Elsevier

Atherosclerosis

Volume 201, Issue 1, November 2008, Pages 217-224
Atherosclerosis

Relation of smoking status to a panel of inflammatory markers: The Framingham offspring

https://doi.org/10.1016/j.atherosclerosis.2007.12.058Get rights and content

Abstract

Aims

We sought to investigate the hypothesis that smoking is accompanied by systemic inflammation.

Methods and results

We examined the relation of smoking to 11 systemic inflammatory markers in Framingham Study participants (n = 2944, mean age 60 years, 55% women, 12% ethnic minorities) examined from 1998–2001. The cohort was divided into never (n = 1149), former (n = 1424), and current smokers with last cigarette >6 h (n = 134) or ≤6 h (n = 237) prior to phlebotomy. In multivariable-adjusted models there were significant overall between-smoking group differences (defined as p < 0.0045 to account for multiple testing) for every inflammatory marker tested, except for serum CD40 ligand (CD40L), myeloperoxidase (MPO) and tumor necrosis factor receptor-2 (TNFR2). With multivariable-adjustment, pair-wise comparisons with never smokers revealed that former smokers had significantly lower concentrations of plasma CD40L (p < 0.0001) and higher concentrations of (CRP) C-reactive protein (p = 0.002).

Conclusions

As opposed to never smokers, those with acute cigarette smoke exposure (≤6 h) had significantly higher concentrations of all markers (p < 0.0001) except serum CD40L, MPO, and TNFR2; plasma CD40L were significantly lower. Compared with never smokers, cigarette smokers have significantly elevated concentrations of most circulating inflammatory markers, consistent with the hypothesis that smoking is associated with a systemic inflammatory state.

Introduction

Cigarette smoking confers a higher risk for peripheral arterial disease, myocardial infarction, heart failure [1], and stroke [2], as well as for lung, pancreatic, renal, cervical, and gastric cancers [3]. Whereas efforts have been made to reduce cigarette smoking in public areas both in Europe and North America, 17.5–45% of adults in the European Union and United States continue to smoke [4]. Because those in lower socio-economic strata tend to smoke more, a study of adult men in Europe and the United States revealed that smoking accounted for almost half of the mortality in persons in the lowest socio-economic stratum [5], [6]. Additionally, a study of adolescents in ten European countries reported up to 20% of boys and 24.7% of girls smoke daily, implying that smoking-related health complications will persist in the next 20–30 years [7]. The World Health Organization estimates that of the 1.1 billion smokers worldwide, 800 million (73%) are in developing nations [8], thereby placing a disproportionate burden on those health-care systems. Globally, cigarette smoking remains a major public health concern and a premier modifiable risk factor for cardiovascular disease.

We and others have noted that systemic markers of inflammation, such as C-reactive protein (CRP) [9], [10], [11], [12], [13], [14], fibrinogen [10], [12], [14], interleukin-6 (IL-6) [9], [11] soluble intercellular adhesion molecule-1 (ICAM-1) [15], and monocyte chemoattractant protein-1 (MCP-1) [16] are elevated in smokers but there is little data on other novel markers of inflammation in smokers such as myeloperoxidase (MPO) and tumor necrosis factor receptor 2 (TNFR2). Whereas previous studies have examined inflammatory markers in smokers, they have been limited by small sample sizes [9], [17], hospital-based samples [17], and examination of ≤3 markers [10], [18]. Additionally, most previous studies have not examined the relation of exposure acuity on markers.

We sought to study markers that would reflect critical phases in the inflammatory pathway of atherosclerotic plaque development. Up-regulation of serum and plasma CD40 ligand (CD40L), urinary isoprostanes, and P-selectin are thought to represent the initiation of the atherothrombotic cascade by stimulating cytokines (such as tumor necrosis factor-α, whose effects are mediated in part by TNFR2) in response to damage of the endothelium or vascular smooth muscle [19], [20]. P-selectin and ICAM-1 are involved in the rolling phase of leukocyte adhesion and early plaque development [15], [19]. MCP-1, a chemokine found in atherosclerotic plaque, attracts monocytes to developing plaque [21], [22]. MPO, a leukocyte enzyme, is elevated in culprit lesions of patients with acute coronary syndrome [20]. Urinary isoprostanes indexed to urinary creatinine (isoprostanes) are measures of oxidative stress [23]. The remainder of the markers in our panel (fibrinogen, CRP, and IL-6) are non-specific inflammatory markers found in multiple sites. The current investigation expands upon previous reports by examining a broad panel of circulating biomarkers that we hypothesized reflects the multiple inflammatory pathways activated by smoking. Further, we hypothesized that inflammatory markers would be elevated in a dose–response relation to smoking, and that acute exposure would result in higher inflammatory markers than less proximate exposure. We analyzed the relation of various aspects of smoking behavior to circulating CD40L, CRP, fibrinogen, ICAM-1, IL-6, urinary isoprostanes, MCP-1, MPO, P-selectin, and TNFR2 in the community-based Framingham Heart Study.

Section snippets

Study sample

We examined participants of the Framingham Heart Study Offspring cohort (largely white of European descent) and the Omni study of ethnic/racial minorities (African Americans, Hispanic Americans and Asian Americans), who attended Exams 7 and 2, respectively (1998–2001). Design and inclusion criteria of the Framingham Heart Study and the Omni Cohort have been described elsewhere [24], [25], [26]. The Framingham Study is reviewed by the Boston University Medical Center Institutional Review Board

Participant characteristics and inflammatory markers

We studied the relation of smoking to inflammatory markers in the Framingham Heart Study (n = 2944, mean age 60 years, 55% women, 12% ethnic minorities) participants examined from 1998–2001. Clinical characteristics of the cohort stratified by smoking status at examinations 7 and 2 for Offspring and Omni participants, respectively, are shown in Table 1.

Inflammatory markers and smoking status

Adjusting for 16 potential clinical confounders, we observed that marker concentrations differed significantly (p < 0.0045) across smoking groups

Discussion

Our panel of inflammatory markers was significantly elevated in current and former smokers as compared with never smokers. Examining individual markers across smoking groups, CRP concentrations were significantly elevated and plasma CD40L concentrations were significantly lower in former smokers. Current smokers had elevations of several systemic markers reflecting activation of many inflammatory pathways. Additionally, we observed a trend between lower plasma CD40L, and higher CRP, ICAM-1,

Acknowledgements

This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study N01-HC 25195; RO1 HL076784; RO1 HL064753, R01 AG028321; and the Flight Attendants Medical Research Institute's Young Clinical Scientist Award (Dr. Walter).

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