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REVIEW ARTICLE

C-Reactive Protein and Cardiovascular DiseasesIs it


Ready for Primetime?
Carl J. Lavie, MD, Richard V. Milani, MD, Anil Verma, MD and James H. OKeefe, MD

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

CRP and CV Diseases

Approximately 5 years ago, Danesh et al16 performed a


meta-analysis of 22 prospective studies and found that after
adjusting for the major CHD risk factors, patients with high
levels of CRP had a 45% increase in CHD events compared
with those with lower CRP. In comparison to standard CV risk
factors, such as LDL cholesterol, smoking, and blood pressure,
hsCRP provided similar to or superior ability to predict CV
risk. When CRP is added to standard risk factor assessment,
such as the National Cholesterol Education Program Global
Risk Score or the Framingham Risk Score, many patients with
intermediate risk are able to be classified into either the lowrisk or high-risk groups.9,13 In a large prospective study of
asymptomatic middle-aged women in the Womens Health
Study,17 incorporation of hsCRP allowed 32% of women with
a 10-year risk, according to the Framingham Risk Score, in the
5% to 10% range and 42% of women with a 10-year absolute
risk in the 10% to 20% range to be reclassified into either the
low-risk or high-risk groups, which dramatically changes their
requirement for aggressive medical assessment and treatment
for prevention of CHD. Using hsCRP along with traditional
risk factors (age, cholesterol, blood pressure, smoking, DM,
and parental history of premature MI before 60 years of age) in
the Reynold Risk Score, CV events were predicted better than
when using standard risk equations.13 The value of adding
hsCRP to standard risk equations was also noted in analyses of
separate cohorts of women,13 middle-aged asymptomatic
men,18 and elderly men and women.9,19
Currently, the incorporation of hsCRP into CHD risk
assessment seems to be most useful in patients who are classified as intermediate risk (eg, 10%20% 10-year risk or
possibly 5%20% 10-year risk), whereas it may not be as
useful in low-risk or high-risk patients. In low-risk patients,
however, even if an elevated CRP increases the risk from 1%
to 3% to as much as 2% to 6%, this would not substantially
change the patients need for additional testing or treatment.
Similarly, very high-risk patients (10-year risk 20%) are
probably candidates for aggressive treatment with lipid therapy,
aspirin, and other preventive therapies regardless of their CRP
values. However, in intermediate-risk patients, the levels of
CRP may allow for the patient to be reclassified as low or high
risk, which may significantly alter their need for additional
testing and treatment.
CRP Target of Therapy?
There is considerable controversy on whether CRP is
pathogenic in itself or just a marker of CV diseases and
CHD.20 22 Human genetic studies demonstrate a dominant
genetic variance found for CRP in a large population-based
twin study.23 Recent studies provide evidence supporting the
association of genetic polymorphism related with the CRP gene
and CHD.24 In addition, genetic variations in the CRP gene is
associated with lifelong increased CRP levels but not necessarily with increased risk of atherothrombosis.20 Studies assessing the single-nucleotide polymorphism in the CRP locus have
suggested a lack of concordance between the effects of CRP
genotypes on CHD, thus arguing against a causal association of
CRP and CHD.25 Clearly, mechanistic and animal studies
provide evidence both for and against a causal relationship of
CRP with atherothrombosis.20 Although a detailed discussion
of this is beyond the scope of this review, several studies
suggest direct effects of CRP on atherothrombosis, including
blunting systemic endothelial vasoreactivity21 and mediating
LDL uptake by macrophages.22
Although CRP is clearly a marker of increased CV risk,
evidence to support efforts to reduce CRP levels are more
2009 Lippincott Williams & Wilkins

