C-Reactive Protein Research

C-REACTIVE PROTEIN

2011-11-15T10:04:00.000-06:00

Just a Biomarker of Inflammation or a Pathophysiological Player in Myocardial Function and Morphology?
bY: Rainer Schulz, Gerd Heusch

In response to inflammatory stress, C-reactive protein (CRP) is predominantly secreted from the liver and adipose tissue(s), and an independent relationship exists between different markers of overweight/obesity and elevated high sensitive (hs) CRP levels

Higher hsCRP levels predict incident myocardial infarction (MI), stroke, peripheral arterial disease, sudden cardiac death, and all-cause mortality in healthy individuals with no history of cardiovascular disease.1,2 hsCRP at admission predicts in-hospital outcome, and hsCRP at discharge predicts 6-month event rate and 30-day mortality (Global Utilization of Strategies To Open occluded arteries [GUSTO] IV) in patients with an acute coronary syndrome. Indeed, adding hsCRP levels to the Global Registry in Acute Coronary Events (GRACE) acute coronary syndrome risk model improves the prediction of 30-day mortality. In patients with non-ST-elevated MI, an increased hsCRP level predicts the death rate even at 20-month follow-up but does not predict stent-related complications.

The question of whether CRP, apart from serving as a biomarker, acts as a causal factor in vascular/coronary artery disease has been addressed in animal models, in which CRP was injected or genetically …

Cross-Sectional Associations of Albuminuria and C-Reactive Protein With Functional Disability in Older Adults With Diabetes

2011-04-04T12:58:00.000-05:00

OBJECTIVE To examine the relationship between albuminuria, inflammation, and disability in older adults with diabetes.

RESEARCH DESIGN AND METHODS Data were from 1,729 adults (≥60 years) with diabetes in the National Health and Nutrition Examination Survey, 1999–2008. Disability in activities of daily living (ADL), instrumental activities of daily living (IADL), leisure and social activities (LSA), general physical activities (GPA), and lower-extremity mobility (LEM) was obtained from self-reports. Urinary albumin-to-creatinine ratio (UACR) (mg/g) was categorized into normal (UACR <30 mg/g), microalbuminuria (UACR 30–300 mg/g), and macroalbuminuria (UACR >300 mg/g). C-reactive protein (CRP) levels were quantified by latex-enhanced nephelometry.

RESULTS In the full-adjusted model, microalbuminuria was associated with disability in ADL, LSA, and LEM with corresponding odds ratios (ORs) (95% CIs) of 1.51 (1.16–1.98), 1.62 (1.23–2.14), and 1.34 (1.03–1.74), respectively, compared with participants without albuminuria. Macroalbuminuria was associated with disability in ADL, IADL, and LEM with corresponding ORs (95% CIs) of 1.94 (1.24–3.03), 1.93 (1.23–3.02), and 2.20 (1.38–3.49), respectively, compared with participants without albuminuria. Elevated CRP (>0.3 mg/dL) was associated with increased odds of disability in ADL and LEM, with corresponding ORs (95% CIs) of 1.28 (1.00–1.62) and 1.68 (1.34–2.11), respectively. Subjects with both albuminuria and elevated CRP had higher odds of disability than individuals with no albuminuria and normal CRP.

CONCLUSIONS Albuminuria and inflammation were independent correlates for disability among older adults with diabetes. There was an interaction of albuminuria and elevated CRP on disability, suggesting that the presence of subclinical inflammation may amplify the effect of albuminuria on disability in older adults living with diabetes.

Hsu-Ko Kuo, MD, MPH1, Soham Al Snih, MD, PHD1,2, Yong-Fang Kuo, PHD1,2,3 and Mukaila A. Raji, MD1,2

Changes in C-reactive protein from low-fat diet and/or physical activity in men and women with and without metabolic syndrome

2010-09-15T16:01:00.000-05:00

Change in high-sensitivity C-reactive protein (CRP) from low-fat diet (diet) and physical activity (PA) interventions is relatively unknown for adults with metabolic syndrome. The objective of the study was to assess CRP change (ΔCRP) with diet and/or PA in men and women with and without metabolic syndrome. Men (n = 149) and postmenopausal women (n = 125) with elevated low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol were recruited into a 1-year randomized controlled trial.

Treatment groups were as follows: control, diet (reduced total fat, saturated fat, and cholesterol intake), PA (45-60 minutes at 60%-85% maximum heart rate), or diet + PA. Weight loss was not an intervention focus. Metabolic syndrome was defined using the American Heart Association/National Heart, Lung, and Blood Institute criteria.

Stored plasma samples were analyzed for CRP. Change in CRP was compared between treatments, within sex and metabolic syndrome status, using analysis of covariance, including covariates for baseline CRP and body fat change. For women with metabolic syndrome (n = 39), ΔCRP was greater in diet vs control (-1.2 ± 0.4, P = .009), diet + PA vs control (-1.3 ± 0.4, P = .006), and diet + PA vs PA (-1.1 ± 0.4, P = .02). Women with metabolic syndrome receiving the diet component (diet or diet + PA) had greater ΔCRP compared with those who did not (control or PA) (P = .001).

Change in CRP was not significantly different between intervention groups in men overall, women overall, men with (n = 47) or without metabolic syndrome (n = 102), or women without metabolic syndrome (n = 86). Low-fat diet may be the most effective treatment for reducing CRP in women with metabolic syndrome.

