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Aims: This study aimed to evaluate the prognostic value of high-sensitivity C-reactive protein (hsCRP) during 10-year follow-up after percutaneous coronary intervention (PCI)., Methods and Results: Between April and October 2002, hsCRP was measured in 468 all-comer patients who underwent PCI with sirolimus-eluting stent implantation for stable coronary artery disease or acute coronary syndrome. The primary endpoint was the composite of all-cause mortality or myocardial infarction at 10-year follow-up. Kaplan-Meier event curves displayed ongoing divergence of the hsCRP groups (hsCRP <1 mg/L: 14.7% vs. 1-3 mg/L: 31.1% vs. >3 mg/L: 43.1%). After adjustment for established cardiovascular risk factors and clinical presentation in a Cox regression model, higher CRP levels were associated with a higher incidence of the composite endpoint (>3 mg/L vs. <1 mg/L: HR 2.87, 95% CI: 1.69-4.87, p<0.001; 1-3 mg/L vs. <1 mg/L: HR 2.30, 95% CI: 1.31-4.03, p=0.004). Although adding hsCRP to a prediction model containing conventional cardiovascular risk factors did not significantly improve discriminatory power (area under the receiver operating characteristic curve 0.71 to 0.73, p=0.56), hsCRP was able to improve risk classification (net reclassification index=0.40, p=<0.001)., Conclusions: In patients undergoing PCI, higher CRP levels at the time of the procedure are predictive for 10-year mortality and myocardial infarction. High-sensitivity CRP may be a useful biomarker to improve further risk assessment in patients undergoing PCI.

Background: Studies on the prognostic value of serial biomarker assays for future occurrence of allograft rejection (AR) are scarce. We examined whether repeated measurements of NT-pro-B-type natriuretic peptide (NT-proBNP), troponin T (TropT) and C-reactive protein (CRP) predict AR., Methods: From 2005 to 2010, 77 consecutive heart transplantation (HTx) recipients were included. The NT-proBNP, TropT, and CRP were measured at 16 ± 4 (mean ± standard deviation) consecutive routine endomyocardial biopsy surveillance visits during the first year of follow-up. Allograft rejection was defined as International Society for Heart and Lung Transplantation (ISHLT) grade 2R or higher at endomyocardial biopsy. Joint modeling was used to assess the association between repeated biomarker measurements and occurrence of future AR. Joint modeling accounts for dependence among repeated observations in individual patients., Results: The mean age of the patients at HTx was 49 ± 9.2 years, and 68% were men. During the first year of follow-up, 1,136 biopsies and concurrent blood samples were obtained, and 56 patients (73%) experienced at least one episode of AR. All biomarkers were elevated directly after HTx and achieved steady-state after ∼ 12 weeks, both in patients with or without AR. No associations were present between the repeated measurements of NT-proBNP, TropT, or CRP and AR both early (weeks 0-12) and late (weeks 13-52) in the course after HTx (hazard ratios for weeks 13-52: 0.96 (95% confidence interval, 0.55-1.68), 0.67 (0.27-1.69), and 1.44 (0.90-2.30), respectively, per ln[unit]). Combining the three biomarkers in one model also rendered null results., Conclusion: The temporal evolution of NT-proBNP, TropT, and CRP before AR did not predict occurrence of acute AR both in the early and late course of the first year after HTx.

