreciation of the presence of
ease. 135 The fact that no association was demonstrated for minor elevation in CRP levels in individuals without gross in-
VCAM-1 levels in the ARIC cohort 135 is potentially caused by the flammation has lead to the development of a high-sensitivity test,
fact that VCAM-1 production is limited to vascular wall compo- which permits detection of minor fluctuations of CRP not de-
nents, whereas ICAM-1 is also expressed by fibroblasts and he- tectable by conventional assays. Several large epidemiological
mopoietic cells. This suggests that ICAM-1 acts as a more general studies have supported a role for elevated high-sensitivity CRP
marker of inflammation. In the secondary preventive setting, all (hsCRP) predicting future CVD.
three biomarkers appear to be significantly and independently re- The Physicians’ Health Study (PHS) consists of a cohort of
lated to future death from cardiovascular causes in patients with nearly 15,000 middle-aged to elderly men followed-up prospec-
confirmed coronary artery disease. 137 This study also indicated tively and free of disease at baseline. When participants with base-
that VCAM-1 levels increased the predictive value of classic risk line levels of hsCRP in the lowest quartile were compared with in-
factors. Taken together, these data suggest that ICAM-1 has pre- dividuals in the highest quartile, they exhibited a two-fold
dictive usefulness for CVD in healthy people, whereas VCAM-1 increase in the risk of subsequent stroke or peripheral vascular dis-
is an appropriate biomarker in individuals with established ather- ease and a three-fold increase in the risk of myocardial infarc-
osclerotic disease. In a recent population genetic study, several sol- tion. 136,161,162 These findings have already been consistently sup-
uble adhesion molecules (soluble P-selectin, soluble intercellular ad- ported by six other large population studies: the Air Force/Texas
hesion molecule-1, and soluble vascular cell adhesion molecule-1) Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), 163
were found to be lower in individuals of West African origin smokers from the Multiple Risk Factor Intervention Trial
(a population with lower risk for CHD) compared with European (MRFIT) study, 164 elderly patients from the Cardiovascular
individuals. 138 Although preliminary evidence supports a role for Health Study (CHS), 154,165 postmenopausal women in the
circulating adhesion molecules as predictors of CVD risk, addi- Women’s Health Study (WHS), 166 the Augsburg cohort of the
tional research is necessary before widespread clinical use. Monitoring Trends and Determinants in Cardiovascular Disease
(MONICA) Study, 167 and the Helinski Heart Study. 168
Fibrinogen hsCRP was the strongest independent risk factor for future
Fibrinogen is an acute phase reactant synthesized in the liver and myocardial infarction in the PHS and the WHS studies, even con-
is the substrate of the enzyme thrombin and the precursor to fib- sidering traditional risk factors or equivalent levels of homocys-
rin. Fibrinogen binds platelet glycoproteins, which facilitates teine. 136,161,164,166,169 Modeling of risk factors indicated that an
platelet aggregation, and plays a central role in the coagulation absolute risk assessment incorporating the ratio of total choles-
cascade. 139,140 These properties make fibrinogen an important de- terol to HDL cholesterol and hsCRP resulted in the most accurate
terminant of thrombogenesis and plasma viscosity, and thus a po- estimation of overall cardiovascular risk. Moreover, in studies of
tentially useful candidate biomarker of CVD risk. While its asso- patients suffering acute coronary syndromes, elevated hsCRP lev-
ciation with the development of CVD is well established 141,142 els were associated with poorer outcomes, 170–172 suggesting prog-
evidence of causality has not been demonstrated. Fibrinogen nostic usefulness in secondary preventive settings.
modulates atherothrombosis, in part by binding LDL and hom- Although no specific treatment currently exists for the modu-
ing in on lesions and inducing proliferation of vascular smooth lation of the determinants of elevated CRP, the predictive value of
muscle. 143,144 Fibrinogen is involved in the initial stages of plaque hsCRP measurement in conjunction with other established risk
formation, where its integration into the artery wall leads to its factors appears to more accurately quantify CVD risk. Preliminary
conversion to fibrin and fibrinogen degradation products. It also studies support the usefulness of incorporating hsCRP in more ac-
binds to high-density lipoprotein (HDL), which sequesters more curate and informed primary and secondary preventive strategies.
fibrinogen. 141 Moreover, fibrinogen and fibrinogen degradation Males with the highest baseline hsCRP levels were found to expe-
products stimulate smooth muscle cell proliferation and migra- rience the greatest risk reduction after the use of aspirin in the
tion, 145,146 and may mediate the adhesion of macrophages into PHS study, 161,163 whereas added benefit of pravastatin treatment
the subendothelial space and further migration into the intima. 147 was observed in individuals with elevated hsCRP in the Choles-
A host of epidemiological evidence supports a positive correla- terol and Recurrent Events (CARE) trial. 173 In the AFCAPS/
tion between plasma fibrinogen levels and risk of CVD. 148–155 TexCAPS, treatment with lovastatin was also associated with re-
Taken together, there exists an approximate doubling in risk for duction in hsCRP levels. 163
CHD between individuals from the extreme quartiles for plasma At the present time, hsCRP represents the most promising
fibrinogen. Plasma fibrinogen levels have been variably correlated of all new risk biomarkers of CVD. The AHA and the Centers
with incidence of ischemic stroke. 156,157 The observation that fib- for Disease Control and Prevention published a joint scientific