Author(s)
CAMHI Sarah M. (1) ; STEFANICK Marcia L. (2) ; RIDKER Paul M. (3) ; ROHM YOUNG Deborah (4) ;

Increased Consumption of Fatty and Lean Fish Reduces Serum C-Reactive Protein Concentrations but Not Inflammation Markers

2010-02-22T15:41:00.001-06:00

Journal of Nutrition, doi:10.3945/jn.109.113472
Vol. 140, No. 2, 371-376, February 2010

Fish consumption is associated with a reduced colorectal cancer risk. A possible mechanism by which fish consumption could decrease colorectal cancer risk is by reducing inflammation. However, thus far, intervention studies investigating both systemic and local gut inflammation markers are lacking. Our objective in this study was to investigate the effects of fatty and lean fish consumption on inflammation markers in serum, feces, and gut. In an intervention study, participants were randomly allocated to receive dietary advice (DA) plus either 300 g of fatty fish (salmon) or 300 g of lean fish (cod) per week for 6 mo, or only DA.

Serum C-reactive protein (CRP) concentrations were measured pre- and postintervention (n = 161). In a subgroup (n = 52), we explored the effects of the fish intervention on fecal calprotectin and a wide range of cytokines and chemokines in fecal water and in colonic biopsies. Serum CRP concentrations were lower in the salmon (–0.5 mg/L; 95% CI –0.9, –0.2) and cod (–0.4 mg/L; 95% CI –0.7, 0.0) groups compared with the DA group. None of the inflammation markers in fecal water and colonic biopsies differed between the DA group and the groups that consumed extra fish.

In conclusion, increasing salmon or cod consumption for 6 mo resulted in lower concentrations of the systemic inflammation marker CRP. However, exploratory analysis of local markers of inflammation in the colon or feces did not reveal an effect of fish consumption.

Gerda K. Pot5, Anouk Geelen5, Gosia Majsak-Newman6, Linda J. Harvey6, Fokko M. Nagengast7, Ben J. M. Witteman8, Paul C. van de Meeberg9, Andrew R. Hart10,11, Gertjan Schaafsma1, Elizabeth K. Lund2, Ger T. Rijkers12,13 and Ellen Kampman5,*

5 Division of Human Nutrition, Wageningen University, Wageningen 6703 HD, The Netherlands; 6 Nutrition and Gastrointestinal Health, Institute of Food Research, Norwich NR4 7UA, UK; 7 UMC St Radboud, Nijmegen 6525 GA, The Netherlands; 8 Gelderse Vallei Hospital, Ede 6716 RP, The Netherlands; 9 Slingeland Hospital, Doetinchem 7000 AD, The Netherlands; 10 Norfolk and Norwich University Hospital NHS Trust, NR4 7UY, UK; 11 University of East Anglia, Norwich NR4 7TJ, UK; 12 Department of Surgery, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands; 13 Laboratory of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein 3430 EM, The Netherlands

C-Reactive Protein Inhibits Insulin Activation of Endothelial Nitric Oxide Synthase via the Immunoreceptor Tyrosine-Based Inhibition Motif of FcRIIB a

2009-11-24T13:16:00.000-06:00

Keiji Tanigaki, Chieko Mineo, Ivan S. Yuhanna, Ken L. Chambliss, Michael J. Quon, Ezio Bonvini, Philip W. Shaul

Insulin promotes the cardiovascular protective functions of the endothelium including NO production by endothelial NO synthase (eNOS), which it stimulates via Akt kinase which phosphorylates eNOS Ser1179. C-reactive protein (CRP) is an acute-phase reactant that is positively correlated with cardiovascular disease risk in patients with type 2 diabetes.

We previously showed that CRP inhibits eNOS activation by insulin by blunting Ser1179 phosphorylation. We now elucidate the underlying molecular mechanisms. We first show in mice that CRP inhibits insulin-induced eNOS phosphorylation, indicating that these processes are operative in vivo. In endothelial cells we find that CRP attenuates insulin-induced Akt phosphorylation, and CRP antagonism of eNOS is negated by expression of constitutively active Akt; the inhibitory effect of CRP on Akt is also observed in vivo.

A requirement for the IgG receptor FcRIIB was demonstrated in vitro using blocking antibody, and reconstitution experiments with wild-type and mutant FcRIIB in NIH3T3IR cells revealed that these processes require the ITIM (immunoreceptor tyrosine-based inhibition motif) of the receptor. Furthermore, we find that endothelium express SHIP-1 (Src homology 2 domain–containing inositol 5'-phosphatase 1), that CRP induces SHIP-1 stimulatory phosphorylation in endothelium in culture and in vivo, and that SHIP-1 knockdown by small interfering RNA prevents CRP antagonism of insulin-induced eNOS activation.

Thus, CRP inhibits eNOS stimulation by insulin via FcRIIB and its ITIM, SHIP-1 activation, and resulting blunted activation of Akt. These findings provide mechanistic linkage among CRP, impaired insulin signaling in endothelium, and greater cardiovascular disease risk in type 2 diabetes.

C-reactive protein elicits white blood cell activation in humans.

2009-09-08T10:09:00.001-05:00

C-Reactive Protein Study:
OBJECTIVE: Consistent epidemiologic evidence suggests that acute infections increase the risk for acute cardiovascular events. We tested in humans whether activation of peripheral leukocytes in reaction to the administration of recombinant human C-reactive protein (rhCRP) may provide a mechanism for infectious diseases to promote atherosclerotic disease.

METHODS AND RESULTS: By using quantitative real-time polymerase chain reaction analysis, whole-blood expression profiles were analyzed for 95 inflammatory markers before and after infusion of 1.25 mg/kg rhCRP in 5 male volunteers. Relevant transcript levels were measured at baseline and 4 and 8 hours after rhCRP-infusion. CRP caused significant up-regulation of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-1, plasminogen activator urokinase, macrophage inflammatory protein 1 alpha, and nuclear factor of kappa B inhibitor mRNAs in peripheral leukocytes. mRNA up-regulation of MMP-9 and MCP-1 was 17- and 11-fold, respectively. The corresponding increase in plasma protein levels of MMP-9 (78+/-32 ng/mL to 109+/-41 ng/mL; P=.014) and MCP-1 (312+/-92 pg/mL to 2590+/-898 pg/mL; P=.007) closely mirrored mRNA findings. Also, in whole-blood culture stimulation assays, CRP induced proinflammatory changes. Notably, heat inactivation abolished the capacity of CRP to evoke these proinflammatory changes, excluding a role for contaminants within the purified CRP preparation.

