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Meta-Analysis
. 2016 Jan;23(2):194-205.
doi: 10.1177/2047487314560664. Epub 2014 Nov 21.

Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration

Peter Willeit  1 , Simon G Thompson  2 , Stefan Agewall  3 , Göran Bergström  4 , Horst Bickel  5 , Alberico L Catapano  6 , Kuo-Liong Chien  7 , Eric de Groot  8 , Jean-Philippe Empana  9 , Thorleif Etgen  10 , Oscar H Franco  11 , Bernhard Iglseder  12 , Stein H Johnsen  13 , Maryam Kavousi  11 , Lars Lind  14 , Jing Liu  15 , Ellisiv B Mathiesen  13 , Giuseppe D Norata  16 , Michael H Olsen  17 , Aikaterini Papagianni  18 , Holger Poppert  19 , Jackie F Price  20 , Ralph L Sacco  21 , David N Yanez  22 , Dong Zhao  15 , Ulf Schminke  23 , Alpaslan Bülbül  24 , Joseph F Polak  25 , Matthias Sitzer  26 , Albert Hofman  27 , Liliana Grigore  16 , Marcus Dörr  28 , Ta-Chen Su  29 , Pierre Ducimetière  30 , Wuxiang Xie  15 , Kimmo Ronkainen  31 , Stefan Kiechl  32 , Tatjana Rundek  21 , Christine Robertson  20 , Björn Fagerberg  4 , Lena Bokemark  4 , Helmuth Steinmetz  24 , M Arfan Ikram  11 , Henry Völzke  33 , Hung-Ju Lin  34 , Matthieu Plichart  35 , Tomi-Pekka Tuomainen  31 , Moise Desvarieux  36 , Stela McLachlan  20 , Caroline Schmidt  4 , Jussi Kauhanen  31 , Johann Willeit  32 , Matthias W Lorenz  24 , Dirk Sander  37 ; PROG-IMT study group
Affiliations
Meta-Analysis

Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration

Peter Willeit et al. Eur J Prev Cardiol. 2016 Jan.

Abstract

Background: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.

Methods: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.

Results: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015).

Conclusion: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.

Keywords: Inflammation; atherosclerosis; meta-analysis.

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Conflict of interest statement

Conflict of interest

SA has received speaker’s honoraria from Sanofi, Siemens, Pfizer, Boehringer-Ingelheim, Orion Pharma, and Astra Zeneza and is on the advisory board for Astra Zeneca. OHF works in ErasmusAGE, a centre for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc., and AXA. Nestlé Nutrition (Nestec Ltd.), Metagenics Inc. and AXA had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript. MHO received a Research Grant from Merck & Co., Inc., West Point, PA. None of the other authors report conflicts of interest.

Figures

Figure 1
Figure 1
Shape of association of inflammation markers with common carotid artery intima-media thickness (CCA-IMT). Panel (a): baseline inflammatory markers and baseline CCA-IMT; panel (b): baseline inflammatory markers and yearly CCA-IMT progression; panel (c): change in inflammatory markers and yearly CCA-IMT progression. aModels in panel (c) were additionally adjusted for mean CCA-IMT. bModels in panels (a) and (b) were further adjusted for baseline traditional risk factors (i.e. systolic blood pressure, total cholesterol, history of diabetes, current smoking, use of anti-hypertensive medication), models in panel (c) for means and changes in traditional risk factors. hsCRP: high-sensitivity C-reactive protein; CI: confidence interval
Figure 2
Figure 2
Association of inflammation markers with common carotid artery intima-media thickness (CCA-IMT). Panel (a): baseline inflammatory markers and baseline CCA-IMT; panel (b): baseline inflammatory markers and yearly CCA-IMT progression; panel (c): change in inflammatory markers and yearly CCA-IMT progression. aModels in panels (a) and (b) were further adjusted for baseline traditional risk factors (i.e. systolic blood pressure, total cholesterol, history of diabetes, current smoking, use of anti-hypertensive medication), models in panel (c) for means and changes in traditional risk factors. The number of participants contributing to the analysis in panel (c) is less than in Table 1 because of missing values in the variables for which the analysis was adjusted. bModels in panel (c) were additionally adjusted for mean CCA-IMT. CI: confidence interval
Figure 3
Figure 3
Associations between number of elevated inflammation markers at baseline and common carotid artery intima-media thickness (CCA-IMT). Panel (a): baseline inflammatory load and baseline CCA-IMT; panel (b): baseline inflammatory load and yearly CCA-IMT progression. For each of the three inflammatory markers (high-sensitivity C-reactive protein, fibrinogen, leucocyte count), levels were deemed to be elevated if they were in the top two fifths of the study-specific distribution. People with no elevated inflammatory markers served as the reference group. Models were adjusted for baseline age, sex, systolic blood pressure, total cholesterol, history of diabetes, current smoking, and use of anti-hypertensive medication. CI: confidence interval
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