C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk

C-reactive protein (CRP), a blood marker of inflammation and a hallmark of the acute-phase response, has been shown to be a powerful and specific predictor of cardiovascular event risk in populations of otherwise healthy persons. Here we review what is known about CRP gene polymorphisms, discuss how these might affect the epidemiology of CRP and our understanding of CRP's contribution to cardiovascular disease, and examine their potential clinical usefulness. Evidence shows that certain subtle variations in the CRP gene sequence, mostly single nucleotide polymorphisms, predictably and strongly influence the blood level of CRP. Some of these variations are associated with clinical correlates of cardiovascular disease. If future studies can establish with certainty that CRP influences cardiovascular biology, then CRP gene profiling could have clinical utility.     

The role of C-reactive protein in cardiovascular disease risk

Over the past few years, a flurry of data in the medical literature has strongly implicated C-reactive protein (CRP) as a marker of inflammation in coronary artery disease (CAD). Recognizing the likely integral role that inflammation plays in the pathogenesis of atherosclerosis, many hospital laboratories have tests to measure CRP concentration in the clinical setting. However, the clinical use of these tests still need definition. To date, of the plasma-based markers investigated, CRP provides the strongest risk prediction for cardiovascular disease in men and women. Questions remain regarding the degree to which CRP can improve risk stratification beyond that of the traditional risk factors of CAD.     

The role of C-reactive protein in cardiovascular disease risk

The genesis of an atherosclerotic plaque depends on interplay of cellular components of the immune system such as monocytes, cytokines, and cell adhesion molecules with lipids, platelets and endothelial cells. Thus, inflammation may play a pivotal role in the propagation of coronary artery disease. Several reports have linked inflammation and cardiovascular risk, particularly a novel acute inflammatory peptide, C-reactive protein (CRP), with future risk of coronary events independent of the traditional coronary artery disease risk factors. To this end, many studies suggest that CRP may be used as a marker of sub-clinical atherosclerosis and cardiovascular risk. Specifically, CRP has been positively linked to future cardiovascular events in healthy women, healthy men, elderly patients, and high-risk individuals. In addition, reports have shown associations between CRP and peripheral vascular disease and stroke. Furthermore, preliminary data suggest that the relative efficacy of secondary preventive therapies such as statin drugs and aspirin may depend on the individual patient's baseline CRP level.     

C-reactive protein, inflammatory conditions, and cardiovascular disease risk

Background

It is uncertain to what extent high C-reactive protein (CRP) concentrations reflect the presence of inflammatory conditions in the community.

Methods

We evaluated 3782 Framingham Offspring Study participants (mean age 55 years; 52% women) free of baseline cardiovascular disease. Logistic regression models examined the prevalence of common inflammatory conditions by CRP categories, while a separate matched case-referent analysis evaluated the prevalence of uncommon inflammatory conditions. Cox models were used to assess the influence of common inflammatory conditions on relations between CRP and incident cardiovascular disease.

Results

Common inflammatory conditions were reported by nearly half of the participants; these individuals were more likely to have markedly high CRP concentrations (>10 mg/L, P for trend = .001). In multivariable models, there were increased odds of having at least one common inflammatory condition with CRP concentrations of 1-3.0, 3.01-10, and >10 mg/L, compared with the referent category (<1 mg/L); the respective odds ratios with 95% confidence intervals were 1.41 (1.07-1.86), 1.45 (1.07-1.98), and 1.64 (1.09-2.47) in men, and 1.08 (0.82-1.43), 1.07 (0.80-1.44), and 1.38 (0.97-1.96) in women. In case-referent analyses, uncommon inflammatory conditions were more common in individuals with CRP >10 mg/L compared with those with CRP <1 mg/L (12.1% vs 6.6%; P = .0001). In multivariable models, higher CRP categories were not associated with incident cardiovascular disease, and with additional adjustment for inflammatory conditions, results remained unchanged.