CONCLUSION: CRP elicits activation of peripheral leukocytes with ensuing secretion of plaque-destabilizing mediators. These findings are consistent with the hypothesis that infectious diseases trigger manifestations of atherosclerosis, in which CRP elevation might contribute to the onset of cardiovascular events.

Bisoendial RJ, Birjmohun RS, Akdim F, van 't Veer C, Spek CA, Hartman D, de Groot ER, Bankaitis-Davis DM, Kastelein JJ, Stroes ES.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

Are there Bi-directional Associations between Depressive Symptoms and C-Reactive Protein in Mid-life Women?

2009-08-20T10:54:00.000-05:00

OBJECTIVE: To test whether depressive symptoms are related to subsequent C-reactive protein (CRP) levels and/or whether CRP levels are related to subsequent depressive symptoms in mid-life women. METHODS: Women enrolled in the Study of Women's Health Across the Nation (SWAN) were followed for seven years and had measures of CES-Depression scores and CRP seven times during the follow-up period. Women were pre- or early peri-menopausal at study entry and were of Caucasian, African American, Hispanic, Japanese, or Chinese race/ethnicity. Analyses were restricted to initially healthy women.

RESULTS: Longitudinal mixed linear regression models adjusting for age, race, site, time between exams, and outcome variable at year X showed that higher CES-D scores predicted higher subsequent CRP levels and vice versa over a 7-year period. Full multivariate models adjusting for body mass index, physical activity, medications, health conditions, and other covariates showed that higher CRP levels at year X predicted higher CES-D scores at year X+1, p = 0.03. Higher depressive symptoms predicted higher subsequent CRP levels at marginally significant levels, p=0.10.

CONCLUSIONS: Higher CRP levels led to higher subsequent depressive symptoms, albeit the effect was small. The study demonstrates the importance of considering bi-directional relationships for depression and other psychosocial factors and risk for heart disease.

Matthews KA, Schott LL, Bromberger JT, Cyranowski JM, Everson-Rose SA, Sowers M.
University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213

C-Reactive Protein: Fitness level and body composition are associated with inflammation in non-obese children

2009-05-20T16:29:00.000-05:00

Childhood obesity and poor fitness are associated with insulin resistance (IR), risk for coronary heart disease (CHD), and type 2 diabetes mellitus. Elevated markers of inflammation (e.g., C-reactive protein [CRP]) are independent predictors of CHD. Whether higher percent body fat and poor fitness in non-obese children are associated with evidence of inflammation and IR is unclear.

We evaluated 75 children with non-obese body mass index (BMI) for age (<95th percentile), ages 11-14 years for fasting insulin, glucose, adiponectin, CRP, body composition, and maximum oxygen-consumption (VO2max). CRP correlated positively with body composition (BMI z-score, p = 0.00062; percent body fat, p = 0.00007; and total body fat in grams, p = 0.00006) and negatively with VO2max, p = 0.036. Using multivariate analysis, VO2max and percent body fat were both independent predictors of CRP. Fasting insulin and insulin resistance as assessed by QUICKI did not correlate with CRP, fitness, or fatness in these non-obese children.

Adiponectin showed no significant correlations, and gender did not influence correlation analyses. We conclude that in non-obese children, low fitness and higher body fat are both associated with inflammation (i.e., higher levels of CRP). This observation strengthens the importance of promoting both fitness and healthy body composition in all children.

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 54650, USA.

C-Reactive Protein Is a Determinant of First-Ever Stroke: Prospective Nested Case-Referent Study

2009-05-12T10:47:00.002-05:00

Background and Purpose: C-reactive protein ,(CRP) is a determinant of stroke, but there are no prospective studies on CRP and first ischemic stroke divided into etiologic subtypes. Our primary aim was to study C-reactive protein as a determinant of ischemic stroke, classified according to Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria, and intracerebral hemorrhage (ICH) in a prospective study. A secondary aim was to study the relationship between the 1444C>T polymorphism, plasma levels of C-reactive protein and stroke. Methods: The study was a prospective population-based case-referent study nested within the Northern Sweden Cohorts. We defined 308 cases of ischemic stroke and 61 ICH. Two controls for each case were defined from the same cohort. Results: The OR for the highest (>3 mg/l) versus lowest group (<1 mg/l) of CRP was 2.58 (95% CI 1.74-3.84) for ischemic stroke and 1.63 (95% CI 0.67-3.93) for ICH. In a multivariate model including traditional risk factors, CRP remained associated with ischemic stroke (OR 2.06; 95% CI 1.29-3.29). Small-vessel disease was associated with C-reactive protein CRP in the multivariate model (OR 3.88; 95% CI 1.10-13.7). The C-reactive protein 1444 (CC/CT vs. TT) polymorphism was associated with plasma levels of C-reactive protein but neither with ischemic stroke nor with ICH. Conclusions: This prospective population-based study shows that CRP is significantly associated with the risk of having a first ischemic stroke, especially for small-vessel disease. No significant associations were found between the CRP 1444C>T polymorphism and any stroke subtype.

Jonas Sven Olof Andersson
Department of Medicine and Geriatrics
Skellefteå County Hospital
SE-931 86 Skellefteå (Sweden

Evaluation Of C-Reactive Protein

2009-01-02T14:12:00.003-06:00

An evaluation of the association between C-reactive protein , the change in C-reactive protein over one year, and all-cause mortality in chronic immune-mediated inflammatory disease managed in UK general practice.

Objectives. To evaluate the association between systemic inflammation , as measured by (CRP), , and all-cause mortality. To also evaluate the association between change in CRP status (sub-acute, 10 mg/l and acute >10 mg/l) and all-cause mortality.

