Central obesity and smoking are key modifiable risk factors for elevated C-reactive protein in Asian individuals who are not eligible for statin therapy

Objective:

Statin therapy reduces coronary heart disease (CHD) and mortality in individuals with elevated C-reactive protein (CRP) but low-density lipoprotein cholesterol below the threshold at which statin therapy is recommended. We determined the proportion of individuals with elevated CRP in whom statin therapy was not indicated, and examined predictors for elevated CRP in a multi-ethnic Asian population.

Design:

We studied 3404 participants (Chinese, Malays and Asian-Indians) without a history of hypercholesterolemia living in Singapore (mean age±s.d.: 48.9±11.2 years). Eligibility for statin therapy was determined based on the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III (ATPIII)) guideline. CRP was measured by high-sensitivity enzyme-linked immunosorbent assay method. CRP level greater than 2 mg l⁻¹ was considered as elevated.

Results:

Elevated CRP was found in 29.3% participants who were not eligible for statin therapy (n=2974). Elevated CRP was more common in females and amongst those of Malay or Asian-Indian ethnicity. Compared with participants with low CRP, those with elevated CRP were shown to have higher levels of obesity, blood pressure, triglyceride and insulin resistance (IR), but lower high-density lipoprotein cholesterol levels (all Ps<0.001). After multivariate analysis, gender (odds ratio (OR) 3.34 for females), ethnicity (Malay OR 1.57, 95% confidence interval (CI) 1.25–1.96; Asian-Indian OR 1.97, 95% CI 1.55–2.50), waist circumference (OR 1.06, 95% CI 1.05–1.07), smoking (OR 1.49, 95% CI 1.08–2.05) and IR (OR 1.14, 95% CI 1.07–1.22) were significant predictors of CRP (all Ps--values<0.05).

Conclusion:

Routine measurement of CRP identifies a substantial number of Asian individuals at risk of CHD in whom statin therapy is not currently indicated, particularly in women and certain ethnic groups (Malays and Asian Indians). Weight loss and smoking cessation are important measures to reduce the proportion of individuals with elevated CRP.     

High-sensitivity C-reactive protein levels fall during statin therapy in HIV-infected patients receiving ritonavir-boosted protease inhibitors

HIV-infected patients are at an increased risk of developing cardiovascular disease. Elevated levels of C-reactive protein (CRP) are associated with an increased risk of cardiovascular disease in the general population and are reduced by statin therapy. We examined the effect of pravastatin and rosuvastatin on CRP levels in 58 dyslipidemic HIV-infected patients. A 45-day course of either statin reduced the median CRP level from 3.0 to 2.4 mg/l (P < 0.001) with no correlation with changes in lipid parameters.     

Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein

The Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is a randomized, double-blind, placebo-controlled primary prevention trial of statin therapy among persons with average to low levels of low-density lipoprotein (LDL) cholesterol who are at increased cardiovascular risk due to elevated plasma concentrations of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP). A total of 17,802 persons with LDL cholesterol<130 mg/dl (3.36 mmol/L) and hs-CRP>or=2 mg/L were recruited from 26 countries and randomly allocated to 20 mg/day rosuvastatin or placebo. In contrast to previous studies of statin therapy in primary prevention, JUPITER is evaluating a group with modest plasma concentrations of LDL cholesterol (median 108 mg/dl, interquartile range 94 to 119). Further, the trial includes 6,801 women (38.2%) and 5,577 participants with metabolic syndrome (32.1%). Thus, in addition to broadening our understanding of statin therapy and inflammation, the JUPITER trial will provide important and clinically relevant information on primary prevention among patients who do not currently qualify for lipid-lowering therapy. In conclusion, as 20 mg of rosuvastatin can reduce LDL cholesterol by up to 50%, JUPITER will also provide crucial safety data for several thousand patients who should achieve LDL cholesterol levels<50 mg/dl on a long-term basis.     