Conclusion

There is high prevalence of common and uncommon inflammatory conditions in individuals with high CRP concentrations. Higher CRP concentrations should be interpreted with caution in cardiovascular disease risk assessment.     

C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk.

C-reactive protein (CRP), a blood marker of inflammation and a hallmark of the acute-phase response, has been shown to be a powerful and specific predictor of cardiovascular event risk in populations of otherwise healthy persons. Here we review what is known about CRP gene polymorphisms, discuss how these might affect the epidemiology of CRP and our understanding of CRP's contribution to cardiovascular disease, and examine their potential clinical usefulness. Evidence shows that certain subtle variations in the CRP gene sequence, mostly single nucleotide polymorphisms, predictably and strongly influence the blood level of CRP. Some of these variations are associated with clinical correlates of cardiovascular disease. If future studies can establish with certainty that CRP influences cardiovascular biology, then CRP gene profiling could have clinical utility.     

Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease

Some experts propose C-reactive protein (CRP) as a screening tool for prediction of cardiovascular disease (CVD). Many epidemiologic studies show positive associations between elevated CRP levels and incident CVD. Assessment of the value of new prognostic tests, however, must rely on understanding of test characteristics rather than on associations measured by relative risks. In the case of CRP, test characteristics must be judged in the context of currently available CVD risk prediction algorithms. In this review of literature published before January 2006, the authors describe what is known about the additional utility of CRP in risk prediction. They find no definitive evidence that, for most individuals, CRP adds substantial predictive value above that provided by risk estimation using traditional risk factors for CVD. Use of CRP may add to risk estimation in a limited subset of individuals who are at intermediate predicted risk according to the Framingham risk score. The authors propose that many questions still must be addressed before CRP is incorporated into risk prediction algorithms and before universal screening with CRP can be recommended.     

High-sensitivity C-reactive protein as a risk assessment tool for cardiovascular disease

Almost half of first cardiovascular events occur in individuals with no known risk factors. Attempts in the last decade to predict cardiovascular risk more accurately have led to the emergence of a novel risk factor, C-reactive protein (CRP), which has proved to be as good a risk predictor as low-density lipoprotein cholesterol. C-reactive protein is an index of inflammation that is now believed to promote directly all stages of atherosclerosis, including plaque rupture. As measured by high-sensitivity assays, high-sensitivity CRP (hs-CRP) also independently predicts recurrent events in patients with known coronary artery diseases. Recent evidence implicates hs-CRP, and thus inflammation, in the metabolic syndrome and diabetes mellitus, particularly in women. As a clinical tool for cardiovascular risk assessment, hs-CRP testing enhances information provided by lipid screening or global risk assessment. Statin therapy and other interventions can lower hs-CRP. Whether or not such reductions can prevent cardiovascular events is under investigation.     

C-reactive protein: a novel marker of cardiovascular risk

Patients without traditional cardiovascular risk factors continue to suffer from cardiovascular events, which has prompted a search for novel markers to better assess cardiovascular risk. Inflammatory biomarkers have surfaced as prime candidates, given the integral role of inflammation in atherosclerosis. C-reactive protein (CRP) measurements in particular have emerged as powerful predictors of cardiovascular risk in a broad spectrum of patient populations. Newer high sensitivity CRP assays now in use are standardized and reproducible, and can detect variations in CRP below the limit of standard assays. In primary prevention populations, studies have shown up to a 2-4-fold increased risk of cardiovascular events in healthy patients with elevated CRP levels. In this population, models incorporating CRP and lipid parameters appear to predict risk significantly better than lipids alone. In patients with established cardiovascular disease and in patients undergoing percutaneous coronary interventions, CRP levels may help predict short- and long-term prognosis, identifying subgroups of patients at increased risk of recurrent events. CRP levels may also prove useful in targeting therapy for primary and secondary prevention, by identifying patients who would most benefit from medications such as statins and aspirin. This review presents an overview of the data regarding CRP measurement for cardiovascular risk assessment.     