Methods. A cohort of patients was selected from The Health Improvement Network (THIN) data set of anonymized patient-level data from UK general practice. Patients were selected if they had a diagnosis of RA, psoriasis, AS or PsA. Survival was evaluated using " Cox proportional hazards regression models (CPHMs).

Results. A total of 11 362 cases had at least one CRP measurement. Analysis grouped by each additional unit increase in log-CRP (range 1–6) across the observed range was associated with a 21% increase in the hazard ratio (HR) of death, after controlling for cardiovascular risk factors (P < 0.001). This observation was consistent in separate analysis of cases with either RA or psoriasis. Repeated CRP observations around 1 yr apart were recorded in 2802 subjects. After controlling for confounding factors, in cases whose CRP changed from sub-acute (10 mg/l) to acute (>10 mg/l), the HR for death increased 2-fold (P < 0.001) relative to cases whose CRP remained sub-acute. In comparison, among those subjects whose CRP was reduced from acute to sub-acute, the HR was virtually identical to those who stayed sub-acute (P = 0.571).

Conclusions. C-reactive protein ( level predicted all-cause mortality after standardization for traditional risk factors, as did change in CRP status from sub-acute to acute observed over 1 yr.

KEY WORDS: C-reactive protein, Systemic inflammation, Survival, Rheumatoid arthritis, Psoriasis, Ankylosing spondylitis, Psoriatic arthritis

Rheumatology 2009 48(1):78-82; doi:10.1093/rheumatology/ken415

LPS-induced MCP-1 and IL-6 production is not reversed by oestrogen in human periodontal ligament cells

2008-07-30T16:16:00.002-05:00

Objective
Periodontal ligament (PDL) cells express oestrogen receptors but the functional importance of oestrogen in PDL cells exposed to bacterial endotoxins is not known. Here we investigate if the inflammation promoter lipopolysaccharide (LPS) affects PDL cell production of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP) and/or normal functional PDL cell characteristics such as collagen synthesis and cell proliferation and if oestrogen modulates the effects of LPS.

Methods
PDL cells were obtained from periodontal ligament of premolars. PDL cells were treated with Escherichia coli LPS in the absence or presence of oestrogen (17β-oestradiol, E2). Cellular concentration of IL-6, MCP-1 and CRP was determined by enzyme-linked immunosorbent assay (ELISA). Collagen synthesis was determined by l-[3H]proline incorporation. Cell proliferation was assessed by DNA synthesis measurement using [3H]thymidine incorporation.

Results
Stimulation with LPS (500 ng/ml to 10 μg/ml) increased IL-6 production in a concentration-dependent manner. Lower concentration (100 ng/ml) of LPS had no effect. LPS-induced stimulation of IL-6 was not reversed by a physiologically high concentration (100 nM) of E2. LPS increased also MCP-1 production which was unaffected by E2. Treatment with E2 alone had no effect on either IL-6 or MCP-1. Stimulation with LPS had no effect on CRP. LPS did not affect collagen synthesis and cell proliferation, reflecting normal physiological properties of PDL cells.

Conclusions
LPS stimulates PDL cell IL-6 and MCP-1 production but has no effect on the normal physiological properties of PDL cells. LPS-induced IL-6 and MCP-1 is not reversed by oestrogen suggesting that oestrogen exerts no anti-inflammatory effect via this mechanism.

ARTICLE

The Utility of Serum C-Reactive Protein in Differentiating Bacterial from Nonbacterial Pneumonia in Children: A Meta-Analysis of 1230 Children.

2008-07-15T11:32:00.003-05:00

Background:
Differentiating bacterial from nonbacterial community-acquired pneumonia in children is difficult. Although several studies have evaluated serum concentrations of C-reactive protein (CRP) as a predictor of bacterial pneumonia in this patient population, the utility of this test remains unclear.

Objective:
The purpose of this meta-analysis was to quantitatively define the utility of serum CRP as a predictor of bacterial pneumonia in acutely ill children.

Methods:
Multiple databases were searched, bibliographies reviewed, and 2 authorities in the field were queried. Studies were included if: (1) the patient population was between 1 month and 18 years of age; (2) C-reactive protein (CRP) was quantified in all subjects as part of the initial evaluation of a suspected, infectious, pulmonary process; (3) a cutoff serum CRP concentration between 30 and 60 mg/dL was used to distinguish nonbacterial from bacterial pneumonia; (4) some criteria were applied to differentiate bacterial from nonbacterial or viral pneumonia; (5) all patients were acutely ill; and (6) a chest radiograph was obtained as part of the initial evaluation. The quality of each included study was determined across 4 metrics: diagnostic criteria; study design; exclusion of chronically ill or human immunodeficiency virus infected subjects; and exclusion of patients who recently received antibiotics. Data was extracted from each article; the primary outcome measure was the odds ratio of patients with bacterial or mixed etiology pneumonia and serum CRP concentrations exceeding 30-60 mg/L. Heterogeneity among the studies was determined by Cochran's Q statistic; the methods of both Mantel and Haenszel, and DerSimonian and Laird were used to combine the study results.

Results:
Eight studies fulfilled inclusion criteria. Combining all of the studies demonstrated a pooled study population of 1230 patients with the incidence of bacterial infection of 41%. Children with bacterial pneumonia were significantly more likely to have serum C-reactive protein (CRP) concentrations exceeding 35-60 mg/L than children with nonbacterial infections (odds ratio = 2.58, 95% confidence interval = 1.20-5.55). Sensitivity analysis demonstrated that this difference was robust. There was significant heterogeneity among the 8 studies (Q = 37.7, P < 0.001, I2 = 81.4) that remained throughout the sensitivity analysis.

Serum C-Reactive Protein at Admission Predicts In-Hospital Mortality in Medical Patients

2008-07-01T12:28:00.006-05:00

Background
Previous studies have examined the role of inflammatory markers in patients with coronary heart disease, stroke, chronic renal failure and other selected patient populations. The aim of this study was to assess the clinical utility of serum C-reactive protein (CRP) at admission in predicting outcome in hospitalized medical patients.