高敏C反应蛋白联合低密度脂蛋白胆固醇作为他汀治疗靶目标的临床研究

目的:探讨急性冠状动脉综合征(ACS)介入术后,以高敏C反应蛋白(hs-CRP)联合低密度脂蛋白胆固醇(LDL-C)作为他汀治疗靶目标的可行性。方法:2007-01-2009-01期间,连续纳入ACS患者400例,随机分为A、B组(每组200例),常规行介入手术,术后每组给予阿托伐他汀40mg/d,口服1个月;此后给予阿托伐他汀20mg/d,口服维持。A组治疗靶目标为LDL-C<2.07mmol/L,B组治疗靶目标为LDL-C<2.07mmol/L且hs-CRP<3mg/L,观察2组LDL-C、hs-CRP指标变化,随访6个月、12个月、18个月主要心血管不良事件(MACE:全因性死亡、非致死性心肌梗死、靶血管再次血运重建)。结果:2组患者基线特征差异无统计学意义;2组在18个月时均达到各自治疗靶目标;2组LDL-C水平差异无统计学意义;hs-CRP在12个月和18个月随访时差异有统计学意义,分别为(5.96±3.51)和(3.85±2.23)mg.L-1(P<0.05),(4.68±2.81)和(2.05±0.91)mg.L-1(P<0.05);在18个月随访时,2组靶血管再次血运重建率和MACE发生率差异有统计学意义,分别为8.6%和3.6%(P<0.05),16.8%和9.7%(P<0.05)。A组发生MACE的概率是B组的1.73倍(HR=1.73,95%CI:1.12～5.27,P=0.025)。结论:ACS介入术后,对于血脂已达标但炎症仍较为活跃患者,hs-CRP和LDL-C双重达标可进一步减少MACE发生,降低残余心血管风险。hs-CRP可能是他汀治疗的另一有效靶目标。     

Extremely elevated C-reactive protein

BACKGROUND: C-reactive protein (CRP) is a widely used inflammatory marker. Yet, the clinical significance and outcome of extremely elevated CRP levels are poorly characterized. METHODS: We collected all patients seen at a university hospital in 2004 with at least one CRP level above 500 mg/l and retrospectively analyzed their electronic files, focusing on patient characteristics, clinical diagnosis, microbiology and vital outcome. RESULTS: CRP was above 500 mg/l in 130 patients with a median age of 62 years. Patient characteristics, settings, etiologies of inflammation, comorbidities and microbiology varied widely. Infections, mainly bacterial, accounted for 88% of episodes. Outcome was fatal in 36% of all patients and in 61% of patients with active malignancies. CONCLUSION: A wide variety of infections, especially bacterial, that are generally readily identified account for the majority of instances of extreme CRP elevation. Mortality is high, certainly in oncological patients.     

Relation of serum total cholesterol, C-reactive protein levels, and statin therapy to survival in heart failure

Although increased cholesterol levels predict mortality in patients with coronary artery disease, it is unclear whether hypercholesterolemia is associated with adverse survival in patients with heart failure. A cohort of subjects derived from the Intermountain Heart Collaborative Study Registry (1993 to 2003) who had ejection fractions < or = 40% or clinical diagnoses of heart failure and long-term follow-up for death were studied (n = 1,646). Total cholesterol (TC) was divided into quartiles: quartile 1, < 141.3 mg/dl; quartile 2, 141.3 to 167.9 mg/dl; quartile 3, 168.0 to 201.0 mg/dl; and quartile 4, > 201.0 mg/dl. Multivariate Cox regression models were used to evaluate the associations of cholesterol, statin therapy, and C-reactive protein to mortality. The mean age was 65.5 years; 65% of the subjects were men and 65% had coronary artery disease. Although 53% were using statins, statin use was not different across TC quartiles. Average time to death was 2.4 years (maximum 10). Mortality for quartile 4 versus quartile 1 was not different (hazard ratio [HR] 1.12, p = 0.52); mortality was reduced for quartile 3 versus quartile 1 (HR 0.66, p = 0.027) and tended to be reduced for quartile 2 versus quartile 1 (HR 0.77, p = 0.14). Subanalysis of patients not using statins (n = 737, death = 20.2%) found no association between TC and survival (for quartile 3 vs quartile 1, HR 0.97, p = 0.89), but for patients using statins (n = 848, death = 16.3%), the effect was even greater for quartile 3 versus quartile 1 (HR 0.40, p = 0.002) than in the overall population. Nonsurvivors had higher levels of C-reactive protein than survivors. In conclusion, elevated TC appears to be associated with improved survival. The effect was stronger in patients receiving statin therapy, but the cause of this differential effect is uncertain.     

Relation of C-reactive protein and one-year survival after acute myocardial infarction with versus without statin therapy

We evaluated the interaction between inflammation and survival benefit from statin therapy in patients who had acute myocardial infarction. Although 1-year mortality did not differ between patients who used statin therapy and those who did not, among patients who had C-reactive protein (CRP) concentrations in the lower 2 tertiles (<2.9 mg/L), 1-year mortality was higher in patients who used statin therapy than in those who did not within the highest CRP-defined tertile (> or =2.9 mg/L). Statin therapy significantly decreased the hazard ratio for 1-year mortality in patients who had high CRP levels to approximately the hazard present for patients who had low CRP levels and did not receive statin therapy.     

