CRP Abstracts 1

©

Vitamin C treatment reduces elevated C-reactive protein
            (Block et al., 2009) Download
Plasma C-reactive protein (CRP) is an inflammatory biomarker that predicts cardiovascular disease. Lowering elevated CRP with statins has reduced the incidence of cardiovascular disease. We investigated whether vitamin C or E could reduce CRP. Healthy nonsmokers (N=396) were randomized to three groups, 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Median baseline CRP was low, 0.85 mg/L. No treatment effect was seen when all participants were included. However, a significant interaction was found, indicating that treatment effect depends on baseline CRP concentration. Among participants with CRP indicative of elevated cardiovascular risk (> or =1.0 mg/L), vitamin C reduced the median CRP by 25.3% vs placebo (p=0.02) (median reduction in the vitamin C group, 0.25 mg/L, 16.7%). These effects are similar to those of statins. The vitamin E effect was not significant. In summary, treatment with vitamin C but not vitamin E significantly reduced CRP among individuals with CRP > or =1.0 mg/L. Among the obese, 75% had CRP > or =1.0 mg/L. Research is needed to determine whether reducing this inflammatory biomarker with vitamin C could reduce diseases associated with obesity. But research on clinical benefits of antioxidants should limit participants to persons with elevations in the target biomarkers.

C-reactive protein increases plasminogen activator inhibitor-1 expression in human endothelial cells
            (Chen et al., 2008) Download
C-reactive protein (CRP) is an inflammatory marker which predicts cardiovascular disease. However, it is not fully understood whether CRP has direct effects on endothelial functions and gene expression. The purpose of current study was to determine the effects and molecular mechanisms of CRP on the expression of plasminogen activator inhibitor-1 (PAI-1) in human endothelial cells. Human coronary artery endothelial cells (HCAEC) were treated with CRP at clinically relevant concentrations for different durations. PAI-1 mRNA, protein and enzyme activities were studied. The effects of CRP on MAPK p38 phosphorylation was also studied by Bio-Plex luminex immunoassay. In addition, other types of human endothelial cells isolated from umbilical vein, skin, and lung microvessels were tested. CRP significantly increased PAI-1 mRNA levels in a time- and concentration-dependent manner. The protein level and enzyme activity of PAI-1 in the supernatant of CRP-treated HCAEC cultures were significantly increased. Anti-CD32 antibody effectively blocked CRP-induced PAI-1 mRNA expression. In addition, CRP significantly increased CD32 mRNA levels and enhanced phosphorylation of MAPK p38. Furthermore, antioxidant curcumin dramatically inhibited CRP-induced PAI-1 mRNA expression. The effect of CRP on PAI-1 expression was also confirmed in other types of human endothelial cells. In conclusion, CRP significantly increased the expression of PAI-1 in HCAEC and other human endothelial cells. CRP also increased its receptor CD32 expression which may further enhance its action. CRP-induced PAI-1 expression may be mediated by oxidative stress and p38 signal pathway as antioxidant effectively blocks the effect of CRP on HCAEC.

Plasma pyridoxal 5'-phosphate and high-sensitivity C-reactive protein are independently associated with an increased risk of coronary artery disease
            (Cheng et al., 2008) Download
OBJECTIVE: Whether vitamin B6 exerts an independent or a synergic effect in combination with inflammation for the risk of coronary artery disease (CAD) is unclear. The purpose of this study was to investigate whether plasma pyridoxal 5'-phosphate (PLP) is dependent on or independent of the inflammation marker C-reactive protein (CRP) to associate with the risk of CAD. METHODS: This was a hospital-based case-control. Patients were identified with cardiac catheterization as having at least 70% stenosis of one major coronary artery were assigned to the case group (n = 184). The control group (n = 516) was comprised of healthy individuals with normal blood biochemical values. All subjects' height, weight, blood pressure, plasma PLP, homocysteine, high-sensitivity CRP (hs-CRP), and lipid profiles were measured. RESULTS: Plasma PLP concentration was only negatively associated with hs-CRP level in the control group (beta = -0.001, P = 0.03) but not in the CAD or pooled groups. The magnitude of the risk of CAD for low plasma PLP (odds ratio [OR] 2.39) and high hs-CRP (OR 3.37) was very similar. Low plasma PLP concentration combined with low hs-CRP level (OR 2.34) and high plasma PLP concentration combined with high hs-CRP level (OR 3.61) were independently associated with risk for CAD. However, the combined presence of low PLP and higher hs-CRP levels enhanced the risk of CAD and the magnitude was substantially greater (OR 4.35). CONCLUSION: Plasma PLP and hs-CRP are independently associated with an increased risk of CAD, the combined presence of low PLP and high hs-CRP enhanced the risk of CAD, and the magnitude was almost double.

Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal
            (de Lorgeril et al., 2010) Download
BACKGROUND: Among the recently reported cholesterol-lowering drug trials, the JUPITER (Justification for the Use of Statins in Primary Prevention) trial is unique: it reports a substantial decrease in the risk of cardiovascular diseases among patients without coronary heart disease and with normal or low cholesterol levels. METHODS: Careful review of both results and methods used in the trial and comparison with expected data. RESULTS: The trial was flawed. It was discontinued (according to prespecified rules) after fewer than 2 years of follow-up, with no differences between the 2 groups on the most objective criteria. Clinical data showed a major discrepancy between significant reduction of nonfatal stroke and myocardial infarction but no effect on mortality from stroke and myocardial infarction. Cardiovascular mortality was surprisingly low compared with total mortality-between 5% and 18%-whereas the expected rate would have been close to 40%. Finally, there was a very low case-fatality rate of myocardial infarction, far from the expected number of close to 50%. The possibility that bias entered the trial is particularly concerning because of the strong commercial interest in the study. CONCLUSION: The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors.

Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels
            (Friso et al., 2001) Download
BACKGROUND: Lower vitamin B(6) concentrations are reported to confer an increased and independent risk for cardiovascular disease (CVD). The mechanism underlying this relationship, however, remains to be defined. Other diseases, such as rheumatoid arthritis, are associated with reduced vitamin B(6) levels. Despite a clear distinction in pathophysiology, inflammatory reaction may be the major link between these diseases. We hypothesized a relationship between pyridoxal 5'-phosphate (PLP), the active form of vitamin B(6), and the marker of inflammation C-reactive protein (CRP). We also evaluated whether total plasma homocysteine (tHcy), a well-defined risk factor for CVD and a major determinant of plasma PLP levels, had a possible role as a mediator of this hypothesized relationship. METHODS AND RESULTS: Data from 891 participants from the population-based Framingham Heart Study cohort were analyzed. Subjects were divided into 2 groups according to normal or elevated CRP values: group 1, CRP <6 mg/L; group 2, CRP >/=6 mg/L. Plasma PLP levels were substantially lower in group 2 than in group 1 (mean values in group 2, 36.5 nmol/L versus 55.8 nmol/L in group 1, P<0.001). In a multiple logistic regression model adjusted for tHcy, the association of PLP with CRP remained highly significant (P=0.003). CONCLUSIONS: Low plasma PLP is associated with higher CRP levels independently of tHcy. This observation may reflect a vitamin B(6) utilization in the presence of an underlying inflammatory process and represent a possible mechanism to explain the decreased vitamin B(6) levels in CVD.

Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial
            (Glynn et al., 2010) Download
BACKGROUND: Randomized data on statins for primary prevention in older persons are limited, and the relative hazard of cardiovascular disease associated with an elevated cholesterol level weakens with advancing age. OBJECTIVE: To assess the efficacy and safety of rosuvastatin in persons 70 years or older. DESIGN: Secondary analysis of JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), a randomized, double-blind, placebo-controlled trial. SETTING: 1315 sites in 26 countries randomly assigned participants in JUPITER. PARTICIPANTS: Among the 17 802 participants randomly assigned with low-density lipoprotein (LDL) cholesterol levels less than 3.37 mmol/L (<130 mg/dL) and high-sensitivity C-reactive protein levels of 2.0 mg/L or more without cardiovascular disease, 5695 were 70 years or older. INTERVENTION: Participants were randomly assigned in a 1:1 ratio to receive 20 mg of rosuvastatin daily or placebo. MEASUREMENTS: The primary end point was the occurrence of a first cardiovascular event (myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes). RESULTS: The 32% of trial participants 70 years or older accrued 49% (n = 194) of the 393 confirmed primary end points. The rates of the primary end point in this age group were 1.22 and 1.99 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio, 0.61 [95% CI, 0.46 to 0.82]; P < 0.001). Corresponding rates of all-cause mortality in this age group were 1.63 and 2.04 (hazard ratio, 0.80 [CI, 0.62 to 1.04]; P = 0.090). Although no significant heterogeneity was found in treatment effects by age, absolute reductions in event rates associated with rosuvastatin were greater in older persons. The relative rate of any serious adverse event among older persons in the rosuvastatin versus placebo group was 1.05 (CI, 0.93 to 1.17). LIMITATION: Effect estimates from this exploratory analysis with age cut-point chosen after trial completion should be viewed in the context of the overall trial results. CONCLUSION: In apparently healthy older persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin reduces the incidence of major cardiovascular events. PRIMARY FUNDING SOURCE: AstraZeneca.

DHA supplementation decreases serum C-reactive protein and other markers of inflammation in hypertriglyceridemic men
            (Kelley et al., 2009) Download
Dietary (n-3) PUFA reduce inflammation, an independent risk factor for cardiovascular disease. The antiinflammatory effects of docosahexaenoic acid (DHA) in hypertriglyceridemic men have not been previously reported, to our knowledge, and were the focus of this study. Hypertriglyceridemic men (n = 17 per group) aged 39-66 y, participated in a double-blind, randomized, placebo-controlled parallel study. They received no supplements for the first 8 d and then received either 7.5 g/d DHA oil (3 g DHA/d) or olive oil (placebo) for the last 90 d. Blood samples were collected from fasting men on study days -7, 0, 45, 84, and 91. DHA supplementation for 45 and 91 d decreased the number of circulating neutrophils by 11.7 and 10.5%, respectively (P < 0.05). It did not alter the circulating concentrations of other inflammatory markers tested within 45 d, but at 91 d it reduced (P < 0.05) concentrations of C-reactive protein (CRP) by 15%, interleukin-6 by 23%, and granulocyte monocyte-colony stimulating factor by 21% and DHA increased the concentration of antiinflammatory matrix metalloproteinase-2 by 7%. The number of circulating neutrophils was positively associated with the weight percent (wt %) of 20:4(n-6) in RBC lipids, and negatively to the wt % of 20:5(n-3) and 22:6(n-3). Concentrations of CRP and serum amyloid A were positively associated with the sum of SFA and negatively with the wt % of 18:1(n-9) and 17:0 in RBC lipids; CRP was also positively associated with the wt % of 20:2(n-6). The mean size of VLDL particles was positively associated with plasma concentrations of neutrophils and CRP. In conclusion, DHA may lessen the inflammatory response by altering blood lipids and their fatty acid composition.