Methods
All patients admitted to our medical department were eligible to be included in the study. At the time of admission, demographic and clinical information was obtained. CPR was measured within 12 h of hospitalization. The results were analyzed using Cox proportional hazards multiple regression model.

Results
Three hundred eighty-two patients were included in the study (186 males and 196 females). Age (mean ± standard deviation) was 70.8 ± 15.7 years. Serum CRP [median (interquartile range) at admission was 29.7 mg/l (6.6–114.3). Serum CRP at admission was independently associated with in-hospital death. Levels above 120 mg/l increased the probability of fatal outcome three fold (hazard ratio = 2.98, 95% confidence interval: 1.35–6.58). In patients older than 80 years, CRP at admission was a stronger predictor of in-hospital death (hazard ratio = 5.41, 95% confidence interval: 1.38–21.26).

Conclusions
Serum CRP at admission is an independent predictor of mortality in hospitalized patients, particularly in the elderly. Admission CRP higher than 120 mg/l was associated with increased probability of in-hospital death (three fold in the overall population and five fold in the elderly subgroup) compared with lower levels.

Phosphoethanolamine-complexed C-reactive protein: A pharmacological-like macromolecule that binds to native low-density lipoprotein in human serum

2008-07-01T12:28:00.005-05:00

Background
C-reactive protein (CRP) is an acute phase plasma protein. An important binding specificity of CRP is for the modified forms of low-density lipoprotein (LDL) in which the phosphocholine-binding sites of CRP participate. CRP, however, does not bind to native LDL.

Methods
We investigated the interaction of CRP with native LDL using sucrose density gradient ultracentrifugation.

Results
We found that the blocking of the phosphocholine-binding sites of CRP with phosphoethanolamine (PEt) converted CRP into a potent molecule for binding to native LDL. In the presence of PEt, CRP acquired the ability to bind to fluid-phase purified native LDL. Because purified native LDL may undergo subtle modifications, we also used whole human serum as the source of native LDL. In the presence of PEt, CRP bound to native LDL in serum also. The effect of PEt on CRP was selective for LDL because PEt-complexed CRP did not bind to high-density lipoprotein in the serum.

Conclusions
The pharmacologic intervention of endogenous CRP by PEt-based compounds, or the use of exogenously prepared CRP-PEt complexes, may turn out to be an effective approach to capture native LDL cholesterol in vivo to prevent the development of atherosclerosis.

ARTICLE

Researcher Identifies Protein That Helps Predict Prostate Cancer Survival

2008-07-01T12:27:00.001-05:00

An Oregon Health & Science University Cancer Institute researcher has identified a protein that is a strong indicator of survival for men with advanced prostate cancer. The C-reactive protein , also known as CRP, is a special type of protein produced by the liver that is elevated in the presence of inflammation.
"This could mean that a simple blood test that is already available could help in clinical decision making and patient counseling. Patients and doctors would know better what to expect from the prostate cancer they are facing," said Tomasz Beer, M.D., director of the Prostate Cancer Research Program at the OHSU Cancer Institute, associate professor of medicine (hematology/medical oncology), OHSU School of Medicine.

Beer's research will be published online in the journal Cancer on Monday, April 21.

Past research has shown that cancer causes an inflammatory response. This research also suggests that inflammation may play an important role in driving prostate cancer progression and resistance to therapy. Inflammatory cells are attracted to cancer sites and this local inflammation can lead to a release of inflammatory markers, like CRP.

"While inflammation may sometimes slow the progression of the cancer, an increasing body of evidence suggests that cancer can actually take advantage of the inflammatory response, and the reaction of the immune system may fuel cancer progression. To the extent that our hypothesis proves true, C-reactive protein may be reflecting the overall intensity of the inflammation," Beer said.

The finding that higher CRP is associated with shorter survival and a lower probability of response to chemotherapy is a result of a secondary analysis of inflammatory markers in patients enrolled in the ASCENT study, a large Phase 2 clinical trial that evaluated treatment with docetaxel and DN-101, a high dose formulation of calcitriol or docetaxel with placebo. This analysis included patients from both groups. The analyses were supported by Novacea Inc., the sponsor of the ASCENT study. This new finding was in collaboration with Novacea.

Because this is the first time CRP has been linked with both response and survival in study subjects with advanced prostate cancer receiving chemotherapy, it will be important to confirm this finding in an independent data set before this can become a routine blood test for men with advanced prostate cancer, Beer explained.

“If confirmed, besides providing useful information for the patient, this finding could also provide us with vital insight into the fundamental role of inflammation in the progression of advanced prostate cancer. A better understanding of this process could provide us with novel therapeutic interventions for control of this disease and its symptoms,” Beer said.

OHSU and Beer have significant financial interest in Novacea Inc., a company that has a commercial interest in the results of this research and technology. This potential conflict was reviewed, and a management plan approved by the OHSU Conflict of Interest in Research Committee and the Integrity Program Oversight Council was implemented.

Maternal serum C-reactive protein concentrations in early pregnancy and subsequent risk of preterm delivery

2008-07-01T12:26:00.006-05:00

OBJECTIVE: To examine the relation between maternal early pregnancy serum C-reactive protein (CRP) and preterm delivery (PTD).

DESIGN AND METHODS: Women were recruited before 20 weeks gestation and were followed up until delivery. Maternal serum C-reactive protein CRP was measured by competitive immunoassay . Logistic regression procedures were used to calculate adjusted odds ratio (OR) and 95% confidence intervals (95%CI).