The relation between C-reactive protein (CRP) and coronary atherosclerosis is not fully understood. This study aims to investigate the associations among high-sensitivity CRP, coronary plaque burden, and the presence of high-risk coronary lesions as measured by intravascular ultrasound (IVUS) and 1-year cardiovascular outcome. Between 2008 and 2011, grayscale and virtual histology IVUS imaging of a nonculprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable angina pectoris. Primary end point consisted of 1-year major adverse cardiac events (MACEs), defined as all-cause mortality, ACS, or unplanned coronary revascularization. After adjustment for established cardiac risk factors, baseline CRP levels were independently associated with higher coronary plaque burden (p = 0.002) and plaque volume (p = 0.002) in the imaged coronary segment. CRP was also independently associated with the presence of large lesions (plaque burden ≥70%; p = 0.030) but not with the presence of stenotic lesions (minimal luminal area ≤4.0 mm(2); p = 0.62) or IVUS virtual histology-derived thin-cap fibroatheroma lesions (p = 0.36). Cumulative incidence of 1-year MACE was 9.7%. CRP levels >3 mg/L were independently associated with a higher incidence of MACE (hazard ratio 2.17, 95% confidence interval [CI] 1.01 to 4.67, p = 0.046) and of all-cause mortality and ACS only (hazard ratio 3.58, 95% CI 1.04 to 13.0, p = 0.043), compared with CRP levels <1 mg/L. In conclusion, in patients who underwent coronary angiography, high-sensitivity CRP is a marker of coronary plaque burden but is not related to the presence of virtual histology-derived thin-cap fibroatheroma lesions and stenotic lesions. CRP levels >3 mg/L are predictive for adverse cardiovascular outcome at 1 year., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: This prospective study investigated the association between preprocedural biomarker levels and incident major adverse cardiac events (MACE) in complex patients undergoing percutaneous coronary intervention (PCI) with sirolimus-eluting stenting., Hypothesis: Lipoprotein(a) (Lp[a]), interleukin-10 (IL-10), and high-sensitivity C-reactive protein (CRP) have long-term prognostic value in patients undergoing PCI., Methods: Between April 2002 and February 2003, 161 patients were included in the study. Blood was drawn before the procedure, and biomarkers were measured. Patients were followed-up for MACE (death, nonfatal myocardial infarction, and repeat revascularization). Cox proportional hazard models were used to determine risk of MACE for tertiles of biomarkers. Both 1-year and long-term follow-up (median, 6 years; maximum, 8 years) were evaluated., Results: Mean age was 59 years, and 68% were men. During long-term follow-up, 72 MACE occurred (overall crude cumulative incidence: 45% [95% confidence interval (CI): 37%-52%]). Lp(a) was associated with a higher 1-year risk of MACE, with an adjusted hazard ratio (HR) of 3.1 (95% CI: 1.1-8.6) for the highest vs the lowest tertile. This association weakened and lost significance with long-term follow-up. IL-10 showed a tendency toward an association with MACE. The 1-year HR was 2.1 (95% CI: 0.92-5.0). Long-term follow-up rendered a similar result. The association of CRP with MACE did not reach statistical significance at 1-year follow-up. However, CRP was associated with long-term risk of MACE, with an HR of 1.9 (95% CI: 1.0-3.5)., Conclusions: In this prospective study, preprocedural Lp(a) level was associated with short-term prognosis after PCI. The preprocedural CRP level was associated with long-term prognosis after PCI., (© 2012 Wiley Periodicals, Inc.)

Background: Staphylococcus aureus is capable of persistently colonizing the vestibulum nasi. We hypothesized that polymorphisms in host inflammatory response genes and genetic variation in S. aureus contribute to susceptibility to S. aureus carriage and infection., Methods: The prevalence of persistent nasal carriage of S. aureus in 3851 participants aged 61-101 years was 18% (678 of 3851 participants), whereas 73% of volunteers (2804 of 3851) were not colonized. A total of 1270 individuals had boils. Polymorphisms in TNFA (C -863T), IL4 (C -542T), CFH (Tyr402His), and CRP (C1184T, C2042T, and C2911G) were determined. Genetic similarity among 428 S. aureus isolates was determined by use of amplified fragment length polymorphism analysis (AFLP)-mediated genotyping., Results: The IL4 -524 C/C host genotype was associated with an increased risk of persistent S. aureus carriage, irrespective of S. aureus AFLP genotype. The CRP haplotype 1184C; 2042C; 2911C was overrepresented in individuals who were not colonized . In individuals with boils, carriers of the CFH Tyr402 variant, and the CRP 2911 C/C genotype were overrepresented., Conclusion: Persistent carriage of S. aureus is influenced by genetic variation in host inflammatory response genes. As would be expected in multifactorial host-microbe interactions, these effects are limited. Interestingly, host genotype was associated with the carriage of certain S. aureus genotypes. Apparently, a close interaction between host and bacterial determinants are prerequisites for long-term colonization.

