Serum C-Reactive Protein (CRP), Target for Therapy or Trouble?
ABSTRACT High sensitivity serum C-reactive protein (hs-CRP) has come into clinical use as a marker of risk for cardiovascular disease (CVD). In addition to a role as a marker of disease, CRP has also been implicated in the pathogenesis of CVD. Specific small-molecule inhibitors of CRP have recently been developed with the intent of mitigating cardiac damage during acute myocardial infarction. However, the use of CRP, both as a risk marker and a disease target are controversial for several reasons. Serum hs-CRP concentrations can be elevated on the basis of genetics, female gender, and non-Caucasian ethnicity. It is not clear, in these contexts, that elevations of hs-CRP have any pathological significance. As a non-specific indicator of inflammation, CRP is also not a specific indicator of a single disease state such as cardiovascular disease but elevated concentrations can be seen in association with other comorbidities including obesity and pulmonary disease. In sharp contrast to the proposed inhibition of CRP for cardiovascular disease treatment, the infusion of CRP has been shown to have profound therapeutic benefits for autoimmune disease and septic shock. The balance between the risks and benefits of these competing views of the role of CRP in disease and disease therapy is reminiscent of the ongoing controversy regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs) for musculoskeletal disease and their cardiovascular side effects. Soon, NSAIDs may not be the only agents about which Rheumatologists and Cardiologists may spar.
- SourceAvailable from: Juan Salazar[Show abstract] [Hide abstract]
ABSTRACT: An important etiopathogenic component of cardiovascular disease is atherosclerosis, with inflammation being an essential event in the pathophysiology of all clinical pictures it comprises. In recent years, several molecules implicated in this process have been studied in order to assess cardiovascular risk in both primary and secondary prevention. C-reactive protein is a plasmatic protein of the pentraxin family and an acute phase reactant, very useful as a general inflammation marker. Currently, it is one of the most profoundly researched molecules in the cardiovascular field, yet its clinical applicability regarding cardiovascular risk remains an object of discussion, considered by some as a simple marker and by others as a true risk factor. In this sense, numerous studies propose its utilization as a predictor of cardiovascular risk through the use of high-sensitivity quantification methods for the detection of values <1 mg/L, following strict international guidelines. Increasing interest in these clinical findings has led to the creation of modified score systems including C-reactive protein concentrations, in order to enhance risk scores commonly used in clinical practice and offer improved care to patients with cardiovascular disease, which remains the first cause of mortality at the worldwide, national, and regional scenarios.Cardiology research and practice. 02/2014; 2014:605810.
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ABSTRACT: The concept of the cardiovascular continuum, introduced during the early 1990s, created a holistic view of the chain of events connecting cardiovascular-related risk factors with the progressive development of pathological-related tissue remodelling and ultimately, heart failure and death. Understanding of the tissue-specific changes, and new technologies developed over the last 25-30 years, enabled tissue remodelling events to be monitored in vivo and cardiovascular disease to be diagnosed more reliably than before. The tangible product of this evolution was the introduction of a number of biochemical markers such as troponin I and T, which are now commonly used in clinics to measure myocardial damage. However, biomarkers that can detect specific earlier stages of the cardiovascular continuum have yet to be generated and utilised. The majority of the existing markers are useful only in the end stages of the disease where few successful intervention options exist. Since a large number of patients experience a transient underlying developing pathology long before the signs or symptoms of cardiovascular disease become apparent, the requirement for new markers that can describe the early tissue-specific, matrix remodelling process which ultimately leads to disease is evident. This review highlights the importance of relating cardiac biochemical markers with specific time points along the cardiovascular continuum, especially during the early transient phase of pathology progression where none of the existing markers aid diagnosis.Biomarker insights 01/2012; 7:45-57.
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ABSTRACT: Biomarkers in acute cardiac care are gaining increasing interest given their clinical benefits. This study is a review of the major conditions in acute cardiac care, with a focus on biomarkers for diagnostic and prognostic assessment. Through a PubMed search, 110 relevant articles were selected. The most commonly used cardiac biomarkers (cardiac troponin, natriuretic peptides, and C-reactive protein) are presented first, followed by a description of variable acute cardiac conditions with their relevant biomarkers. In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care. Point-of-care testing and multi-markers use are essential for prompt diagnostic approach and tailored strategic management.Biomarker insights 01/2013; 8:115-26.