limited. However, the best evidence to support reducing levels


of CRP comes from studies of statin therapy in secondary
prevention. In the Reversal of Atherosclerosis with Aggressive
Lipid Lowering (REVERSAL) trial, 502 patients with angiographically proven coronary artery disease (CAD) were randomized to standard therapy with pravastatin 40 mg versus
intensive therapy with high-dose atorvastatin 80 mg, and
intravascular coronary ultrasound (IVUS) was performed at
baseline and after18 months.26 Therapy with high-dose atorvastatin resulted in reductions in LDL cholesterol and hsCRP of
46% and 36%, respectively, compared with only 25% and 5%
reductions, respectively, with pravastatin. In the entire group,
the correlation between reductions in LDL cholesterol and
hsCRP was weak but statistically significant (r 0.13; P
0.005).27 In univariate analysis, the percent change in both LDL
cholesterol and CRP (as well as non high-density lipoprotein
cholesterol and apolipoprotein B levels) related to the rate of
progression of atherosclerosis by IVUS. After adjusting for
these lipid levels, the reductions in hsCRP were independent
and significantly correlated with the rate of atherosclerosis
progression by IVUS (r 0.09; P 0.04). Importantly,
patients with reductions in both hsCRP and LDL cholesterol to
levels that were greater than the median had significantly lower
rates of atherosclerosis progression than did patients with
reductions in only one of the markers and those with reductions
in both markers that were less than the median (P 0.001).
In another trial [Pravastatin or Atorvastatin Evaluation
and Infection Therapy (PROVE-IT)Thrombolysis in Myocardial Infarction 22], 4162 patients with acute coronary syndrome were also randomized to standard therapy with pravastatin 40 mg versus intensive therapy with atorvastatin 80
mg.28 In this trial, both patients who achieved an LDL cholesterol 70 mg/dL and those who achieved a CRP 2 mg/L had
substantial reductions in major CV events during the 2-year
follow-up (Figure 1).29 Those who achieved both LDL cholesterol and CRP goals had the lowest risk (essentially half the risk
compared with those who achieved neither of the goals for
LDL and CRP), whereas those who achieved one of the 2 goals
(either an LDL cholesterol 70 mg/dL or a CRP 2 mg/L) had
an intermediate event rate during follow-up (Figure 2).29
In another acute coronary syndrome trial, CRP was
assessed at 30 days and 4 months to predict prognosis in 3813
patients enrolled in the Aggrastat-to-Zocor (A to Z) Trial of
early versus a delayed, less intensive, statin regimen.30 Patients
with CRP 3 mg/L at 30 days had significantly higher 2-year
mortality rates than those with CRP 1 to 3 mg/L or hsCRP 1
mg/L (6.1% versus 3.7% versus 1.6%, respectively; P
0.0001) with similar results noted at 4 months. Patients subjected to early intensive statin therapy (40 mg simvastatin for 1
month then 80 mg simvastatin) were slightly more likely to
achieve CRP levels 1 mg/L at 30 days (22% versus 18%; P
0.03) and 4 months (30% versus 22%; P 0.0001) compared
with patients who were administered simvastatin 20 mg. Nevertheless, as was discussed in the original trial31 and in the
accompanying editorial,32 and as we have recently reviewed,33
we believe that simvastatin 80 mg may be too toxic to use,
and we generally do not recommend this dose of simvastatin
because of the potential for drug-drug interactions and myopathy/rhabdomyolysis. Nevertheless, this trial along with the
REVERSAL and PROVE-IT trials provides support for intervention directed at CRP in patients with CHD.
In the recent primary prevention trial (Justification for
the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), 17,802 patients with LDL cholesterol

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Lavie et al

FIGURE 1. Cumulative incidence of recurrent myocardial infarction or death


from coronary causes, according to whether the
achieved LDL cholesterol or
CRP levels were above or
below the median. 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.