RESULTS: Elevations in CRP ( concentrations were associated with the risk of PTD overall. After adjusting for confounding, the OR for highest quartile (> or = 7.5 vs. < 2.0 mg/L) of C-reactive protein ( was 2.04 (95%CI: 1.13-3.69). Stratified analyses indicated that elevated CRP was associated with an increased risk of spontaneous preterm labour (OR=2.15, 95%CI: 0.85-5.42), medically indicated preterm delivery (OR=3.29, 95%CI: 0.98-11.02), and very preterm delivery (OR=20.6, 95%CI: 2.53-168.03), but not with preterm premature rupture of membranes (OR=1.48, 95%CI: 0.56-3.86).

CONCLUSIONS: Elevated C-reactive protein ( concentrations in early pregnancy are associated with an increased risk of PTD, particularly medically indicated PTD and very PTD.

Department of Preventive and Social Medicine, Faculty of Medicine, Chulalongkorn University , Bangkok

Rheumatoid Arthritis Linked To Early Death From Cardiovascular Disease

2008-07-01T12:26:00.005-05:00

People with rheumatoid arthritis (RA), an inflammatory autoimmune disease, tend to die younger and, largely from cardiovascular disease (CVD). One explanation for this increasingly recognized fact is that inflammation promotes atherosclerosis. A marker of inflammation, elevation of the C-reactive protein (CRP) level has been shown to predict CVD in the general population. However, other highly inflammatory diseases--Crohn's, for example--do not carry the same high risk of premature death from heart disease.

To identify other possible suspects, researchers in the United Kingdom investigated whether genetic variants linked to the likelihood of developing RA might also make patients more likely to die from CVD. Led by Dr. Tracey M. Farragher at the University of Manchester and funded by the Arthritis Research Campaign (arc), the study focused on two genes--HLA-DRB1and PTPN22--and their interactions with known RA risk factors. The evidence implicates
HLA-DRB1 genotypes , already associated with RA susceptibility and severity, as a predictor of premature death from CVD for inflammatory arthritis patients. For RA patients in particular, having the shared epitope (SE)--a group of HLA-DRB1 alleles with kindred amino acid traits--plus anti-cyclic citrullinated peptide (anti-CCP) antibodies and current smoking is an especially deadly combination.

The study focused on 1,022 patients with inflammatory polyarthritis (IP) recruited from a primary-care-based register of adults. The subjects were all white and nearly 65 percent female, with a mean age of 54 at the onset of symptoms. Starting anywhere between 1989 and 1994, data on file for each participant included the results of blood tests for rheumatoid factor (RF), elevation of the C-reactive protein ((CRP), and anti-CCP antibodies; evaluations of joint pain and functional disability; smoking habits; and, when applicable, the cause and date of death. DNA samples were also available. 751 of the total patients met the American College of Rheumatology criteria for RA.

HLA-DRB1 and PTPN22 genotyping was performed on every patient's DNA. Using Cox proportional hazards regression models, researchers assessed the association of each gene family with the risk of death from all causes and from cardiovascular disease. They also examined the interactions between SE presence, anti-CCP status, and smoking history, adjusted by patient sex and age at symptom onset.

In the years between the register's inception and the study's completion, 242 (24 percent) of the patients died. CVD was named as the cause of death for 76 (31.4 percent) of the deceased. Based on the researchers' analyses, having two copies of the SE alleles increased the risk of death from all causes and from CVD. For individuals with the HLA-DRB1 combination, the risk of death from CVD was increased more than 3-fold. The fatal impact was independent of RF and C-reactive protein ( levels. It was aggravated, however, by the interaction of SE, anti-CCP antibodies, and smoking. Current smokers who carried 2 SE alleles and had anti-CCP antibodies had the highest risk of dying from all causes, as well as a substantially higher risk of dying early from CVD. In calculations focusing on RA patients only, this finding remained consistent. Researchers found no evidence of any association between the PTPN22 gene and the risk of death.

This study is the first to link the HLA-DRB1 genotype with premature death, particularly from cardiovascular disease, for those afflicted with any form of inflammatory arthritis, including RA. As Dr. Farragher stresses, the results "raise the possibility of a targeted strategy to prevent CVD in these patients," while reinforcing the lethal danger of smoking for anyone with a genetic predisposition for arthritis.

Journal article: "Association of the HLA-DRB1 Gene With Premature Death, Particularly From Cardiovascular Disease, in Patients With Rheumatoid Arthritis and Inflammatory Polyarthritis," Tracey M. Farragher, Nicola J. Goodson, Haris Naseem, Alan J. Silman, Wendy Thomson, Deborah Symmons, and Anne Barton, Arthritis & Rheumatism, February 2008; 58:2, pp. 359-369.

What is High Sensitivity C-reactive Protein (HS-CRP)?

2008-07-01T12:26:00.001-05:00

CRP is short for "C-reactive protein " a protein found in the blood. C-Reactive Protein is what we call a marker for inflammation , meaning its presence indicates a heightened state of inflammation in the body. Inflammation is a normal response to many physical states including fever, injury and infection. Inflammation is now believed to play a role in the initiation and progression of cardiovascular disease .

Is HS-C-reactive protein a real risk factor, like cholesterol or smoking?

In studies involving large numbers of patients, C-Reactive Protein levels seem to be correlated with levels of cardiac risk . In fact, CRP seems to be at least as predictive of cardiac risk as cholesterol levels. Data from the Physicians Health Study , a clinical trial involving 18,000 apparently healthy physicians, found that elevated levels of C-Reactive Protein were associated with a threefold increase in the risk of heart attack.

In the Harvard Women's Health Study , results of the CRP test were more accurate than cholesterol levels in predicting coronary problems. Twelve different markers of inflammation were studied in healthy, postmenopausal women . After three years, CRP was the strongest predictor of risk. Women in the group with the highest C Reactive Protein CRP levels were more than four times as likely to have died from coronary disease, or suffered a nonfatal heart attack or stroke. This group was also more likely to have required a cardiac procedure such as angioplasty or bypass surgery than women in the group with the lowest levels.