Correspondence: Virginia B. Kraus, P.O. Box: 3416, Duke University Medical Center, Durham, NC 27710.
Tel: 919-681-6652; Fax: 919-684-8907; Email: firstname.lastname@example.org
Serum C-Reactive Protein (CRP),
Target for Therapy or Trouble?
Virginia B. Kraus1 and Joanne M. Jordan2
1Duke University Medical Center, Durham, NC 27710.
2Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599.
Abstract: High sensitivity serum C-reactive protein (hs-CRP) has come into clinical use as a marker of risk for cardio-
vascular disease (CVD). In addition to a role as a marker of disease, CRP has also been implicated in the pathogenesis of
CVD. Specifi c small-molecule inhibitors of CRP have recently been developed with the intent of mitigating cardiac damage
during acute myocardial infarction. However, the use of CRP, both as a risk marker and a disease target are controversial for
several reasons. Serum hs-CRP concentrations can be elevated on the basis of genetics, female gender, and non-Caucasian
ethnicity. It is not clear, in these contexts, that elevations of hs-CRP have any pathological signifi cance. As a non-specifi c
indicator of infl ammation, CRP is also not a specifi c indicator of a single disease state such as cardiovascular disease but
elevated concentrations can be seen in association with other comorbidities including obesity and pulmonary disease. In sharp
contrast to the proposed inhibition of CRP for cardiovascular disease treatment, the infusion of CRP has been shown to have
profound therapeutic benefi ts for autoimmune disease and septic shock. The balance between the risks and benefi ts of these
competing views of the role of CRP in disease and disease therapy is reminiscent of the ongoing controversy regarding the
use of non-steroidal anti-infl ammatory drugs (NSAIDs) for musculoskeletal disease and their cardiovascular side effects.
Soon, NSAIDs may not be the only agents about which Rheumatologists and Cardiologists may spar.
Keywords: C-reactive protein, osteoarthritis, cardiovascular disease risk, infl ammation.
C-reactive protein (CRP) is produced by the liver as part of the ‘reorchestration’ of hepatic gene expres-
sion in response to infl ammation and infection (Black et al. 2004). An extremely sensitive acute phase
reactant, CRP concentrations increase rapidly in serum and often exceed the reference range by 1000
times or more (Mortensen, 2001). Its rapid synthesis after infection suggests it contributes to host
defense (Black et al. 2004). Barring recent infections, changes in disease state, or stress, CRP baseline
concentrations are reported to be relatively steady with minimal diurnal or seasonal variation (Meier-
Ewert et al. 2001). Moreover, unlike the cytokines, IL-6, IL-1ß, and TNF-a that elicit CRP production
from the liver (Mortensen, 2001), this protein has a relatively long plasma half-life (19 hours) and is
quite stable in vitro (Aziz et al. 2003).
C-reactive protein was named for its ability to precipitate the “C” polysaccharide extracted from
the pneumococcal cell wall (Black et al. 2004). Synthesis of the protein is now known to be stimulated
in response to many pathogens including gram-positive (Mold et al. 1981) and gram-negative patho-
gens, fungi, and malarial parasites (Volanakis, 2001; Szalai, 2002). By binding to specifi c ligands of
the pathogen’s cell wall, CRP activates the classical complement pathway and provides a means of
defense against the invading pathogen. The fi nding of homologous CRP-like pentameric proteins, called
pentraxins, in numerous vertebrates, as well as invertebrates (Magor and Magor, 2001), suggests it is
an ancient element of an innate host immune defense strategy dependent upon the ability to opsonize
pathogenic ligands (Tharia et al. 2002). Unlike the activation of complement by immunoglobulin,
complement activation initiated by CRP is limited to C1-C4 by the complement-control protein, factor
H (Giannakis et al. 2003; Du Clos, 2002; Giannakis et al. 2001). Therefore, CRP promotes phagocytosis
of particles without generating a strong infl ammatory response (Du Clos, 2002).
