Measurement of C-Reactive Protein for the Targeting of Statin Therapy in the Primary Prevention of Acute Coronary Events

Ridker, Paul M.; Rifai, Nader; Clearfield, Michael; Downs, John R.; Weis, Stephen E.; Miles, J. Shawn; Gotto, Antonio M.

doi:10.1056/nejm200106283442601

Cited by 1,433 publications

(564 citation statements)

References 27 publications

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“…We present evidence that lower birth weight and shorter durations of breastfeeding both predict elevated concentrations of CRP in young adulthood, indicating increased risk for cardiovascular and metabolic diseases that are major health burdens in the USA and the UK. Clinical trials have demonstrated that statin therapy reduces CRP in healthy adults by 14.8-17.4% [53][54][55]. Our results suggest that the effects of breastfeeding on adult CRP are comparable, or larger, in magnitude.…”

Section: Discussionsupporting

confidence: 49%

Long-term effects of birth weight and breastfeeding duration on inflammation in early adulthood

et al. 2014

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Chronic inflammation is a potentially important physiological mechanism linking early life environments and health in adulthood. Elevated concentrations of C-reactive protein (CRP)-a key biomarker of inflammation-predict increased cardiovascular and metabolic disease risk in adulthood, but the developmental factors that shape the regulation of inflammation are not known. We investigated birth weight and breastfeeding duration in infancy as predictors of CRP in young adulthood in a large representative cohort study (n ¼ 6951). Birth weight was significantly associated with CRP in young adulthood, with a negative association for birth weights 2.8 kg and higher. Compared with individuals not breastfed, CRP concentrations were 20.1%, 26.7%, 29.6% and 29.8% lower among individuals breastfed for less than three months, three to six months, 6-12 months and greater than 12 months, respectively. In sibling comparison models, higher birth weight was associated with lower CRP for birth weights above 2.5 kg, and breastfeeding greater than or equal to three months was significantly associated with lower CRP. Efforts to promote breastfeeding and improve birth outcomes may have clinically relevant effects on reducing chronic inflammation and lowering risk for cardiovascular and metabolic diseases in adulthood.

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Section: Discussionsupporting

confidence: 49%

Long-term effects of birth weight and breastfeeding duration on inflammation in early adulthood

et al. 2014

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“…29). A more recent study determined that elevated levels of C-reactive protein, even in the absence of hyperlipidemia, are associated with an increased risk of coronary events (30). Statin therapy reduces the level of C-reactive protein independent of its effect on FIG.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia-induced Production of Acute Phase Reactants in Adipose Tissue

Lin

Rajala

Berger³

et al. 2001

Journal of Biological Chemistry

244

172

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Chronic elevation of systemic levels of acute phase reactants and inflammatory cytokines found in patients with diabetes and the often-associated metabolic syndrome X (hypertriglyceridemia, low serum high density lipoprotein cholesterol, hypertension, and accelerated atherosclerosis) may be responsible for the increased incidence of cardiovascular problems in this population. Here we examine the contribution of adipose tissue to the systemic elevation of acute phase reactants associated with chronic hyperglycemia. We demonstrate that adipose tissue expresses a number of acute phase reactants at high levels, including serum amyloid A3 (SAA3), ␣l-acid glycoprotein, the lipocalin 24p3 as well as plasminogen activator inhibitor-1 (PAI-1). Additionally, we show SAA3 is expressed at low levels under normal conditions but in the diabetic state is dramatically up-regulated in adipose tissue while down-regulated in liver. Furthermore, pro-inflammatory stimuli and high glucose can lead to the induction of SAA3 in adipose tissue in vivo as well as in the 3T3-L1 adipocyte cell line. Adipose tissue may therefore play a major role in the pathogenic sequelae of Type II diabetes, in particular the cardiovascular problems associated with prolonged hyperglycemia.