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

achieved one or neither target (P 0.0001 across treatment


groups).35 Moreover, in participants who achieved LDL cholesterol 70 mg/dL and CRP 1 mg/L, a 79% reduction in
major vascular events was noted (Table 1).35 These data support the importance of treating patients with elevated CRP and
LDL cholesterol 130 mg/dL with intensive statin therapy and
the impact of reducing both levels of LDL cholesterol and CRP
in these patients without known CHD, similar to the data
previously noted in patients with CHD.
hsCRP Predicts Other CV Disease
Although much of the research directed at CRP has
focused on its ability to predict atherosclerotic CV diseases,
particularly CHD events, many studies have demonstrated
other important implications of elevated CRP. Most, but not all,
studies demonstrate that hsCRP is a potent predictor of CVA,
even after adjusting for multiple conventional CV risk factors.9,36 42 Patients with metabolic syndrome (MS) have higher
levels of CRP,43 45 and in patients with MS, higher hsCRP
predicts the development of frank DM9,46,47 and the increased
risk of CV events.9,43,48,49 In patients with DM, who are already
at high risk of CV diseases, an elevated level of hsCRP further

TABLE 1. Hazard ratios for CV events based on LDL


cholesterol and on hsCRP

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

Adapted with permission from Ridker PM, Danielson E, Fonesca


FA, et al. Reduction in C-reactive protein and LDL cholesterol and
cardiovascular event rates after initiation of rosuvastatin: a prospective
study of the JUPITER trial. Lancet 2009;373:1175 82.
CV, cardiovascular; LDL, low-density lipoprotein; hsCRP, highly
sensitive C-reactive protein.

Volume 338, Number 6, December 2009

CRP and CV Diseases

FIGURE 3. A highly significant relation exists between


LDL-C reduction and CRP
reduction in randomized
trials of various lipid-lowering therapies. Reprinted
with permission from The
American Journal of Cardiology, OKeefe JH, Cordain L,
Jones PG, et al. Coronary
artery disease prognosis and
C-reactive protein levels
improve in proportion to
percent lowering of lowdensity lipoprotein. Am J
Cardiol 2006;98:1359,
Copyright 2006, Elsevier.

predicts increased CV risk. Elevated levels of hsCRP have been


identified as a marker of prognosis in chronic obstructive
pulmonary disease,50 and as predictors of pulmonary hypertension,51 and have recently been demonstrated to predict outcomes in response to therapy in patients with advanced pulmonary hypertension.52 We have recently demonstrated that
higher baseline hsCRP predicts failure to improve levels of
arterial pressure following vigorous therapeutic lifestyle
changes (TLCs) with formal cardiac rehabilitation and exercise
training (CRET) programs.53 In this issue of the Journal,54 both
smoking and elevated hsCRP were shown to be the most potent
predictors of CAD vasospasm in patients without hemodynamically significant macrovascular CAD stenoses, and these 2 risk
factors potentiated each other in the prediction of coronary
vasospasm.
Reducing Levels of CRP
Statin Therapy
Most studies have demonstrated that statin therapy significantly reduces levels of CRP.33,55,56 Although intensive
statin therapy that results in marked lowering of LDL cholesterol is associated with greater reductions in CRP (Figure 3),57
there is relatively weak correlation between the degree of LDL
cholesterol reduction and falls in CRP noted in individual
patients.9,27,29,35 Several studies have demonstrated that CV
event reduction is more marked in hyperlipidemic patients who
also have concomitant elevations in CRP.27,29,35,58,59 Similarly,
as reviewed above, greater clinical event reduction is evident in
both secondary and primary prevention among patients who
have more significant reductions in both LDL cholesterol
and CRP.27,29,35 Currently, as we have recently reviewed,33
moderate and high doses of atorvastatin (as used in the
REVERSAL26,27 and PROVE-IT trials28,29) and rosuvastatin
(as used in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin
trial34,35) are probably required to achieve 35% to 40%
average reductions in levels of CRP.
2009 Lippincott Williams & Wilkins