Elevated hs-CRP is related to increased risk for heart attack, restenosis of coronary arteries after angioplasty, stroke, and peripheral vascular disease (PVD).

So how can I be tested?

A simple blood test can be done at the same time as a cholesterol screening. The high-sensitivity C-reactive protein (hs-CRP) test, helps determine heart disease risk and is widely available. Patients should ask their doctors about hs-CRP specifically.

It is important to remember that the usefulness of knowing hs- C-Reactive Protein levels in a particular individual is still unknown. For the time being, The American Heart Association recommends hs- C-Reactive Protein as part of routine screening for those who are at intermediate risk for heart disease. HS-CRP results in that risk group can help the physician determine additional testing and treatment. The American Heart Association adds that patients at low risk probably do not need their hs-CRP tested and those at high risk should be treated agressively regardless of their CRP test results. Certain medical centers, including The Cleveland Clinic Foundation, are investigating what the exact role of hs- C-Reactive Protein measurement should be in a physician's daily clinical practice.

What can I do if my HS-CRP level is high?

Inflammation should be treated by lifestyle change, such as losing weight, exercising, controlling diabetes, stopping smoking, controlling high blood pressure, and reducing alcohol intake. Antithrombotic medications such as aspirin or clopidogrel may provide protection. Cholesterol-lowering statin drugs and ACE inhibitors may also reduce CRP. Your doctor will prescribe the correct medications and dosage to treat your condition.

Source of this article:
Preventive Cardiology and Rehabilitation Program
The Cleveland Clinic Foundation, Desk C5
9500 Euclid Avenue
Cleveland, OH 44195

The Utility of Serum C-Reactive Protein in Differentiating Bacterial from Nonbacterial Pneumonia in Children: A Meta-Analysis of 1230 Children.

2008-06-26T16:31:00.000-05:00

Background: Differentiating bacterial from nonbacterial community-acquired pneumonia in children is difficult. Although several studies have evaluated serum concentrations of C-reactive protein (CRP) as a predictor of bacterial pneumonia in this patient population, the utility of this test remains unclear.

Objective: The purpose of this meta-analysis was to quantitatively define the utility of serum CRP as a predictor of bacterial pneumonia in acutely ill children.

Methods: Multiple databases were searched, bibliographies reviewed, and 2 authorities in the field were queried. Studies were included if: (1) the patient population was between 1 month and 18 years of age; (2) CRP was quantified in all subjects as part of the initial evaluation of a suspected, infectious, pulmonary process; (3) a cutoff serum CRP concentration between 30 and 60 mg/dL was used to distinguish nonbacterial from bacterial pneumonia; (4) some criteria were applied to differentiate bacterial from nonbacterial or viral pneumonia; (5) all patients were acutely ill; and (6) a chest radiograph was obtained as part of the initial evaluation. The quality of each included study was determined across 4 metrics: diagnostic criteria; study design; exclusion of chronically ill or human immunodeficiency virus infected subjects; and exclusion of patients who recently received antibiotics. Data was extracted from each article; the primary outcome measure was the odds ratio of patients with bacterial or mixed etiology pneumonia and serum CRP concentrations exceeding 30-60 mg/L. Heterogeneity among the studies was determined by Cochran's Q statistic; the methods of both Mantel and Haenszel, and DerSimonian and Laird were used to combine the study results.

Results: Eight studies fulfilled inclusion criteria. Combining all of the studies demonstrated a pooled study population of 1230 patients with the incidence of bacterial infection of 41%. Children with bacterial pneumonia were significantly more likely to have serum C-reactive protein (CRP) concentrations exceeding 35-60 mg/L than children with nonbacterial infections (odds ratio = 2.58, 95% confidence interval = 1.20-5.55). Sensitivity analysis demonstrated that this difference was robust. There was significant heterogeneity among the 8 studies (Q = 37.7, P < 0.001, I2 = 81.4) that remained throughout the sensitivity analysis.

Conclusions: In children with pneumonia, serum CRP concentrations exceeding 40-60 mg/L weakly predict a bacterial etiology.

(C) 2008 Lippincott Williams & Wilkins, Inc

ARTICLE

Usefulness of C-Reactive Protein and Left Ventricular Diastolic Performance for Prognosis in Patients With Left Ventricular Systolic Heart Failure

2008-06-26T16:25:00.000-05:00

High-sensitivity C-reactive protein (hs-CRP) is a hepatocyte-derived inflammatory cytokine shown to be increased in the setting of acute heart failure (HF), particularly with increased intracardiac filling pressures. In the chronic HF setting, the relation between hs-CRP and echocardiographic indexes of left ventricular (LV) diastolic performance has not been examined. We measured plasma hs-CRP levels using a particle-enhanced immunonephelometry assay (Dade Behring, Inc., Deerfield, Illinois) in 136 subjects with chronic HF (LV ejection fraction [EF] ≤35%, New York Heart Association functional classes II to IV). We performed echocardiography, including color M-mode and tissue Doppler methods. We prospectively examined subjects’ death, cardiac transplantation, and HF hospitalization status over 33 ± 17 months. In our study cohort (mean LVEF 26 ± 6%, median plasma hs-CRP 3.19 mg/L), plasma hs-CRP levels progressively increased with worsening LV diastolic dysfunction. In particular, plasma hs-CRP levels correlated with mitral E/A wave ratio (Spearman r = 0.25, p = 0.004), mitral deceleration time (r = −0.28, p = 0.002), pulmonary vein systolic wave/diastolic wave ratio (r = −0.32, p <0.001), mitral E wave/color M-mode velocity of propagation ratio (r = 0.28, p = 0.001), and mitral E wave/tissue Doppler septal E′ wave ratio (r = 0.28, p = 0.001). Plasma hs-CRP levels independently predicted adverse clinical events even after adjustment for LVEF and mitral E wave/tissue Doppler septal E′ wave ratio (hazard ratio 2.28, 95% confidence interval 1.18 to 4.39). In conclusion, in patients with chronic systolic HF, expression of circulating CRP was associated with increasing echocardiographic indexes of diastolic dysfunction. High plasma hs-CRP levels portend poor long-term outcomes, particularly in those with severe concomitant systolic and diastolic dysfunctions.