Effect of withdrawal of statin on C-reactive protein

BACKGROUND: C-reactive protein is considered a risk factor for coronary artery disease. In addition to its lipid-lowering properties, statin decreases the level of C-reactive protein. Abrupt cessation of statin therapy during treatment could increase the incidence of cardiac events in patients with atherosclerotic heart disease. The changes of C-reactive protein after withdrawal of statin therapy are still unknown. METHODS: Twenty patients with hyperlipidemia received statin (atorvastatin, 10 mg/day) therapy for 3 months. The levels of lipid profiles and C-reactive protein were assessed before receiving the statin therapy, immediately after 3 months of therapy, and on the 3 consecutive days after withdrawal of statin treatment. RESULTS: After 3 months of statin therapy, the total cholesterol, low-density lipoprotein cholesterol (LDL-chol), and C-reactive protein were significantly reduced (264.94 +/- 16.23 vs. 183.44 +/- 16.34 mg/dl, 183.17 +/- 34.56 vs. 122.00 +/- 17.66 mg/dl, and 2,309.00 +/- 437.85 vs. 1,257.95 +/- 207.99 ng/ml, respectively). The level of C-reactive protein increased on the second day after withdrawal of statin therapy (2,590.14 +/- 1,045.05 vs. 1,257.95 +/- 207.99 ng/ml); however, the total cholesterol and LDL-chol did not increase during the 3-day period after withdrawal of statin therapy. CONCLUSIONS: The increase in the level of C-reactive protein after withdrawal of statin therapy may be a contributing factor to the increased incidence of cardiac events in patients who have abruptly stopped statin therapy.     

Cholesterol, C-reactive protein, and cerebrovascular events following intensive and moderate statin therapy

Background: While statins have been shown to reduce cerebrovascular events (CVE), the relationship between cholesterol, C-reactive protein (CRP), and CVE in patients treated with different statin strategies is still being explored. Methods: PROVE IT-TIMI 22 was a randomized trial of intensive (atorvastatin 80 mg/day) and moderate (pravastatin 40 mg/day) statin therapy in 4,162 patients with acute coronary syndromes followed for an average of 24 months; serial biomarkers allowed for an assessment of the lipid and non-lipid effects of statins as they relate to CVE. Results: In this study, 45 patients on intensive statin therapy and 40 patients on moderate statin therapy had a CVE during the study period (2.1% v. 1.9%, P = 0.62). While the lipid profiles of patients with and without CVE were similar, those with CVE had higher CRP levels at 30 days and 4 months (2.7 v. 1.9, 2.4 v. 1.7 mg/L; P = 0.012, P = 0.005). Day 30 CRP remained an independent predictor of CVE after adjusting for age, development of atrial fibrillation, diabetes, and prior CVE. Patients with low density lipoprotein (LDL) levels < 70 mg/dL and ≥ 70 mg/dL had similar rates of CVE, while patients with CRP < 2 mg/L tended to have lower event rates when compared to those with higher levels. The lowest rates of CVE were seen in patients who had LDL < 70 mg/dL and CRP < 2 mg/L. Conclusion: In PROVE IT - TIMI 22, achieved LDL levels did not appear to independently impact the rate of CVE. In contrast, patients with elevated CRP levels were at higher risk of stroke or transient ischemic attack, reinforcing the link between inflammation and CVE. Condensed abstract The goal of this PROVE IT-TIMI 22 sub-study was to examine the relationship between cholesterol, CRP, and CVE in patients on intensive and moderate statin therapy. The achieved lipid levels were similar in patients with and without a CVE; however, the achieved levels of CRP were higher in patients who subsequently developed a stroke or TIA. These findings further support the relationship between inflammation and CVE.     

Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.

PURPOSE: To investigate whether interleukin-6 and C-reactive protein levels predict all-cause and cause-specific mortality in a population-based sample of nondisabled older people. SUBJECTS AND METHODS: A sample of 1,293 healthy, nondisabled participants in the Iowa 65+ Rural Health Study was followed prospectively for a mean of 4.6 years. Plasma interleukin-6 and C-reactive protein levels were measured in specimens obtained from 1987 to 1989. RESULTS: Higher interleukin-6 levels were associated with a twofold greater risk of death [relative risk (RR) for the highest quartile (> or = 3.19 pg/mL) compared with the lowest quartile of 1.9 [95% confidence interval, CI, 1.2 to 3.1]). Higher C-reactive protein levels (> or = 2.78 mg/L) were also associated with increased risk (RR = 1.6; CI, 1.0 to 2.6). Subjects with elevation of both interleukin-6 and C-reactive protein levels were 2.6 times more likely (CI, 1.6 to 4.3) to die during follow-up than those with low levels of both measurements. Similar results were found for cardiovascular and noncardiovascular causes of death, as well as when subjects were stratified by sex, smoking status, and prior cardiovascular disease, and for both early (<2.3 years) and later follow-up. Results were independent of age, sex, body mass index, and history of smoking, diabetes, and cardiovascular disease, as well as known indicators of inflammation including fibrinogen and albumin levels and white blood cell count. CONCLUSIONS: Higher circulating levels of interleukin-6 and C-reactive protein were associated with mortality in this population-based sample of healthy older persons. These measures may be useful for identification of high-risk subgroups for anti-inflammatory interventions.     

