Margit Fröhlich

C-Reactive Protein, a Sensitive Marker of Inflammation, Predicts Future Risk of Coronary Heart Disease in Initially Healthy Middle-Aged Men Results From the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992

BACKGROUND Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events; inflammation elsewhere is also associated with both atherogenesis generally and its thrombotic complications. Recent studies indicate that systemic markers of inflammation can identify subjects at high risk of coronary events. METHODS AND RESULTS We used a sensitive immunoradiometric assay to examine the association of serum C-reactive protein (CRP) with the incidence of first major coronary heart disease (CHD) event in 936 men 45 to 64 years of age. The subjects, who were sampled at random from the general population, participated in the first MONICA Augsburg survey (1984 to 1985) and were followed for 8 years. There was a positive and statistically significant unadjusted relationship, which was linear on the log-hazards scale, between CRP values and the incidence of CHD events (n=53). The hazard rate ratio (HRR) of CHD events associated with a 1-SD increase in log-CRP level was 1.67 (95% CI, 1.29 to 2. 17). After adjustment for age, the HRR was 1.60 (95% CI, 1.23 to 2. 08). Adjusting further for smoking behavior, the only variable selected from a variety of potential confounders by a forward stepping process with a 5% change in the relative risk of CRP as the selection criterion, yielded an HRR of 1.50 (95% CI, 1.14 to 1.97). CONCLUSIONS These results confirm the prognostic relevance of CRP, a sensitive systemic marker of inflammation, to the risk of CHD in a large, randomly selected cohort of initially healthy middle-aged men. They suggest that low-grade inflammation is involved in pathogenesis of atherosclerosis, especially its thrombo-occlusive complications.

C-Reactive Protein Frequently Colocalizes With the Terminal Complement Complex in the Intima of Early Atherosclerotic Lesions of Human Coronary Arteries

There is increasing evidence that complement activation may play a role in atherogenesis. Complement proteins have been demonstrated to be present in early atherosclerotic lesions of animals and humans, and cholesterol-induced atherosclerotic lesion formation is reduced in complement-deficient animals. Potential complement activators in atherosclerotic lesions are now a subject matter of debate. C-reactive protein (CRP) is an acute-phase protein that is involved in inflammatory processes in numerous ways. It binds to lipoproteins and activates the complement system via the classic pathway. In this study we have investigated early atherosclerotic lesions of human coronary arteries by means of immunohistochemical staining. We demonstrate here that CRP deposits in the arterial wall in early atherosclerotic lesions with 2 predominant manifestations. First, there is a diffuse rather than a focal deposition in the deep fibroelastic layer and in the fibromuscular layer of the intima adjacent to the media. In this location, CRP frequently colocalizes with the terminal complement complex. Second, the majority of foam cells below the endothelium show positive staining for CRP. In this location, no colocalization with the terminal complement proteins can be observed. Our data suggest that CRP may promote atherosclerotic lesion formation by activating the complement system and being involved in foam cell formation.

Independent association of various smoking characteristics with markers of systemic inflammation in menResults from a representative sample of the general population (MONICA Augsburg Survey 1994/95)

AIMS Aim of the study was to investigate the association between various markers of systemic inflammation and a detailed history of smoking in a large representative sample of the general population. METHODS AND RESULTS The effects of chronic smoking on white blood cell (WBC) count, fibrinogen, albumin, plasma viscosity (PV), and high-sensitivity C-reactive protein (CRP) were measured in 2305 men and 2211 women, age 25-74 years, participating in the third MONICA Augsburg survey 1994/95. In men, current smokers showed statistically significantly higher values for WBC count, fibrinogen, PV, and CRP, compared to never smokers, with intermediate, but only slightly increased values for ex-smokers and for occasional smokers. No consistent associations were seen with albumin. Duration of smoking was positively associated with markers of inflammation as were pack-years of smoking. Conversely, duration of abstinence from smoking was inversely related to these markers. Except for WBC count, no such associations were found in women. CONCLUSION Data from this large representative population show strong associations between smoking and various markers of systemic inflammation in men. They also show that cessation of smoking is associated with a decreased inflammatory response, which may represent one mechanism responsible for the reduced cardiovascular risk in these subjects.

Distributions of C-reactive Protein Measured by High-Sensitivity Assays in Apparently Healthy Men and Women from Different Populations in Europe

C-reactive protein (CRP), the classic marker of acute-phase response, is an indicator of a variety of pathologic processes, including infections, tissue damage, and chronic inflammatory diseases (1)(2). The majority of more than 15 well-conducted prospective studies in initially healthy individuals have shown a strong and independent association between concentrations of CRP within the reference interval (<5 mg/L) and future major cardiovascular events (3), although in some of them, no such association could be established (4)(5)(6)(7). The summary estimate of the relative risk in formal metaanalysis was 2.0 (95% confidence interval, 1.6–2.5) (3). Furthermore, CRP has been shown to add to risk prediction beyond and above established cardiovascular risk factors (8). On the basis of data from the Physicians’ Health Study and the Nurses’ Health Study, an algorithm for risk assessment of future coronary events that combines both CRP concentration and the ratio of total cholesterol to HDL-cholesterol has recently been proposed (9). Because atherosclerosis represents a low-grade inflammatory process in the vascular bed, high-sensitivity (hs) assays are needed when using circulating CRP concentrations for risk prediction in cardiovascular diseases. Such assays have been developed and are now commercially available (10)(11). However, before screening of individuals at risk can be recommended, CRP distributions in apparently healthy adults in the general population must be known. Such information is scarce. Furthermore, in previous reports, women using oral contraceptives or receiving hormone replacement therapy (HRT), both of which have been shown to significantly increase CRP concentrations, had not been excluded (12)(13)(14)(15). In this report, we describe the frequency distribution of CRP concentrations in 13 527 adult men and women from different representative populations in Western Europe. Furthermore, for one area [the MONICA (Monitoring Trends and Determinants in …