High-sensitivity C-reactive protein and cardiovascular risk in patients with coronary heart disease

High-sensitivity C-reactive protein levels have received widespread attention because of a multitude of prospective studies that have shown that high levels of high-sensitivity C-reactive protein identify increased risk of initial cardiovascular events in coronary heart disease patients and increased risk of recurrent cardiac events in patients with stable and unstable angina, patients with acute myocardial infarction, and patients undergoing elective coronary revascularization procedures. In contrast to several other inflammatory markers, high-sensitivity C-reactive protein measurements are standardized and reproducible. The clinical significance of a reliable inflammatory marker includes identification of high-risk individuals, a gauge to monitor the activity of the disease, and a potential therapeutic target to alter the inflammatory component of the disease process. This review focuses on the importance of high-sensitivity C-reactive protein in cardiovascular risk stratification in coronary heart disease patients and discusses several preventive therapies that may reduce cardiovascular risk through reduction in high-sensitivity C-reactive protein.     

C-reactive protein and cardiovascular disease: Weighing the evidence

C-reactive protein (CRP) has been widely promoted as a strong, independent predictor of cardiovascular events and metabolic syndrome, both in general populations and in patients with clinical cardiovascular disease, and as a causal player in atherothrombosis. However, recent evidence shows that the association of CRP with cardiovascular events is weaker than previously thought, that it may be largely attributed to confounding by established causal risk factors, and that CRP is, therefore, probably not a clinically useful risk predictor. The lack of association of non-coding CRP gene polymorphisms (which determine different baseline CRP values) with coronary events or metabolic syndrome does not support a causal role for CRP, and most of the putatively proatherothrombotic in vitro effects claimed for CRP were caused by contaminants in commercial CRP preparations and not by CRP. Future clinical trials of specific CRP inhibitors now in development could directly test the contribution of CRP to pathogenesis of cardiovascular disease.     

C-reactive protein and cardiovascular disease: a critical appraisal

PURPOSE OF REVIEW: C-reactive protein, a nonspecific marker of inflammation, has recently been proposed both as a marker of low-grade inflammation involved in atherogenesis and as a predictor of disease progression. RECENT FINDINGS: The physiologic functions of C-reactive protein as an anti-inflammatory scavenger molecule have begun to emerge. For example, C-reactive protein binds to damaged lipoproteins and facilitates their removal by phagocytes without full complement activation. Increased levels of C-reactive protein may result in direct effects on vascular cells, including induction of cytokines and prothrombotic factors. Several sources of biologic variation in the levels of C-reactive protein have been identified, chief among which are abdominal obesity and the metabolic syndrome. Although previous studies showed a potent independent association of C-reactive protein levels with cardiac events, the strength of association was shown to be much weaker than previously reported in recent large meta-analyses. Therapy with nonspecific anti-inflammatory agents such as statins in patients with coronary artery disease has been found to reduce adverse outcomes in association with reductions in C-reactive protein, on the basis of retrospective analysis of stored blood specimens. SUMMARY: Despite a relatively strong epidemiologic association with future adverse cardiovascular events, the great majority of apparently healthy individuals with elevated C-reactive protein will not experience cardiovascular disease. Even though more than 15 000 articles in PubMed mention C-reactive protein, current knowledge is insufficient to implicate C-reactive protein as a causative factor in atherothrombosis or to enable the recommendation of C-reactive protein testing to guide preventive or therapeutic interventions in cardiovascular diseases.     