Other Lipid Agents and CRP


Other lipid agents have more limited data for reducing
levels of CRP.56 In a meta-analysis of 3 randomized control
trials, colesevelam reduced CRP by an average of 23% (P
0.007).60 In patients with type II DM and dyslipidemia, 1000 to
1500 mg/d of extended release prescription niacin reduced CRP
by 11% and 20%, respectively.61 Although clinical event reduction with fibrates has not been as marked as with other lipid
therapies, these agents have been associated with up to 50%
reductions in CRP.56 Ezetimibe has not been shown to reduce
CRP when used as monotherapy, but the addition of ezetimibe
to statins markedly reduced levels of CRP, particularly noted
when used in combination with rosuvastatin or atorvastatin
(Figure 3).33,55,57
Antidiabetic Agents and hsCRP
Patients with poorly controlled type II DM show significant reductions in CRP after 2 weeks of intensive insulin
treatment.62 In patients undergoing coronary artery bypass
surgery, insulin has reduced CRP concentrations by approximately 40%.63 In a small study of 12 patients with poorly
controlled DM, the addition of metformin to sulfonylurea
therapy (which has been shown to have only minimal effects on
CRP) resulted in a 33% reduction in CRP (P 0.01).64 The
effect of thiazolidinediones, which act as agonists of the peroxisome proliferators-activated receptors, on levels of CRP
have recently been reviewed in detail.56 These agents have
generally been shown to reduce CRP concentrations in patients
with and without type II DM (from 15% to nearly 60%, with
most studies demonstrating 25% to 30% reductions in CRP).
Nonpharmacologic Therapies and hsCRP
Although most of the enthusiasm for reducing levels of
CRP have been directed at various pharmacologic therapies,
particularly statins, substantial evidence exists to support the
role of nonpharmacologic therapies, including TLCs, to reduce
levels of CRP. In patients with CHD, one of the most studied

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Lavie et al

cessation,54 moderate levels of alcohol,68 low glycemic load


diets, Mediterranean diets, and vitamin D supplementation.69

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
through cardiac rehabilitation and exercise training. J Am Coll
Cardiol 2004;43:1056 61, Copyright 2004, Elsevier.

therapies using TLCs is that with formal CRET, and the


benefits of this therapy have recently been reviewed in detail.2
We recently demonstrated that CRET was associated with
nearly 40% reductions in levels of CRP assessed by the hs
assay (hsCRP) in patients with CHD (Figure 4).65 Moreover,
currently, although most patients with CHD are treated with
statins, reductions in CRP after CRET were fairly similar in
patients receiving and those not receiving statins.65 Theoretically, one could assume that because fat cells produce cytokines that stimulate hepatic synthesis of CRP, weight loss and,
particularly, fat reduction with CRET may be the mechanism
responsible for the reduction of CRP. However, although most
patients enrolled in CRET either maintain their body weight or
lose some weight, we also demonstrated that reductions in CRP
after CRET were independent of weight change.65 Although
both patients with and without MS had significantly reduced
levels of CRP after CRET (Figure 5),44 this reduction may be
even more important in patients with MS because these patients
have markedly elevated levels of CRP, proportionate to the
number of abnormal metabolic factors that may be present.44
Other nonpharmacologic therapies that have been shown to
reduce levels of CRP include weight reduction,66,67 smoking

Currently, the weight of evidence indicates that hsCRP is


associated with increased risk of CV diseases in many cohorts
of patients. Moreover, levels of hsCRP add significantly to the
information available from the standard CHD risk factors and,
particularly, are valuable to patients with intermediate risk of
CHD (10-year risk in the 5%20% range based on traditional
risk factors). In most patients with intermediate risk who have
evidence of elevated CRP levels, we believe that more intensive preventive treatment is likely warranted. In both primary
and secondary prevention statin trials, greatest clinical event
reduction has been noted in patients who achieved LDL cholesterol levels 70 mg/dL and CRP levels 2 mg/L (even
more so with CRP levels 1 mg/L). Currently, we believe that
statin therapy should be intensified to achieve these combined
LDL cholesterol and CRP goals, and usually, statin therapy
should be combined with intensive nonpharmacologic therapies, which are also proven to reduce levels of CRP. Further
studies are needed evaluating additional therapies added to
high-dose statins, particularly for patients who do not achieve
these LDL cholesterol and/or CRP goals with the combination
of intensive statin and vigorous nonpharmacologic treatments.
With the current level of evidence, the value of CRP, particularly when assessed by the hs assay (hsCRP) in primetime
seems to be forging ahead.
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Volume 338, Number 6, December 2009