W.H. Wilson Tang, MDa, Kevin Shrestha, ABa, Frederick Van Lente, PhDb, Richard W. Troughton, MBBSc, Maureen G. Martin, RDCSa, Allen G. Borowski, RDCSa, Sue Jasper, RN, BSNa, Allan L. Klein, MDa

InfectCheck CRP Barcode-Style Lateral Flow Assay for Semi-Quantitative Detection of C-reactive Protein in Distinguishing between Bacterial and Viral..

2008-06-03T16:35:00.000-05:00

In the present study, we describe an InfectCheck barcode-style lateral flow assay for semi-quantitative detection of C-Reactive Protein in distinguishing between bacterial and viral infections. The severity of bacterial infection can be assessed by simply counting the number of red lines developed at the CRP test zone of the test device. If only one visible line appeared at the CRP test zone, it represents a low or mild inflammation with C-Reactive Protein levels < 10 mg/L. Two and three visible lines mean moderate (≥ 10–25 mg/L) and severe (≥ 25–50 mg/L) inflammations respectively while four visible lines stand for a very severe inflammation (≥ 50–100 mg/L). If the visible lines become faint and the intensity of the first line is weaker than that of the control line and may even disappear, this outcome corresponds to the stage of having super severe inflammation (≥ 100 mg/L). A total of 500 patients admitted to hospital through the Accident and Emergency Unit at the Prince of Wales Hospital were examined. The InfectCheck CRP barcode-style rapid test gave a high sensitivity of 88.7% and a high negative predictive value of 93.8%. This result indicates that the rapid test is reliable to exclude non-infected patients. The calculated intra- and inter-assay coefficient of variation for the five C-Reactive Protein concentration ranges was both within 20.0%. It is a one-step whole blood rapid test without any sample pre-treatment and the result is available within 20 min. This user friendly diagnostic tool can allow self-testing by interested individuals without any expensive reading device.

Leung W, Chan CP, Rainer TH, Ip M, Cautherley GW, Renneberg R.

Human C-Reactive Protein Activates Monocyte-Derived Dendritic Cells and Induces Dendritic Cell-Mediated T-Cell Activation

2008-01-29T13:31:00.000-06:00

OBJECTIVE: Recent studies proposed a pathogenic role for C-reactive protein (CRP), an independent predictor of cardiovascular disease (CVD), in atherosclerosis. Therefore, we tested whether CRP may modulate dendritic cell (DC) function, because these professional antigen-presenting cells have been implicated in atherogenesis .

METHODS AND RESULTS: Human monocyte-derived immature DCs were cultured with human CRP (0 to 60 microg/mL) for 24 hours. Thereafter, activation markers were measured by flow-cytometry and DCs were cocultured with CFSE-labeled lymphocytes to measure T-cell proliferation and interferon (IFN)-gamma secretion after 8 days. Exposure to 60 microg/mL CRP (n=5) induced an activated cell morphology and significant (CD40 increase MFI 5.23+/-0.28, P<0.01 paired t test; CD80 6.18+/-0.51, P<0.01) to modest (CD83 1.38+/-0.17, P<0.05, CCR7 1.60+/-0.29, P=0.05) upregulation of DC activation markers. The expression of CD86 and HLA-DR was high, but not affected. T-lymphocytes incubated with CRP-pulsed DCs displayed increased IFN-gamma secretion and proliferation (P<0.001). DC activation was concentration-dependent and detected from 2 microg/mL CRP; the maximum effect was equivalent to that seen with 0.1 microg/mL lipopolysaccharide (LPS). Polymyxin B abolished the LPS response, without influencing CRP effects. Finally, immunohistochemistry could demonstrate DC/CRP colocalization in human atherosclerotic lesions .

CONCLUSIONS: These findings suggest that CRP in plaques or found circulating in CVD patients can influence DC function during atherogenesis.

source: Departments of Cardiology, and Pharmacology, University of Antwerp , Wilrijk, Belgium and the Centre for Regenerative Medicine and Cell Therapy, Departments of Cardiology, and Experimental Haematology, University Hospital of Antwerp, Edegem, Belgium

C-Reactive Protein and its implications in Systemic Lupus Erythematosus

2007-12-27T09:55:00.000-06:00

C-reactive protein CRP is an acute-phase protein known as a biomarker for inflammation. As such CRP levels have been traditionally used to detect and predict the outcome of infections inflammatory and necrotic processes and to monitor the efficacy of treatment in these conditions.

With the development of high sensitivity assays C-reactive protein has resurfaced as a very strong predictor in cardiovascular disease and as a mediator of atherosclerosis . The Centers for Disease Control and American Heart Association have elaborated guidelines for the use of C-reactive protein in the primary prevention setting and in patients with stable coronary disease or acute coronary syndromes .

C-reactive protein has been used for differentiation between Systemic Lupus Erythematosus activity and infection in individuals without serositis. More recently C-reactive protein has also elicited interest as a therapeutic option in lupus. Murine lupus models treated with CRP have been reported to present delayed Lupus onset decreased antibody levels enhanced survival and reversal of ongoing proteinuria. In this paper we reviewed the multiple roles of CRP particularly in lupus .

Source: Acta Reumatol Port. 2007 Oct-Dec;32(4):317-322Carvalho JF, Hanaoka B, Szyper-Kravitz M, Shoenfeld Y.

Rheumatology Division Faculdade de Medicina da Universidade de Sao Paulo e Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo Sao Paulo Brazil Center for Autoimmune Diseases and Department of Medicine B Chaim Sheba Medical Center Tel-Hashomer Sackler Faculty of Medicine Tel Aviv University Israel.