C-reactive protein and cardiovascular disease: Weighing the evidence

C-reactive protein (CRP) has been widely promoted as a strong, independent predictor of cardiovascular events and metabolic syndrome, both in general populations and in patients with clinical cardiovascular disease, and as a causal player in atherothrombosis. However, recent evidence shows that the association of CRP with cardiovascular events is weaker than previously thought, that it may be largely attributed to confounding by established causal risk factors, and that CRP is, therefore, probably not a clinically useful risk predictor. The lack of association of noncoding CRP gene polymorphisms (which determine different baseline CRP values) with coronary events or metabolic syndrome does not support a causal role for CRP, and most of the putatively proatherothrombotic in vitro effects claimed for CRP were caused by contaminants in commercial CRP preparations and not by CRP. Future clinical trials of specific CRP inhibitors now in development could directly test the contribution of CRP to pathogenesis of cardiovascular disease.     

The novel role of C-reactive protein in cardiovascular disease: risk marker or pathogen

C-reactive protein (CRP) is a non-specific biomarker of inflammation. Recent research has shown that inflammation is an important step in the genesis of atherosclerosis, and is involved in the development of unstable plaques. Measurement of serum levels of CRP using a high sensitivity assay (hsCRP) can demonstrate subclinical inflammatory states, which may reflect vascular inflammation. Clinical studies have shown that elevated hsCRP levels in healthy populations predict vascular events such as myocardial infarction (MI) and stroke as well as the development of diabetes. In patients with acute coronary syndromes, higher hsCRP levels are associated with adverse outcomes and subsequent vascular events. There is data to suggest that aspirin, angiotensin converting enzyme (ACE) inhibitors and HMG Co-A reductase inhibitors (statins), which all reduce vascular event rates, also reduce serum levels of hsCRP and therefore hsCRP levels may potentially guide therapy. As well as having a critical role in risk prediction, recent evidence has emerged implicating CRP directly in atherogenesis. CRP has been found in human atherosclerotic plaque and CRP has been shown to cause endothelial cell dysfunction, oxidant stress and intimal hypertrophy in experimental models. We review the postulated roles of CRP in atherogenesis and prediction of vascular events, as well as discussing current recommendations for CRP testing in patients.     

Utility of C-reactive protein measurement in risk stratification during primary cardiovascular disease prevention

High-sensitivity C-reactive protein (hs-CRP) adds prognostic information beyond that provided by the Framingham risk score. The clinical utility of hs-CRP evaluation per guidelines was investigated by determining how it changed the cardiovascular risk stratification of 100 patients deemed at intermediate risk. Screening guidelines defined the cardiovascular risk due to hs-CRP as low (<1.0 mg/L), intermediate (1.0 to 3.0 mg/L), or high (>3.0 mg/L). After hs-CRP evaluation, risk was adjusted in 66% of the patients. Because hs-CRP evaluation significantly altered the cardiovascular risk strata of most intermediate-risk patients, it may therefore be a useful test during primary cardiovascular disease prevention.     

High sensitivity C-reactive protein in systemic lupus erythematosus: relation to disease activity, clinical presentation and implications for cardiovascular risk

Measurement of high sensitivity C-reactive protein (hs-CRP), has been used in the assessment of disease activity in numerous rheumatic conditions including systemic lupus erythematosus (SLE). However, the utility of hs-CRP measurement in patients with lupus is uncertain. This study examined if hs-CRP can be used to assess disease activity, severity and cardiovascular risk in SLE. Serum samples from 601 visits of 213 SLE patients and 134 controls were analysed for hs-CRP by nephelometry. Detailed demographic data were obtained from all subjects and medication history and key laboratory parameters were collected. Disease activity was assessed using the SLEDAI. High sensitivity CRP was not associated with disease activity (SLEDAI), number of ACR SLE criteria or presence of any particular organ involvement. hs-CRP levels were significantly correlated with standard cardiovascular risk factors including body weight (P = 0.0002), hypertension (P = 0.001), and apolipoprotein A-I (P < 0.0001). Interestingly an inverse correlation was seen between hs-CRP levels and antimalarial use (P = 0.0018). Our results suggest that measurement of hs-CRP, though not valuable as marker of disease activity in SLE may be of some use in the assessment of cardiovascular risk. We speculate that antimalarials may help to reduce cardiovascular risk in patients with SLE.