Serum vitamin C concentration and hs-CRP level in middle-aged Japanese men and women
            (Kubota et al., 2009) Download
OBJECTIVE: To examine the association between concentrations of serum vitamin C, a contributive factor to prevention of cardiovascular disease and levels of hs-CRP, a risk factor for cardiovascular disease, in population-based samples of middle-aged men and women. DESIGN: A cross-sectional study. METHODS AND RESULTS: The subjects were 778 men and 1404 women, aged 40-69 years, who participated in a cardiovascular risk survey in Kyowa, Ibaraki prefecture in 2002 as part of the Circulatory Risk in Communities Study (CIRCS). Inverse associations between serum vitamin C concentrations and hs-CRP levels were established for both men and women. Multivariable-adjusted mean values of hs-CRP for the lowest to highest quintiles of vitamin C levels were 0.75, 0.65, 0.61, 0.61 and 0.47 mg/L (P for trend <0.001) for men, and 0.56, 0.51, 0.49, 0.41 and 0.41 mg/L (P for trend <0.001) for women. The inverse association between vitamin C and hs-CRP was stronger for non-smoking men and women, non-overweight women and postmenopausal women. CONCLUSIONS: Serum vitamin C concentrations were found to be inversely associated with hs-CRP levels in both men and women, primarily among non-smokers, non-overweight women and postmenopausal women. The respective roles of serum vitamin C and hs-CRP levels in the development of cardiovascular disease thus warrant further investigation.

C-reactive proteins and chronic disease: what role does nutrition play?
            (Liepa and Basu, 2003) Download
The following review provides an update on C-reactive proteins (CRPs) and how they are related to chronic diseases and diet. Emphasis is placed on the mechanism that is involved in the infection/stress-induced formation of CRPs. CRPs' role as biomarkers for coronary heart disease is discussed. This review also discusses the roles that obesity, diabetes, smoking, and synthetic hormones play in increasing serum CRP concentrations. It also summarizes information about how dietary manipulation and exercise can decrease CRP concentrations. The dietary components that seem to lead to a decrease in CRPs include omega-3 fatty acids (fish oil), vitamin E, and moderate amounts of alcohol. Aspirin intake is also discussed as a method that can be used to decrease CRP concentrations.

Total n-3 polyunsaturated fatty acid intake is inversely associated with serum C-reactive protein in young Japanese women
            (Murakami et al., 2008) Download
Little is known about the relation of dietary factors to circulating C-reactive protein (CRP) concentrations in young adults and non-Western populations. We cross-sectionally examined associations between dietary intake and serum CRP concentrations in young Japanese women. The subjects were 443 female Japanese dietetic students aged 18 to 22 years. Dietary intake was assessed with a validated, self-administered, comprehensive, diet history questionnaire. Serum CRP concentrations were measured by highly sensitive nephelometry. The prevalence of elevated CRP (> or = 1 mg/L) was 5.6%. After adjustment for possible confounding factors including body mass index, a significant inverse association was seen between total n-3 polyunsaturated fatty acid intake and elevated CRP. The multivariate adjusted odds ratios of elevated CRP for women with intake below and above the median (1.1% of energy) were 1.00 and 0.33 (95% confidence interval, 0.13-0.82; P = .02), respectively. Intake of eicosapentaenoic acid + docosahexaenoic acid and alpha-linolenic acid was not associated with elevated CRP concentrations (P = .62 and P = .27, respectively). Vitamin C intake was independently inversely associated with elevated CRP, although the association was nonsignificant (P = .10). No clear associations were observed for other dietary factors examined including total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, total dietary fiber, soluble dietary fiber, insoluble dietary fiber, and magnesium; fruits, vegetables, and fish and shellfish; and dietary glycemic load (P = .27 to P = .99). In conclusion, total n-3 polyunsaturated fatty acid intake showed an independent inverse association with elevated serum CRP concentration in a group of young Japanese women.