Aims: Although prospective studies have unequivocally shown that C-reactive protein (CRP) is an independent predictor of future cardiovascular events, studies on the association between CRP and atherosclerosis have provided inconsistent results. We investigated the association of CRP with extent and progression of atherosclerosis in multiple vessel beds in a large, population-based cohort study., Methods: In the Rotterdam Study, standardized measurements of coronary and extra-coronary atherosclerosis were performed in 1962 persons and 6582 persons, respectively. Progression of extra-coronary atherosclerosis during a mean follow-up period of 6.4 years was assessed in 3757 persons., Results: Independent and graded associations were found of CRP with the number of carotid plaques and carotid plaque progression ((OR 1.72; 95% CI 1.14-2.59) for severe progression in participants with CRP>3mg/dl versus participants with CRP<1mg/dl). Similarly, CRP was independently and graded related to ankle-brachial-index (ABI) and worsening ABI over the years ((OR 1.99; 95% CI 1.37-2.88) for severe progression in participants with CRP>3mg/dl versus participants with CRP<1mg/dl). Although CRP was independently related to the highest level of carotid intima-media thickness (IMT), the association with change in IMT was not significant. Furthermore, there was an independent, graded relation between CRP and aortic calcification, but no independent association was observed with progression of aortic calcification, nor with the amount of coronary calcification., Conclusion: In this population-based study, independent and graded associations were present of CRP with extent and progression of carotid plaques and ABI, while associations with carotid IMT and aortic and coronary calcification were less pronounced.

Objective: Inflammation plays a role in the pathogenesis of dementia and Alzheimer's disease (AD). Studies examining serum levels of C-reactive protein in relation to dementia yielded conflicting results. Since serum levels of C-reactive protein are partly determined by genetic factors, we examined the association between genetic variation in the C-reactive protein gene with dementia and AD., Methods: This study was performed in the Rotterdam Study, a population-based prospective cohort study among elderly. Polymorphisms in the C-reactive protein gene (1184C>T, 2042C>T and 2911C>G) tagging the common haplotypes were genotyped and haplotypes were constructed. During follow-up (mean 9.2 years) 607 dementia cases were identified. We estimated the association between polymorphisms and haplotypes with dementia and AD with Cox' proportional hazard models., Results: The T allele of the C-reactive protein 2042C>T polymorphism, related to lower serum levels of C-reactive protein, was associated with a lower risk of dementia and AD. This association was strongest in APOE epsilon4 allele carriers., Conclusion: These findings suggest that C-reactive protein plays a role in development of dementia.

Complement factor H (CFH) is an important regulator of the complement cascade. Binding of C-reactive protein (CRP) to CFH augments the ability of CFH to downregulate the effect of complement in atherosclerotic lesions. The CFH Tyr402His polymorphism has been suggested to influence the ability of CFH to bind CRP. We hypothesized that the combined presence of unfavorable CRP and CFH genetic profiles is associated with risk of myocardial infarction (MI). The Rotterdam Study is a population-based cohort study in 7,983 men and women aged > or =55 years. The CFH Tyr402His (rs1061170) polymorphism was determined (His(402) allele 37%), and using 3 tagging polymorphisms (rs1130864, rs1205, and rs3093068), CRP haplotypes were inferred (1 = CTC, 2 = TCC, 3 = CCC, 4 = CCG; frequencies of 33%, 32%, 30%, and 6%, respectively). Participants were grouped by CFH genotype (TyrTyr [reference], TyrHis, and HisHis) and CRP haplotype (haplotype 1 homozygotes [reference], haplotype 2 carriers, haplotype 3 carriers, and haplotype 4 carriers), which resulted in a total of 12 groups. CFH His(402) homozygotes who were also CRP haplotype 3 carriers had an age- and gender-adjusted hazard ratio of 5.9 (95% confidence interval 2.1 to 16.5) to develop MI compared with the reference group. In conclusion, this population-based study suggests that the combined presence of unfavorable CFH and CRP genetic profiles is associated with risk of MI.