High-dose statin and COX-2 inhibitor therapy rapidly decreases C-reactive protein level in patients with unstable angina

BACKGROUND AND AIM: Elevated levels of C-reactive protein (CRP) are associated with an increased risk of coronary events. The levels of CRP and other inflammatory markers are significantly elevated in patients with unstable angina. We hypothesised that a high-dose statin therapy alone or with cyclooxygenase-2 (COX-2) inhibitors, administered before coronary diagnostic or invasive procedures, can attenuate CRP elevation after the procedure and, consequently, more effectively reduce the rate of coronary events. METHODS: All patients with unstable angina in class III and IIB according to Braunwald classification were considered for inclusion in the present study. Finally, 60 patients with elevated CRP level (>3 mg/l) were randomised to three groups of pharmacological treatment before coronary angiography and subsequent angioplasty. Patients from group A received placebo, patients from group B - 80 mg of atorvastatin, and patients from group C - 80 mg of atorvastatin and 25 mg of rofecoxib. The levels of CRP were measured at baseline, after 3 days of therapy and 48 hours after invasive coronary procedure. RESULTS: The mean baseline CRP level in group A was 5.67+/-2.82 mg/l, in group B - 4.7+/-1.32 mg/l, and in group C - 6.78+/-2.56 mg/l (NS). After three days of pharmacological treatment, the mean CRP level was 5.82+/-2.69 mg/l in group A (NS compared with baseline) and was significantly reduced in group B to 2.5+/-1.37 mg/l and in group C to 3.01+/-1.57 mg/l (p<0.0013 compared with group A). Measurements performed 48 hours after the procedure revealed a marked CRP level increase in group A (up to 24.54+/-5.48 mg/l) and a much lower increase in groups B and C (up to 3.02+/-2.0 mg/l and 7.31+/-2.96 mg/l, respectively). CONCLUSIONS: High-dose statin therapy alone or in combination with COX-2 inhibitor, administered before invasive coronary procedure in patients with unstable angina, rapidly lowers CRP levels. This therapy also reduces a marked CRP elevation typically occurring after invasive coronary intervention. Attenuation of inflammatory reaction may be crucial for the reduction of coronary events following invasive coronary interventions.     

Prevalence of low LDL-cholesterol levels and elevated high-sensitivity C-reactive protein levels in apparently healthy Korean adults

Background and aimsThe Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) reported reduced cardiovascular and all-cause mortality in patients with elevated C-reactive protein (CRP) and low LDL-cholesterol (LDL-C) levels treated with statins. The aims of this study were to determine the proportion of “JUPITER-eligible” Korean adults and to describe their characteristics.Methods and resultsAs many as 15,154 subjects with serum LDL-C levels <130 mg/dL were selected among 28,851 middle-aged participants (men ≥ 50 years, women ≥ 60 years) who participated in a routine health check-up program. Among the participants with LDL-C less than 130 mg/dL, only 15% had CRP levels ≥2.0 mg/L (7.9% of original participants). Subjects were divided into four groups according to CRP levels (<0.5, ≥0.5 ? <1.0, ≥1.0 ? <2.0, and ≥2.0 mg/L). Mean HDL-C and apolipoprotein A1 levels decreased significantly as the mean CRP values increased. The insulin and homeostasis model of insulin resistance was significantly different according to CRP quartile. The number of subjects with metabolic syndrome and its components increased significantly as the mean CRP values increased.ConclusionIn this Asian population, few individuals with low LDL-C levels had CRP levels ≥2.0 mg/L. Elevated CRP levels were associated with components of atherogenic dyslipidemia and insulin resistance. Additional clinical trials should be designed and performed in different ethnic groups, as different CRP cut-off levels may be required in different ethnic groups.     

C-reactive protein levels in patients with rheumatoid arthritis: the impact of therapy

Summary C-reactive protein levels were measured in sera of 111 patients with rheumatoid arthritis and were compared with erythrocyte sedimentation rate. The patients were divided into six groups according to drug therapy. Comparison between the groups suggests that CRP correlates best with ESR in patients treated with penicillamine and in patients in clinical remission. Patients treated with gold, NSAID or methotrexate have a weaker correlation between the two parameters, while steroid therapy yields the poorest correlation which is not statistically significant. Our data suggest that although CRP is a sensitive index of disease activity, the specific drug taken by the patient must be considered before interpreting the results.