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Abstract: C-reactive protein (CRP) is a marker of systemic inflammation, and it has been implicated in the pathogenesis of many chronic
diseases, including cardiovascular (CV) diseases. With highly sensitive
CRP assays, serum CRP can add considerably to standard coronary
heart disease risk factors and in the prediction of subsequent major
CV risk. We review evidence supporting the assessment of highly
sensitive CRP both in patients with established CV diseases and in
those without known disease as well as evidence supporting CRP as
a target of therapy. We also review various pharmacologic (especially intensive statin therapy) and nonpharmacologic therapies to
reduce levels of CRP.
Key Indexing Terms: C-reactive protein; Risk factor; Cardiovascular
disease; Coronary heart disease. [Am J Med Sci 2009;338(6):486492.]
n the United States alone, nearly 1.5 million patients experience an acute myocardial infarction (MI) or major cerebrovascular accident (CVA) or stroke annually.1 Patients with
known cardiovascular (CV) diseases have a high prevalence of
recurrent CV events.2 In patients without known CV diseases,
overall risk is considerably lower. However, 15% to 20% of
major CV events in such patients occur in those with none of
the major traditional CV risk factors.3,4
C-reactive protein (CRP) is a nonspecific marker of
systemic inflammation, and it has been implicated in the pathogenesis of many chronic diseases, including diabetes mellitus
(DM), cancers, Alzheimer dementia, and major CV diseases,
such as coronary heart disease (CHD), acute MI, and acute
CVA.57 Recent evidence has focused on the increasing prevalence of obesity in the United States and other westernized
societies worldwide, and many measures of adiposity, including body mass index, waist circumference, and waist-to-hip
ratio, are significantly correlated with higher levels of CRP.8
During the past decade, numerous studies have not only addressed the association of CRP with well-established CV disease risk factors but also focused on the link between chronic
inflammation and CRP with atherosclerosis, as well as with
major CV events resulting from the atherosclerotic process.9
In this review, we discuss the evidence that links CRP
with established CV and CHD risk factors, as well as data that
identify CRP as an independent risk factor for CV disease
events in cohorts without known CV diseases, and the role of
CRP assessment and intervention in those with established
CHD.
Assessing CHD Risk
Although nearly half the women and 60% of men in
the United States are affected by CV disease by middle age,
From the Department of Cardiovascular Diseases (CJL, RVM, AV),
Ochsner Medical Center, New Orleans, LA; and Mid America Heart
Institute (JHO), Kansas City, Missouri.
Submitted June 18, 2009; accepted in revised form October 14, 2009.
Correspondence: Carl J. Lavie, MD, FACC, FACP, FCCP, Ochsner
Medical Center, 1514 Jefferson Highway, New Orleans, LA 70121-2483
(E-mail: clavie@ochsner.org).
486
only a small proportion of asymptomatic U.S. adults are classified as high risk by the commonly used risk assessment
scores.1,9 Recently, this discrepancy has been termed the detection gap, which is clinically very important because internists, primary care physicians, and CV specialists spend considerable time attempting to classify the CV disease risk status
in adult patients.10 Typically, the National Cholesterol Education Program has used the 1998 Framingham Risk Score
equation to estimate the 10-year absolute risk of major CV
disease events (MI, CV death, and major CHD events).11 By
using this algorithm, patients are classified as low risk (10-year
absolute risk 10%), intermediate risk (10-year absolute risk
of 10%20%), and high risk (10-year absolute risk 20%). We
agree with the recent suggestions that the intermediate-risk
group should include individuals with a 10-year absolute risk of
5% to 20%, and the truly low-risk group should only include
individuals with risk 5% over 10 years.9,10,12
Although the Framingham risk equation uses age and
sex in addition to total cholesterol, high-density lipoprotein
cholesterol, systolic blood pressure, and smoking status in
patients without DM (because patients with DM are considered
to have a very high risk, and these patients are considered to
be a CHD risk equivalent), it is limited by not using family
history and low-density lipoprotein (LDL) cholesterol or
triglycerides and by not including any of the parameters of
obesity, stress, or fitness. Considerable efforts have been
made to improve the risk assessment made by the standard
Framingham risk factors.9,13
Recently, Musunuru et al9 reviewed data from 20
prospective studies that assessed the impact of elevated levels
of CRP on future CHD events after adjusting for these 4 major
traditional risk factors, including Framingham risk factor scores
and/or DM and obesity. Although actual risk of CHD was fairly
linear across a wide range of CRP levels in these studies, many
studies have stratified levels of CRP into values 1 mg/L (low
risk), 1 to 3 mg/L (intermediate risk), and 3 mg/L (high risk).
In the past, CRP was used as a test to assess gross inflammation, as noted in bacteremia, vasculitis, and other severe inflammatory conditions, and values 5 mg/L were reported as
negative. These recent studies have typically used a highly
sensitive CRP (hsCRP) or ultraquant CRP, which also evaluates the lower levels of CRP. This new approach is analogous
to the highly sensitive thyroid-stimulating hormone essay compared with the crude thyroid-stimulating hormone essay that
was previously used to assess hypothyroidism, whereas the new
essay assesses both hyper- and hypothyroid states. The hsCRP
essay, therefore, evaluates levels of CRP within the normal
range but represents a range with vastly different levels of
overall CHD risk. When initial CRP assays were used in data
from the Framingham Heart Study, CRP levels did not provide
incremental value above and beyond the standard risk factors.14
However, when this analysis was repeated using hsCRP, there
was a strong correlation between hsCRP and CV disease
events, particularly when hsCRP values exceeded 3 mg/L.15
The American Journal of the Medical Sciences Volume 338, Number 6, December 2009
487
Lavie et al
130 mg/dL and hsCRP 2 mg/L were randomized to rosuvastatin 20 mg daily or placebo.34 This trial was stopped after
a median of only 19 months (maximum 5 years). Rosuvastatin
reduced LDL cholesterol by 50% and CRP by 37%, and
rosuvastatin was associated with a 44% reduction in major
events. Similar to the data noted in secondary prevention,
reductions in LDL cholesterol and CRP were only weakly
correlated (r 0.15); a 65% reduction in major events was
noted in patients who achieved LDL cholesterol 70 mg/dL
and CRP 2 mg/L versus 33% reduction in those who
FIGURE 2. Cumulative incidence of recurrent myocardial infarction or death from coronary causes, according to the achieved
levels of both LDL cholesterol and CRP. Reprinted with permission from Ridker PM, Cannon CP, Morrow D, et al. C-reactive
protein levels and outcomes after statin therapy. N Engl J Med
2005;325:20 8. Copyright 2005 Massachusetts Medical Society. All rights reserved.
488
LDL mg/dL
and hsCRP
mg/L
Events/
Patients
(n)
Event
Rate
Hazard
Ratio (95% CI)
Event
Reduction
(%)
70 and 2
70 and 1
23/2685
5/944
0.38
0.24
0.35 (0.230.54)
0.21 (0.090.51)
65
79
489
Lavie et al
CONCLUSION
FIGURE 4. Median changes in high-sensitivity C-reactive protein (hSCRP) in cardiac rehabilitation and in control patients
with coronary heart disease (CHD). Reprinted with permission
from the Journal of the American College of Cardiology, Milani
RV, Lavie CJ, Mehra MR. Reduction in C-reactive protein
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