C-reactive protein also exhibits a distinct anti-infl ammatory activity indicated by its protective
effects against endotoxic shock, allergic encephalitis, infl ammatory alveolitis, nephrotoxic nephritis, and
systemic lupus erythematosus (SLE) (Black et al. 2004; Rodriguez et al. 2005; Szalai et al. 2000). This
activity is believed to be mediated, at least in part, by the immunosuppressive cytokine IL-10, whose
expression is induced by CRP’s binding to Fcγ receptors on macrophages (Ogden and Elkon, 2005). In
Biomarker Insights 2006:1 77–80
Kraus and Jordon
addition, CRP appears to play a very important role
in preventing autoimmunity (Du Clos and Mold,
2004; Szalai et al. 2002; Russell et al. 2004) by
targeting apoptotic and necrotic cells for removal.
Of note, many of the autoantibodies commonly
associated with SLE are directed against the major
CRP ligands reported in the literature, namely,
chromatin, histones, fi bronectin, small nRNPs, and
laminin (Du Clos et al. 1991; Black et al. 2004);
this suggests for at least this autoimmune disease,
a failure of the normal CRP clearance mechanisms.
However, debate continues over whether CRP
is primarily a passive indicator of infl ammatory
events, a “culprit” mediating disease (Rattazzi
et al. 2003; Bisoendial et al. 2005), or nature’s
own immunosuppressant, functioning to limit
tissue damage, modulating acute infl ammation,
and preventing autoimmunity.
The development of robust assays of supe-
rior sensitivity compared to those for basic CRP
measurement, has allowed the identifi cation of
patients with low levels of infl ammation. These
high-sensitivity CRP (hs-CRP) assays have led to
increasing use of this protein in the study of the
infl ammatory nature of many chronic diseases
such as atherosclerosis (Ridker, 2004; Armani and
Becker, 2005). With the recognition that infl amma-
tion plays a role in CVD and precedes myocardial
infarction, numerous reports have emerged with
plausible explanations for an association between
hs-CRP and CVD (Pepys and Hirschfi eld, 2003)
and for the characterization of hs-CRP as a robust
and independent predictor of future cardiovascular
events (Verma, 2004). The expanding interest in
infl ammation and its relation to CVD resulted in a
2002 workshop sponsored by the American Heart
Association (AHA) and Centers for Disease control
(CDC), and guidelines for the use of hs-CRP in
the assessment of risk of such events have been
proposed (Pearson et al. 2003). This consensus
panel issued a statement regarding interpretive
ranges for hs-CRP for assessment of risk for CVD
(< 1 mg/L low risk group, 1–3 mg/L average risk
group, and > 3 mg/L high risk group) (Pearson
et al. 2003). Since then at least 945 clinical labo-
ratories across the country have begun performing
hs-CRP testing as an assay to assist in the assess-
ment of CVD risk. However, the values on which
these categories are based have been derived
almost exclusively from Caucasian European
and European American reference populations
(Anand et al. 2004).
CRP is strongly associated with obesity, and
weight loss has been shown to decrease CRP in
nine of ten studies in which it has been evaluated
(Dietrich and Jialal, 2005). Race and gender also
strongly infl uence serum hs-CRP concentration
(Khera et al. 2005). In Dallas County, character-
ized as a typical multiethnic U.S. urban popula-
tion, the median hs-CRP level is 30% higher in
blacks than in whites, and almost twice as high
in women as men (Khera et al. 2005). A new
study demonstrated that cardiorespiratory fi tness
level, hormone replacement therapy use, and
high-density lipoprotein cholesterol accounted
for the gender difference in hs-CRP (Huffman
et al. 2006). It is also increasingly evident that
genetic factors, including apoE genotype (Marz
et al. 2004) and polymorphisms in the hs-CRP gene
(Russell et al. 2004; Szalai et al. 2002; Suk et al.
2005), regulate basal hs-CRP concentrations. The
substantial variability in hs-CRP concentrations
in people of different ethnic origins, led Anand
et al. to conclude that uniform hs-CRP cut-points
were not appropriate for defi ning vascular risk
across diverse populations (Anand et al. 2004).
Our fi ndings in an ethnically diverse population
with comorbidities point to similar conclusions.