C-reactive protein (CRP) has been shown to be associated with type 2 diabetes, but whether CRP has a causal role is not yet clear. We examined the association in the Rotterdam Study, a population-based prospective cohort study. The association of baseline serum CRP and incident diabetes during follow-up was investigated, and a meta-analysis was conducted on the BMI-adjusted relation of CRP and diabetes. Furthermore, the association of CRP haplotypes with serum CRP and risk of diabetes was assessed. The age- and sex-adjusted hazard ratio for diabetes was 1.41 (95% CI 1.29-1.54) per 1 SD increase in natural logarithm of CRP, and it was 1.88, 2.16, and 2.83 for the second, third, and fourth quartiles of CRP, respectively, compared with the first quartile. The risk estimates attenuated but remained statistically significant after additional adjustment for obesity indexes, which agreed with the results of the meta-analysis. The most common genetic haplotype was associated with a significantly lower CRP level compared with the three other haplotypes. The risk of diabetes was significantly higher in the haplotype with the highest serum CRP level compared with the most common haplotype (OR 1.45, 95% CI 1.08-1.96). These findings support the hypothesis that serum CRP enhances the development of diabetes.

Aims: C-reactive protein is associated with risk of cardiovascular disease. However, whether C-reactive protein is a marker of severity of cardiovascular disease or actually is involved in its pathogenesis remains unknown. We investigated the relation between C-reactive protein haplotypes, representing the comprehensive variation of the C-reactive protein gene, and coronary heart disease., Methods and Results: The Rotterdam Study is a prospective population-based study among men and women aged 55 years and older. C-reactive protein was associated with risk of coronary heart disease, with a multivariable adjusted hazard ratio of 1.9 (95% CI 1.5-2.4) for the highest vs. the lowest quartile. Four C-reactive protein haplotypes were present with overall frequencies of 32.8, 31.7, 29.5, and 5.9%. C-reactive protein serum levels were significantly different according to C-reactive protein haplotypes. C-reactive protein haplotypes were not associated with coronary heart disease., Conclusion: Steady-state C-reactive protein serum level is influenced by C-reactive protein gene haplotypes. Although elevated C-reactive protein level has lately been found to be a consistent and relatively strong risk factor for cardiovascular disease, our study does not support that the common variation in the C-reactive protein gene has a large effect on the occurrence of coronary heart disease.

Objectives: Details of the biological variability of high-sensitivity C-reactive protein (hs-CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and ST2 are currently lacking in patients with acute coronary syndrome (ACS) but are crucial knowledge when aiming to use these biomarkers for personalized risk prediction. In the current study, we report post-ACS kinetics and the variability of the hs-CRP, NT-proBNP and ST2. Methods: BIOMArCS is a prospective, observational study with high frequency blood sampling during 1 year post-ACS. Using 1507 blood samples from 191 patients that remained free from adverse cardiac events, we investigated post-ACS kinetics of hs-CRP, NT-proBNP and ST2. Biological variability was studied using the samples collected between 6 and 12 months after the index ACS, when patients were considered to have stable coronary artery disease. Results: On average, hs-CRP rose peaked at day 2 and rose well above the reference value. ST2 peaked immediately after the ACS but never rose above the reference value. NT-proBNP level rose on average during the first 2 days post-ACS and slowly declined afterwards. The within-subject variation and relative change value (RCV) of ST2 were relatively small (13.8%, RCV 39.7%), while hs-CRP (41.9%, lognormal RCV 206.1/-67.3%) and NT-proBNP (39.0%, lognormal RCV 185.2/-64.9%) showed a considerable variation. Conclusions: Variability of hs-CRP and NT-proBNP within asymptomatic and clinically stable post-ACS patients is considerable. In contrast, within-patient variability of ST2 is low. Given the low within-subject variation, ST2 might be the most useful biomarker for personalizing risk prediction in stable post-ACS patients. [ABSTRACT FROM AUTHOR]

We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3‐monthly) cardiorenal biomarkers, functional status, and clinical outcomes in 250 patients with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT‐proBNP, troponin T, C‐reactive protein, creatinine, cystatin C; in urine, N‐acetyl‐beta‐ d‐glucosaminidase and kidney‐injury‐molecule‐1. Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) were inversely associated with cardiac impairment, inflammation, and renal tubular damage, but not with glomerular dysfunction. Diuretics were associated with worse biomarker profiles and with a hazard ratio for adverse clinical outcome of 1.12 (95% confidence interval: 1.03–1.22) per 40 mg higher doses. ACE‐inhibitors/ARBs were more frequently downtitrated and diuretics more frequently uptitrated in patients who experienced endpoints than in those who did not. In conclusion, a decrease or withholding of ACE‐inhibitors/ARBs solely based on glomerular function is not justified because of the beneficial effects on the heart, inflammation, and renal tubules. Higher and increased diuretic doses mark progression towards endstage CHF. [ABSTRACT FROM AUTHOR]

