Elsevier

The Lancet

Volume 349, Issue 9050, 15 February 1997, Pages 462-466
The Lancet

Early Report
Production of C-reactive protein and risk of coronary events in stable and unstable angina

https://doi.org/10.1016/S0140-6736(96)07591-5Get rights and content

Summary

Background

Inflammation is an important feature of atherosclerotic lesions, and increased production of the acute-phase reactant, C-reactive protein (CRP), is associated with a poor prognosis in severe unstable angina. We have investigated the existence and possible significance of the acute-phase responses of CRP and another sensitive reactant, serum amyloid A protein (SAA), in patients with unstable or stable angina.

Methods

We used new ultrasensitive immunoassays to measure CRP and SAA concentrations in plasma from 2121 outpatients with angina (1030 unstable, 743 stable, the rest atypical) enrolled in the European Concerted Action on Thrombosis and Disabilities (SCAT) Angina Pectoris Study. All patients underwent coronary angiography and extensive clinical and laboratory assessment at study entry, and were then followed up for 2 years. All suspected coronary events during follow-up were reviewed by an independent endpoint committee.

Findings

75 individuals (41 with unstable, 29 with stable, and 5 with atypical angina) had a coronary event during follow-up. Concentrations of CRP at study entry were associated with coronary events in patients with stable or unstable angina: there was about a two-fold increase in the risk of a coronary event in patients whose CRP concentration was in the fifth quintile (>3·6 mg/L), compared with the first four quintiles. A third of the events occurred among patients who had a CRP concentration of more than 3·6 mg/L CRP concentrations were positively correlated with age, smoking, body-mass index, triglycerides, extent of coronary stenosis, history of myocardial infarction, and lower ejection fraction. By contrast, concentrations of SAA were not associated with risk of a coronary event.

Interpretation

We found that raised circulating concentrations of CRP are predictors of coronary events in patients with stable or unstable angina. The modest acute-phase responses of CRP were probably not the result of myocardial necrosis. Whatever the underlying mechanisms, the sensitive measurement of CRP as a prognostic marker may be useful in the management of coronary heart diease.

Introduction

Inflammation is an important feature of atheroma and is associated with activation and proliferation of macrophages, endothelial cells, and smooth-muscle cells, the generation of cytokines and growth factors, the activation and deposition of complement, and the presence of other proinflammatory mediators, such as oxidised low-density lipoprotein.1 The lipid-rich atheromatous material is itself a potent inducer of inflammation.2 Previous studies have also reported a significant association between microbial infections, both within the arterial lesions themselves and elsewhere, and coronary artery disease.3, 4, 5, 6, 7

A feature of most forms of inflammation, infection, and tissue damage is the increase in the circulating concentrations of various plasma proteins known as acute-phase reactants.8 These reactants are mainly produced by hepatocytes, and the increased expression of the acute-phase protein genes is driven by cytokines, which are produced by activated macrophages and other cells.9 During inflammation, the plasma concentrations of the two most sensitive acute-phase proteins in human beings, C-reactive protein (CRP) and serum amyloid A protein (SAA), can rise by up to 10000 fold.10, 11, 12 The plasma concentration of CRP is determined only by its production rate13 which, provided liver function is normal, depends on the concentration of cytokines and other mediators that reach the hepatocytes. Thus, plasma concentrations of CRP are a precise objective index of overall inflammatory activity in the body;12 they amplify the underlying cytokine signal. Biologically significant direct measurements of cytokines are difficult to obtain, because such mediators are involved in complex molecular and cellular cascades and the only accessible compartment is the circulation, in which such proteins have short in-vivo half-lives. Furthermore, assays for cytokines are technically difficult and generally unreliable. By contrast, sensitive, robust, and reliable immunoassays for CRP and SAA have been developed that cover the normal ranges, and are well below the sensitivity of the widely available commercial assays routinely used for clinical measurements.11, 14 Such assays enable low-grade inflammation, otherwise undetectable in the whole organism, to be detected non-invasively.

Concentrations of CRP are directly correlated with the presence and severity of coronary, cerebral, and peripheral arterial atherosclerosis.15 Substantial increases in the serum concentrations of CRP have been observed in patients with severe unstable angina.16 Liuzzo and colleagues14 reported that in patients admitted to hospital with acute unstable angina, a plasma concentration of CRP above 3 mg/L (the 90th centile of the normal CRP distribution) was associated with a significantly worse prognosis, even though there was no other evidence of more severe disease.14 In the largest study to date, the European Concerted Action on Thrombosis and Disabilities (ECAT) Angina Pectoris Study, the plasma concentration of CRP at study entry was directly and significantly correlated with incidence of myocardial infarction or sudden coronary death during the subsequent 2 years.17 However, the assay used in that study was insufficiently sensitive to detect CRP in about 30% of plasma samples. We, therefore, used new ultrasensitive automated enzyme immunoassays to investigate associations between plasma concentrations of CRP and SAA and known coronary risk factors and coronary events in the EC AT patients with stable or unstable angina.

Section snippets

Methods

Participants were recruited to the ECAT study between October, 1984, and June, 1987. Eligible patients were men and women who had undergone coronary arteriography because of suspected coronary artery disease. We excluded individuals who had had myocardial infarction within the preceding 2 months, and those with severe right heart failure or non-cardiac disease likely to cause death within 1 year. 2121 outpatients from 15 European centres were enrolled and were classified in three groups:

Results

1030 patients had unstable angina, 743 had stable angina, and 326 had atypical chest pain (table 1). The three groups had similar age and sex distributions; 85% of patients were aged 45–69 years. There were 75 coronary events during the 2 years of follow-up: 20 sudden deaths, seven fatal infarcts, and 48 definite but non-fatal myocardial infarcts.

Baseline concentrations of CRP and SAA were highly correlated (r=0·67) and did not differ according to the type of angina (table 1), but were slightly

Discussion

The acute-phase response is a non-specific phenomenon induced by almost all forms of tissue damage and inflammation.8 To assess the specific association between circulating concentrations of acute-phase proteins and coronary-artery disease, other disorders should be excluded as far as possible. In this study, we excluded individuals with recent myocardial infarction, cardiac failure, and other advanced, severe conditions; although some patients with intercurrent disease may have remained in the

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