The association of fruits, vegetables, antioxidant vitamins and fibre intake with high-sensitivity C-reactive protein: sex and body mass index interactions
            (Oliveira et al., 2009) Download
OBJECTIVE: To study the associations of fruits, vegetables, antioxidant vitamins and fibre intake with high-sensitivity C-reactive protein (hs-CRP). Existing literature on these associations is scarce and has rendered conflicting results. METHODS: Cross-sectional study of 1060 individuals (675 women, 385 men), representative of the non-institutionalized population, aged >or=18 years, in Porto, Portugal (70% participation rate). Diet over the previous year was assessed with a validated food frequency questionnaire. Associations between diet and hs-CRP (categorized into <1, 1-3, >3 to <or=10 mg/l) were obtained from ordinal logistic regression models (odds ratio, 95% confidence intervals-OR, 95% CI) adjusted for sociodemographic and behavioural variables. RESULTS: In normal weight men (body mass index (BMI) <25.0 kg/m(2)), for each 100 g increase in fruit and vegetable intake, there was 30% less probability of changing of hs-CRP category (no risk to moderate risk, or moderate to high risk). Protective associations were also observed between hs-CRP and fruits (OR=0.73, 95% CI 0.56-0.96 per 100 g/day), vegetables (OR=0.55, 95% CI 0.35-0.86 per 100 g/day), vitamin C (OR=0.34, 95% CI 0.14-0.80 per 10 mg/day) and vitamin E (OR=0.14, 95% CI 0.02-0.88 per 1000 retinol equivalents per day). Overall, associations tended to be weaker in overweight participants. In men (BMI >or=25.0 kg/m(2)), fibre was also negatively associated with hs-CRP. In women, no significant associations were found between dietary variables and hs-CRP. A significant modification effect of the evaluated associations was found by sex for fruits and vegetables, vitamin C and fibre, but not by BMI. CONCLUSION: Intake of fruits and vegetables, vitamin C, E and fibre were negatively associated with hs-CRP in men.


Cardiovascular disease: C-reactive protein and the inflammatory disease paradigm: HMG-CoA reductase inhibitors, alpha-tocopherol, red yeast rice, and olive oil polyphenols. A review of the literature
            (Patrick and Uzick 2001) Download
The current understanding of the origin of atherosclerosis is that of an inflammatory process that involves the acute phase response -an innate biological response to a disturbance in homeostasis -infection, inflammation, tissue injury, neoplasm, or immune disturbance. The activation of the acute phase response, signaled by interleukin-6, produces proteins (fibrinogen, C-reactive protein (CRP), serum amyloid A) that lead to inflammatory reactions. The tissues themselves contain elevated levels of acute phase proteins and cytokines resulting in a localized inflammatory effect. Localized inflammatory responses in the intimal layer of the arterial wall have been shown to be responsible for many of the aspects of intimal thickening and plaque disruption, leading to acute cardiovascular events. The predictive value of plasma C-reactive protein as a risk factor for cardiovascular events has led some researchers to support the use of CRP as a main cardiovascular risk assessment tool, along with total cholesterol:HDL ratios and homocysteine levels. The ability of HMG-CoA reductase inhibitors to lower C-reactive protein levels has recently brought into question the mechanisms of action of the statin drugs. Because these medications lower incidences of acute cardiovascular events as well as decreasing morbidity and mortality well before the effects of lowered LDL cholesterol can be expected to occur, questions have been asked about whether they may work independently of LDL-lowering mechanisms. Red yeast rice contains a naturally-occurring statin (lovastatin) as well as other cholesterol-lowering compounds, some with antioxidant effects. Alpha-tocopherol also significantly lowers CRP levels in diabetics and nondiabetics, and minimizes other aspects of the acute phase response and inflammatory damage involved in atherosclerosis. This may account for alpha-tocopherol's positive effect on cardiovascular morbidity and mortality. Finally, polyphenolic compounds present in virgin olive oil also have anti-inflammatory and antioxidative effects in cardiovascular disease. The phenolic compounds in virgin olive oil may explain some of the protective effects found in epidemiological studies.