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“…Recent studies point to IL-6 as a marker of cardiovascular disease as well as systemic inflammation (3)(4)(5)(6)(7)(8). IL-6 plasma levels are elevated in myocardial infarction, unstable angina, and atherosclerosis.…”

Section: Il-6 May Decrease Enos Expression In Atherosclerosis-mentioning

confidence: 99%

“…Although the APR is a rapid response to acute stress, chronic activation of the APR is associated with various diseases including cancer, autoimmune diseases, and coronary artery disease. For example, levels of acute phase effector proteins such as C-reactive protein (CRP), fibrinogen, and sICAM-1 are higher in patients with atherosclerosis or acute coronary syndromes compared with healthy controls (3)(4)(5)(6)(7)(8). The APR may play a role in the pathogenesis of endothelial dysfunction, an early stage in atherogenesis.…”

mentioning

confidence: 99%

Stat3 Mediates Interelukin-6 Inhibition of Human Endothelial Nitric-oxide Synthase Expression

Saura

Zaragoza

Bao

et al. 2006

Journal of Biological Chemistry

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Chronic activation of the acute phase response (APR) is associated with atherosclerosis. Elevated levels of interleukin-6, the major inducer of the APR, are associated with an increased risk of cardiovascular events. One of the clinical hallmarks of atherogenesis is endothelial dysfunction, characterized by a decrease in endothelial production of nitric oxide (NO). We hypothesized that interleukin-6 (IL-6) decreases endothelial NO synthase (eNOS) expression. We now show that IL-6 treatment of human aortic endothelial cells (HAEC) decreases steady-state levels of human eNOS mRNA and protein. This decrease in eNOS expression is caused in part by IL-6 inhibition of transactivation of the human eNOS promoter. To explore the mechanism by which IL-6 affects eNOS expression, we examined activation of signal transducer and transactivator-3 (Stat3). The IL-6 receptor (IL-6R) is expressed in HAEC, and Stat3 is phosphorylated in response to IL-6 stimulation of the IL-6R. We identified four consensus sequences for Stat3 binding (SIE) in the eNOS promoter at positions ؊1520, ؊1024, ؊840, and ؊540. Transfection of eNOS promoter mutants revealed that the SIE at ؊1024 mediates Stat3 inhibition of eNOS promoter activity. Gel-shift analysis of nuclear extracts from HAEC treated with IL-6 confirms that Stat3 binds to a complex containing the SIE at ؊1024. RNA silencing of STAT3 blocks the inhibitory effect of IL-6 on eNOS expression. Our data show that IL-6 has direct effects upon endothelial cells, inhibiting eNOS expression in part through Stat3. Decreased levels of eNOS may be an important component of the pro-atherogenic effect of the APR. The acute phase response (APR)3 is a systemic innate inflammatory response to acute injury (1, 2). A variety of triggers such as infection or trauma lead to the rapid synthesis and circulation of a large number of acute phase effector molecules, including anti-microbial proteins, pro-coagulant factors, and metabolic regulators. Although the APR is a rapid response to acute stress, chronic activation of the APR is associated with various diseases including cancer, autoimmune diseases, and coronary artery disease. For example, levels of acute phase effector proteins such as C-reactive protein (CRP), fibrinogen, and sICAM-1 are higher in patients with atherosclerosis or acute coronary syndromes compared with healthy controls (3-8). The APR may play a role in the pathogenesis of endothelial dysfunction, an early stage in atherogenesis.Interleukin-6 (IL-6) is a major activator of the acute phase response (1, 9). IL-6 induces hepatocytes to activate or suppress the synthesis of a variety of acute phase response effector proteins. IL-6 initiates its action by binding to the IL-6 receptor, which is composed of two subunits: an 80-kDa IL-6-binding protein and a 130-kDa transmembrane signal-transducing component (gp130) (9). Activation of IL-6 signal transduction involves gp130 dimerization, ligand-dependent tyrosine phosphorylation of Jak1, Jak2, and Tyk2, followed by tyrosine phosphorylation of sign...

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Measurement of C-Reactive Protein for the Targeting of Statin Therapy in the Primary Prevention of Acute Coronary Events

Abstract: Statin therapy may be effective in the primary prevention of coronary events among subjects with relatively low lipid levels but with elevated levels of C-reactive protein.

Cited by 1,433 publications

References 27 publications

Long-term effects of birth weight and breastfeeding duration on inflammation in early adulthood

Long-term effects of birth weight and breastfeeding duration on inflammation in early adulthood

Hyperglycemia-induced Production of Acute Phase Reactants in Adipose Tissue

Stat3 Mediates Interelukin-6 Inhibition of Human Endothelial Nitric-oxide Synthase Expression

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