In this cohort of 670 individuals (49% African
American and 58% female), mean ln hs-CRP
was higher in African-Americans and in women
(p < 0.0001) and was strongly correlated with body
mass index (r = 0.401, p < 0.0001), but not with age
(r = 0.008, p = 0.841) (Jordan et al. 2002). In addi-
tion to ethnicity and body mass index, ln hs-CRP
was also independently associated with chronic
pulmonary disease. We further evaluated a subset
of individuals in Johnston County, North Carolina,
without self-reported cardiovascular disease and
with a low ten-year risk for cardiovascular disease
based upon the Framingham cardiovascular disease
risk score (Wilson et al. 1998). Notwithstanding
low risk by the Framingham score, the majority
of these individuals were categorized as moderate
or high risk for cardiovascular disease based
upon serum hs-CRP concentration; women (even
after excluding hormone replacement users) and
individuals with osteoarthritis chiefl y comprised
this high-risk group based on hs-CRP (Kraus
et al. 2006).
Controversy also exists regarding the potential
for CRP to act as a mediator of atherothrombotic
disease (Pepys and Hirschfield, 2003; Pepys,
2005). Although bacterial recombinant human CRP
Biomarker Insights 2006:1
CRP as Target
has been shown to induce a massive acute phase
response in humans (Bisoendial et al. 2005), these
results, and possibly most of the proinfl ammatory
activities ascribed to CRP, may be attributable to
contamination of CRP preparations with lipopoly-
saccharide, endotoxin, or the preservative, sodium
azide (Pepys et al. 2005). Moreover, the description
of CRP as a pathogenic agent underlying cardio-
vascular disease (Pearson et al. 2003; Armani and
Becker, 2005) contrasts sharply with the generally
protective and anti-infl ammatory action of CRP
(Volanakis, 2001) described above. The large
population-based Dallas Heart study has recently
reported that hs-CRP was not independently associ-
ated with atherosclerotic burden defi ned by either
coronary artery calcifi cation on cardiac electron-
beam computed tomography scans or by abdominal
aortic plaque on magnetic resonance images (Khera
et al. 2006). Other recent assessments, with careful
control for traditional risk factors for CVD, suggest
that minimal improvement in CVD risk prediction
is provided by hs-CRP over conventional risk
factors (Sepulveda and Mehta, 2005). The relative
risk ratio (RR) of hs-CRP for CVD is estimated to
be much lower (RR=1.45) than originally reported
(Levinson et al. 2004); used alone, hs-CRP has
been estimated to have a very low positive predic-
tive value (≤0.86%) for predicting CVD (Levinson
et al. 2004; Levinson, 2005).
A small-molecule inhibitor of CRP, perhaps the
fi rst of many to come, has recently been designed
and synthesized (Pepys et al. 2006). This inhibitor
abrogated the increase in infarct size and cardiac
dysfunction produced by injection of human CRP
in a rat model of acute myocardial infarction. Thus,
the rationale for targeting CRP is based upon the
ability of human CRP to increase myocardial and
cerebral infarct size in rats subjected to coronary
or cerebral artery ligation, respectively. However,
this may be nothing more than an epiphenomenon
related to the inability of the rat isoform of the
native complement-control protein, factor H, to
interact with human CRP. Of note, rat CRP does
not activate rat complement, nor cause these delete-
rious effects in the rat myocardial infarction model.
In the experiments described above, human CRP
was required to activate rat complement.
Ethnicity and gender exert strong infl uences
on serum hs-CRP concentration and confound
the prediction of CVD risk based upon hs-CRP.
Caution is advised in the use of serum hs-CRP for
predicting CVD or its inhibition for treating CVD
until the consequences of CRP inhibition are better
understood, and further conclusive evidence is
available demonstrating a pathologic role for CRP
in CVD, taking into account the biology of native
interacting factors, and evaluating the pathologic
signifi cance of CRP elevations due to ethnicity,
gender and genetics.
Supported by the following funding sources:
NIH/NIA Claude D. Pepper OAIC 2P60 AG11268
(VBK); Centers for Disease Control and Prevention
and Prevention/Association of Schools of Public
Health grant S043, S1734, S1733, and S3486, the
NIAMS Multipurpose Arthritis and Musculosk-
eletal Disease Center grant 5-P60-AR30701, and
the NIAMS Multidisciplinary Clinical Research
Center grant 5-P60-AR49465-03 (JMJ).
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