Background: Experimental studies have shown that the known biologic effects of proinflammatory cytokines could explain many aspects of the syndrome of heart failure. The inflammatory marker that presently seems most suitable to assess inflammation is C-reactive protein (CRP). This study was designed to investigate the association between serum CRP levels, as determined by high-sensitivity assay, and the occurrence of heart failure. Methods: Serum CRP levels were available from 6437 men and women without heart failure, aged ≥55 years, from the prospective population-based Rotterdam Study. Cox proportional hazards analysis was used to determine risk of heart failure for sex-specific quartiles of CRP. Results: C-reactive protein levels in the highest versus the lowest quartile showed increased hazard ratios of incident heart failure. The age- and sex-adjusted hazard ratio was 2 .64 (95% CI 2.04-3.43) for all participants. For men, the age adjusted hazard ratio was 4.37 (2.87-6.66), and for women, 1.86 (1.32-2.62). The interaction term of CRP with sex was highly significant. After additional adjustment for established cardiovascular risk factors, the association attenuated slightly in men and substantially in women, becoming 3.73 (2.40-5.78) and 1.42 (0.99-2.03), respectively. Excluding participants with prevalent coronary heart disease and accounting for incident coronary heart disease resulted in a further attenuation of the hazard ratios, which was proportionately larger in men than in women. Conclusions: C-reactive protein is strongly and independently associated with occurrence of heart failure in men. In women, the association is weaker and does not persist after accounting for established cardiovascular risk factors. [Copyright &y& Elsevier]

This article focuses on research to analyze associations between the complement factor H (CFH) gene polymorphism and the incidence of age-related macular degeneration (AMD) in the general population. The modifying effects of smoking, serum inflammatory markers, and genetic variations of C-reactive protein are assessed. Methods of the study, main outcome measures, and results are detailed. The CFH Y402H polymorphism could account for a significant proportion of AMD in individuals similar to those who were subjects in the Rotterdam Study, a prospective, population-based study of chronic diseases in the elderly. The polymorphism may confer risk in the presence of environmental and genetic stimulators of the complement cascade.

Objectives: This study was designed to investigate the association between a common polymorphism (Tyr402His, rs1061170) in the complement factor H (CFH) gene and risk of coronary heart disease. Background: The evidence that inflammation is an important mechanism in atherogenesis is growing. C-reactive protein (CRP), complement factors, and complement regulatory factors have all been linked to coronary heart disease. The CFH gene is an important regulator of the alternative complement cascade. We investigated its association with coronary heart disease. Methods: The study was embedded in the Rotterdam Study, a prospective population-based study among men and women aged 55 years and over. A total of 5,520 participants without history of coronary heart disease was genotyped for the Tyr402His polymorphism of the CFH gene. Cox proportional hazards analysis was used to determine risk of myocardial infarction for Tyr402His genotypes. Results: Mean age among participants was 69.5 years (SD 9.1 years). The overall frequency of the His allele was 36%; genotype frequencies were 41%, 45%, and 14% for TyrTyr, TyrHis, and HisHis, respectively. During a mean follow-up period of 8.4 years, 226 myocardial infarctions occurred. After adjustment for age, gender, established cardiovascular risk factors, and CRP level, HisHis homozygotes had a hazard ratio of 1.77 (95% confidence interval 1.23 to 2.55) for myocardial infarction. Total cholesterol level, diabetes mellitus, and smoking modified the effect. The Tyr402His polymorphism was not associated with established cardiovascular risk factors or CRP level. Conclusions: Our data suggest that the CFH gene determines susceptibility to myocardial infarction. This finding underscores the importance of the alternative complement system in cardiovascular disease. [Copyright &y& Elsevier]