Elsevier

Atherosclerosis

Volume 160, Issue 2, February 2002, Pages 457-463
Atherosclerosis

Parameters of inflammation and infection in a community based case-control study of coronary heart disease

https://doi.org/10.1016/S0021-9150(01)00602-5Get rights and content

Abstract

Background: increased levels of systemic inflammatory markers appear to be related to coronary heart disease (CHD) both in asymptomatic individuals and in subjects with established CHD. Whether these associations are related to confounding coronary risk factors or are explicable through chronic infectious conditions is not clear. Objectives: (1) to determine whether subjects with stable CHD differ from normal controls in inflammatory markers (CRP, SAA and fibrinogen) and/or in serostatus of four infectious agents (Helicobacter pylori, Chlamydia pneumoniae, CMV and EBV), independent of classical coronary risk factors. (2) To determine whether these inflammatory markers are related to the serostatus against these four infectious agents either in patients with CHD or in normal subjects. Methods: in a large epidemiologic survey, 446 out of 16 307 men at work, aged 35–59 years, had antecedents of myocardial infarction, CABG or PTCA or had prominent Q/QS waves on their resting ECG. They were compared with double the number (n=892) of men, matched for age, educational level and industry. Inflammatory biomarkers (CRP, fibrinogen and SAA) and antibodies against H. pylori, C. pneumoniae, CMV and EBV were measured, besides classical coronary risk factors. Results: in univariate analyses, cases had higher CRP, fibrinogen and SAA levels than controls, but no differences were observed in serumantibody levels to any of the infectious agents. Markers of previous infections were not related to inflammatory biomarkers. In multivariate analyses CRP was significantly different between cases and controls independent of differences in other coronary risk factors and in the use of lipid lowering drugs and antiplatelet aggregants. Conclusion: in men at work with CHD, CRP levels are significantly different from controls, independent of known risk factors. No association was found between inflammatory biomarkers and positive serostatus against four infectious agents, neither in the patients nor in the healthy controls.

Introduction

In recent years increasing evidence has emerged that circulating levels of several inflammatory markers are significantly higher in patients with acute myocardial ischemia [1], myocardial infarction [2] and unstable angina [3] and prospective studies have shown an association between either fibrinogen [4], [5], [6], [7], [8] or high-sensitivity C-reactive protein (CRP) [9], [10], [11], [12], [13], [14] and the risk of developing CHD. It is at present not known if these associations are causal. Different mechanisms have been proposed:

  • 1

    These inflammatory markers might be related to classic cardiovascular risk factors. In this context elevated CRP has been found in association with smoking, obesity, low social class, low HDL cholesterol and elevated triglycerides [15], [16]. In this case, CRP may be an indicator of intermediate mechanisms.

  • 2

    They might merely be a reflection of atherosclerosis being a chronic inflammatory process [17]. This by itself may be an epiphenomenon with or without a causal role in pathogenesis.

  • 3

    They could reflect a chronic infectious state, which could in turn trigger the process of atherosclerosis. They may thus be indicators of an inflammatory process that plays a direct role in the pathogenesis of atherosclerosis.

The results of the studies relating chronic infection to CHD have been inconsistent [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. Initially case control studies on this subject published a positive association between seropositivity and CHD; more recently however large population studies have reported no such associations [28], [29], [30], [31]. These inconsistencies might have different explanations: insufficient sample size, differences in the design of the study, differences in the definition of seropositivity, incomplete adjustment for confounding factors and publication bias.

With the present study additional observations are presented on the subject.

A case control study was conducted with patients who may be considered to be in a stable condition since they were at work, at the moment of the examination.

The objectives of the study were:

  • 1

    To determine whether subjects with stable CHD differ from normal controls in inflammatory markers and in serological evidence for previous infection with four infectious agents, independent of classical coronary risk factors.

  • 2

    To determine whether inflammatory markers are related to this serostatus in patients with CHD or in normal subjects.

Section snippets

Subjects and methods

The BELSTRESS project is a community based prospective study focused on job stress and health [32]. This report deals with results from a case control study within the BELSTRESS study; 16 307 men at work, aged 35–59 years, were screened for evidence of CHD on the basis of either a personal history of CHD (previous hospitalisation for acute myocardial infarction, coronary angioplasty or bypass surgery) and/or major ECG abnormalities suggestive of a myocardial scar (prominent Q/QS waves on their

Statistics

Equality of distributions of study characteristics between cases and controls was statistically evaluated according to the t-test for continuous data and χ2-test for categorical data. Regarding the skewed nature of their distributions, a non-parametrical Mann–Whitney test was used for comparison of inflammatory markers between both groups. In order to study the association between CRP levels and case/control status independently of conventional coronary risk factors, multiple logistic

Classic coronary risk factors and drug therapy

The matching procedure resulted in two groups of equal age and of comparable educational level (Table 1).

Comparing the different classic coronary risk factors between cases and controls, significant differences were observed in BMI, blood pressure, HDL cholesterol, diabetes, physical activity and drug therapy: cases had a higher BMI and were more obese; cases had a higher systolic blood pressure; cases had a lower HDL cholesterol and therefore more cases had a total/HDL cholesterol ratio ≥5;

Discussion

With the recognition that atherosclerosis is an inflammatory process [17] the research interest into markers of inflammation has significantly increased. Some of these markers have been studied many years ago [46], but these results have received limited attention. Others such as plasma fibrinogen have been studied as a biomarker of the clotting process rather than of inflammation [4], [5], [6], [7], [8]. More recently, slightly elevated concentrations of C-reactive protein, within the ‘normal’

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