C-reactive protein (CRP)-lowering agents
            (Prasad, 2006) Download
C-reactive protein (CRP) plays a role in the pathogenesis of cardiovascular disease. It is a marker and predictor of cardiovascular disease. CRP possesses numerous cardiovascular effects (clotting, generation of oxygen radicals, increase in the expression of adhesion molecules and plasminogen activator inhibitor-1, plaque destabilization) that could result in cardiovascular disease. This review describes the effects of various cardiovascular drugs on the levels of CRP in health and disease. Cyclooxygenase inhibitors (aspirin, rofecoxib, celecoxib), platelet aggregation inhibitors (clopidogrel, abciximab), lipid lowering agents (statins, ezetimibe, fenofibrate, niacin, diets), beta-adrenoreceptor antagonists and antioxidants (vitamin E), as well as angiotensin converting enzyme (ACE) inhibitors (ramipril, captopril, fosinopril), reduce serum levels of CRP; while enalapril and trandolapril have not been shown to have the same effect. Angiotensin receptor blockers (ARBs) (valsartan, irbesartan, olmesartan, telmisartan) markedly reduce serum levels of CRP. The findings with other ARBs (losartan and candesartan) were inconsistent. Antidiabetic agents (rosiglitazone and pioglitazone) reduce CRP levels, while insulin is ineffective. Calcium channel antagonists have variable effects on CRP levels. Hydrochlorothiazide and oral estrogen do not affect CRP. The CRP-lowering effect of statins is more pronounced than their lipid lowering effect and is not dependent on their hypolipemic activity. The effect of atorvastatin on CRP seems to be dose-dependent. CRP-lowering effect of statins is likely to contribute to the favorable outcome of statin therapy. The data suggest that lipid lowering agents, ACE inhibitors, ARBs, antidiabetic agents, antiinflammatory and antiplatelet agents, vitamin E, and beta-adrenoreceptor antagonists lower serum or plasma levels of CRP, while vitamin C, oral estrogen and hydrochlorothiazide do not affect CRP levels.

 


References

Block, G., et al. (2009), ‘Vitamin C treatment reduces elevated C-reactive protein’, Free Radic Biol Med, 46 (1), 70-77. PubMed: 18952164
Chen, C., et al. (2008), ‘C-reactive protein increases plasminogen activator inhibitor-1 expression in human endothelial cells’, Thromb Res, 122 (1), 125-33. PubMed: 17949793
Cheng, C. H., et al. (2008), ‘Plasma pyridoxal 5’-phosphate and high-sensitivity C-reactive protein are independently associated with an increased risk of coronary artery disease’, Nutrition, 24 (3), 239-44. PubMed: 18312786
de Lorgeril, M., et al. (2010), ‘Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal’, Arch Intern Med, 170 (12), 1032-36. PubMed: 20585068
Friso, S., et al. (2001), ‘Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels’, Circulation, 103 (23), 2788-91. PubMed: 11401933
Glynn, R. J., et al. (2010), ‘Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial’, Ann Intern Med, 152 (8), 488-96, W174. PubMed: 20404379
Kelley, D. S., et al. (2009), ‘DHA supplementation decreases serum C-reactive protein and other markers of inflammation in hypertriglyceridemic men’, J Nutr, 139 (3), 495-501. PubMed: 19158225
Kubota, Y., et al. (2009), ‘Serum vitamin C concentration and hs-CRP level in middle-aged Japanese men and women’, Atherosclerosis, 208 (2), 496-500. PubMed: 19717151
Liepa, G. U. and H. Basu (2003), ‘C-reactive proteins and chronic disease: what role does nutrition play?’, Nutr Clin Pract, 18 (3), 227-33. PubMed: 16215039
Murakami, K., et al. (2008), ‘Total n-3 polyunsaturated fatty acid intake is inversely associated with serum C-reactive protein in young Japanese women’, Nutr Res, 28 (5), 309-14. PubMed: 19083425
Oliveira, A., F. Rodriguez-Artalejo, and C. Lopes (2009), ‘The association of fruits, vegetables, antioxidant vitamins and fibre intake with high-sensitivity C-reactive protein: sex and body mass index interactions’, Eur J Clin Nutr, 63 (11), 1345-52. PubMed: 19623199
Prasad, K. (2006), ‘C-reactive protein (CRP)-lowering agents’, Cardiovasc Drug Rev, 24 (1), 33-50. PubMed: 16939632