CD14 C(-260)→T polymorphism, plasma levels of the soluble endotoxin receptor CD14, their association with chronic infections and risk of stable coronary artery disease

OBJECTIVES We sought to investigate the association of CD14 genotype and plasma levels of soluble (s)CD14 with risk of stable coronary artery disease (CAD), chronic infections and sensitive markers of systemic inflammation. BACKGROUND It has been suggested that genetic variation of the CD14 receptor with increased CD14 gene expression might play a role in atherogenesis. A mechanistic link would consist in its contribution to the inflammatory response seen in this disease. METHODS We measured levels of sCD14 (microg/ml; ELISA) in 312 patients with angiographically proven CAD and stable angina pectoris, and in 477 age- and gender-matched healthy blood donors. CD14 genotype was determined by polymerase chain reaction. In addition, seropositivity to Chlamydia pneumoniae and Helicobacter pylori, a complete lipid profile and various sensitive systemic markers of inflammation were measured. RESULTS CD14 C(-260)-->T genotype was not independently associated with increased risk of CAD after multivariable adjustments (odds ratio [OR] 1.34; 95% confidence interval [CI] 0.84 to 2.16). However, sCD14 plasma levels were higher in subjects with TT genotype compared with those with CT or CC genotype (p = 0.005). Plasma levels were not different between cases and controls (4.2 +/- 1.3 microg/ml vs. 4.3 +/- 1.3 microg/ml, p = NS). In multivariable logistic regression, the OR for the presence of CAD was 1.11 (95% CI, 0.65 to 1.91) if the top quintile of the sCD14 distribution was compared with the bottom quintile. There was no consistent association between seropositivity to either C. pneumoniae or H. pylori, or both, and sCD14 levels and between sCD14 levels or CD14 genotype and the various markers of inflammation. CONCLUSIONS These results do not confirm an independent relationship between CD14 genotypes or plasma levels of sCD14 and risk of stable CAD in this population.

Chronic infection with Helicobacter pylori does not provoke major systemic inflammation in healthy adults: results from a large population-based study

It has been suggested that chronic infection with Helicobacter pylori (H. pylori), in particular infection with virulent strains producing the cytotoxin-associated protein CagA, may increase the risk of coronary heart disease by generation of a persistent low-grade inflammatory stimulus. We assessed the relation between serological markers of H. pylori infection and various markers of systemic inflammation in a population-based sample of 1834 men and women aged 18-88. A total of 39.3% of the sample had a positive IgG response, and among these a slight majority was CagA positive. Infection with H. pylori was unrelated to C-reactive protein and the leukocyte count, regardless of CagA status. There was an inverse relation between H. pylori infection and serum albumin. The adjusted OR (95% CI) of an albumin level in the bottom versus the top third were 2.2 (1.5-3.1) and 2.0 (1.4-3.1) for infection with CagA-positive and CagA-negative H. pylori strains, respectively. These results do not support the hypothesis that chronic infection with virulent H. pylori strains provokes major systemic inflammation. The mechanisms underlying the inverse association between H. pylori infection and serum albumin and the clinical relevance of this finding require further research.

Markers of inflammation in women on different hormone replacement therapies

BACKGROUND AND AIM. To measure inflammatory markers in postmenopausal women on different forms of hormone replacement therapy (HRT). METHOD. C-reactive protein (CRP), fibrinogen, plasma viscosity (PV), albumin and white blood cell (WBC) count were determined in 749 postmenopausal women. RESULTS. CRP concentration was significantly higher in women on estrogen monotherapy (difference of the median (d) 0.96 r mg/l, P r = r 0.013), compared to those without HRT, but there was no difference in women on combined HRT. Fibrinogen concentration was significantly lower in women on estrogen monotherapy (d 0.25 r g/l, P r = r 0.004) and combined HRT (d 0.4 r g/l, P r < r 0.001), compared to women without HRT. Similarly, PV was significantly lower in women on estrogen monotherapy (d 0.017 r mPa·s, P r = r 0.007) and women on combined HRT (d 0.039 r mPa·s, P r < r 0.001), compared to those without HRT. No differences were found for WBC count and the negative acute phase marker albumin in the various treatment groups. In contrast to oral estrogen administration, levels of CRP, fibrinogen and PV in women on transdermal estrogen therapy did not differ from the no-HRT group. There was no association between these markers of inflammation and plasma estrogen levels. CONCLUSION. Oral estrogen monotherapy was associated with highest concentrations of CRP. In contrast, other markers of inflammation were either similar or lower in the oral HRT group, compared to the group of women without HRT, suggesting that higher CRP concentrations reflect estrogen effects on CRP expression rather than a systemic pro-inflammatory effect.