High-sensitivity C-reactive protein, inflammation,
and cardiovascular risk: From concept to clinical
practice to clinical benefit
Paul M Ridker, MD, MPH, FACC Boston, Mass
Advances in vascular biology have shown that inflammation plays an integral role in the development of cardiovascular
disease. Extensive study of high-sensitivity C-reactive protein (hs-CRP) has demonstrated that this measure of inflammation
predicts cardiovascular risk not reflected by traditional risk factors, adds prognostic information to traditional risk assess-
ment, and predicts long-term cardiovascular risk in individuals with no prior evidence of cardiovascular disease. Patients
with elevated hs-CRP levels in the absence of elevated cholesterol appear to derive preventive benefit from statin therapy
that is similar in magnitude to that in patients with elevated cholesterol. The large-scale Justification for the Use of statins in
Primary prevention: an Intervention Trial Evaluating Rosvastatin (JUPITER) trial represents a critical study to determine the
utility of a strategy for targeting statin therapy to prevent incident cardiovascular disease in patients at increased cardio-
vascular risk on the basis of elevated hs-CRP who would not be considered candidates for therapy on the basis of hyper-
cholesterolemia or traditional risk assessment. Inclusion of hs-CRP measurement in risk screening and use of this informa-
tion to guide preventive therapy could result in a marked improvement in prevention of cardiovascular morbidity and
mortality. (Am Heart J 2004;148:S19–26.)
Elevated low-density lipoprotein (LDL) cholesterol is
a critical risk factor for cardiovascular disease, and ag-
gressive lowering of cholesterol is a fundamental issue
in reducing risk. Yet half of all myocardial infarctions
(MIs) and strokes occur in individuals without elevated
cholesterol levels. Over the past several years, it has
become increasingly clear that atherosclerotic disease
is driven at a fundamental level by inflammatory pro-
cesses, particularly those of the innate immune sys-
tem—a recognition that encompasses, and does not
diminish, the causal role of cholesterol in disease. Ad-
vances in the understanding of the inflammatory biol-
ogy of atherothrombosis have suggested the need for
inflammatory markers capable of predicting risk of vas-
cular disease in the large number of at-risk individuals
not identified by the presence of elevated cholesterol
or other traditional risk factors. C-reactive protein
(CRP), an acute phase reactant that serves as a marker
for systemic inflammation, has emerged as the leading
candidate marker in this regard as a result of its pre-
dictive ability and the test’s wide availability, low cost,
and ease of use. Use of high-sensitivity CRP (hs-CRP)
has helped provide a more fundamental framework for
understanding vascular risk and is contributing to an
improved understanding of the effects of lipid-lowering
treatment in reducing cardiovascular risk. In many re-
spects, it is through translational studies of hs-CRP that
an improved understanding of the inflammatory nature
of cardiovascular disease has been achieved in clinical
practice.
Initial studies of hs-CRP in predicting
cardiovascular disease
In a study published in 1997, we assessed the rela-
tionship of hs-CRP to occurrence of vascular disease in
apparently healthy men in the Physicians’ Health
Study.
1
Baseline hs-CRP values were compared for 543
subjects without MI, stroke, or venous thrombosis and
for 543 who developed such vascular disease over Ͼ8
years of follow-up; all subjects had been randomized to
receive aspirin or placebo at the start of the trial. Base-
line hs-CRP concentrations were higher in men who
later had an MI (P Ͻ .001) or ischemic stroke (P ϭ
.02). Figure 1 shows the significant association of rela-
tive risks for MI and stroke with increasing levels of
hs-CRP. Men in the highest quartile had a relative risk
for MI of 2.9 (P Ͻ .001) and a relative risk for ische-
mic stroke of 1.9 (P ϭ .02) compared with men in
the lowest quartile. This study showed that a single
baseline measurement of hs-CRP was a strong predic-
tor of future MI or stroke in apparently healthy individ-
uals, independent of usual atherothrombotic risk
factors.
From Brigham and Women’s Hospital, Boston, Mass.
Reprint requests: Paul M Ridker, MD, MPH, Director, Center for Cardiovascular Dis-
ease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Avenue East,
Boston, MA 02215.
E-mail: pridker@partners.org
0002-8703/$ - see front matter
© 2004, Elsevier Inc. All rights reserved.
doi:10.1016/j.ahj.2004.04.028