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; Simon G Thompson; Stefan Agewall; Göran Bergström; Horst Bickel; Alberico L Catapano; Kuo-Liong Chien; Eric de Groot; Jean-Philippe Empana; Thorleif Etgen; Oscar H Franco; Bernhard Iglseder; Stein H Johnsen; Maryam Kavousi; Lars Lind; Jing Liu; Ellisiv B Mathiesen; Giuseppe D Norata; Michael H Olsen; Aikaterini Papagianni; Holger Poppert; Jackie F Price; Ralph L Sacco; David N Yanez; Dong Zhao; Ulf Schminke; Alpaslan Bülbül; Joseph F Polak; Matthias Sitzer; Albert Hofman; Liliana Grigore; Marcus Dörr; Ta-Chen Su; Pierre Ducimetière; Wuxiang Xie; Kimmo Ronkainen; Stefan Kiechl; Tatjana Rundek; Christine Robertson; Björn Fagerberg; Lena Bokemark; Helmuth Steinmetz; M Arfan Ikram; Henry Völzke; Hung-Ju Lin; Matthieu Plichart; Tomi-Pekka Tuomainen; Moise Desvarieux; Stela McLachlan; Caroline Schmidt; Jussi Kauhanen; Johann Willeit; Matthias W Lorenz; Dirk Sander; PROG-IMT study group

doi:10.1177/2047487314560664

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

Eur J Prev Cardiol. 2016 Jan;23(2):194-205. doi: 10.1177/2047487314560664. Epub 2014 Nov 21.

Authors

Peter Willeit¹, Simon G Thompson², Stefan Agewall³, Göran Bergström⁴, Horst Bickel⁵, Alberico L Catapano⁶, Kuo-Liong Chien⁷, Eric de Groot⁸, Jean-Philippe Empana⁹, Thorleif Etgen¹⁰, Oscar H Franco¹¹, Bernhard Iglseder¹², Stein H Johnsen¹³, Maryam Kavousi¹¹, Lars Lind¹⁴, Jing Liu¹⁵, Ellisiv B Mathiesen¹³, Giuseppe D Norata¹⁶, Michael H Olsen¹⁷, Aikaterini Papagianni¹⁸, Holger Poppert¹⁹, Jackie F Price²⁰, Ralph L Sacco²¹, David N Yanez²², Dong Zhao¹⁵, Ulf Schminke²³, Alpaslan Bülbül²⁴, Joseph F Polak²⁵, Matthias Sitzer²⁶, Albert Hofman²⁷, Liliana Grigore¹⁶, Marcus Dörr²⁸, Ta-Chen Su²⁹, Pierre Ducimetière³⁰, Wuxiang Xie¹⁵, Kimmo Ronkainen³¹, Stefan Kiechl³², Tatjana Rundek²¹, Christine Robertson²⁰, Björn Fagerberg⁴, Lena Bokemark⁴, Helmuth Steinmetz²⁴, M Arfan Ikram¹¹, Henry Völzke³³, Hung-Ju Lin³⁴, Matthieu Plichart³⁵, Tomi-Pekka Tuomainen³¹, Moise Desvarieux³⁶, Stela McLachlan²⁰, Caroline Schmidt⁴, Jussi Kauhanen³¹, Johann Willeit³², Matthias W Lorenz²⁴, Dirk Sander³⁷; PROG-IMT study group

Affiliations

¹ The Department of Public Health and Primary Care, University of Cambridge, UK Department of Neurology, Medical University Innsbruck, Austria.
² The Department of Public Health and Primary Care, University of Cambridge, UK.
³ Institute of Clinical Sciences, University of Oslo, and the Department of Cardiology, Oslo University Hospital Ullevål, Norway.
⁴ Wallenberg Laboratory for Cardiovascular Research, University of Gothenburg, Sweden.
⁵ Department of Psychiatry and Psychotherapy, University Hospital of the Technische Universität München, Germany.
⁶ Department of Pharmacological Sciences, University of Milan, and IRCSS Multimedica Sesto S Giovanni, Milan, Italy.
⁷ Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.
⁸ Academic Medical Centre, Cardiology and Thoracic Surgery, and Imagelabonline and Cardiovascular, Amsterdam, The Netherlands.
⁹ INSERM, U970, Université Paris Descartes, France.
¹⁰ Department of Neurology, Kliniken Südostbayern, Klinikum Traunstein, Germany.
¹¹ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
¹² Department of Geriatric Medicine, Paracelsus Medical University, and the Gemeinnützige Salzburger Landeskliniken Betriebsgesellschaft GmbH, Christian-Doppler-Klinik, Salzburg, Austria.
¹³ Department of Neurology and Neurophysiology, University Hospital of Northern Norway, and the Department of Clinical Medicine, University of Tromsø, Tromsø, Norway.
¹⁴ Department of Medicine, Uppsala University, Sweden.
¹⁵ Department of Epidemiology, Beijing Institute of Heart, Lung and Blood Vessel Diseases, PR China.
¹⁶ Department of Pharmacological Sciences, University of Milan, and the SISA Centre for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy.
¹⁷ Department of Endocrinology, Centre for Individualized Medicine in Arterial Diseases, Odense University Hospital, Denmark.
¹⁸ Department of Nephrology, Aristotle University of Thessaloniki, Hippokration General Hospital, Greece.
¹⁹ Department of Neurology, University Hospital of the Technische Universität München, Germany.
²⁰ Centre for Population Health Sciences, University of Edinburgh, UK.
²¹ Department of Neurology, Miller School of Medicine, University of Miami, FL, USA.
²² Department of Biostatistics, University of Washington, Seattle, WA, USA.
²³ Department of Neurology, Greifswald University Clinic, Germany.
²⁴ Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany.
²⁵ Tufts University School of Medicine, Tufts Medical Center, Boston, MA, USA.
²⁶ Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany Department of Neurology, Klinikum Herford, Germany.
²⁷ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
²⁸ Department B for Internal Medicine, University Medicine Greifswald, and the German Centre for Cardiovascular Research (DZHK), partner site Greifswald, Germany.
²⁹ Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.
³⁰ University Paris Sud-XI, Kremlin-Bicêtre, France.
³¹ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
³² Department of Neurology, Medical University Innsbruck, Austria.
³³ Institute for Community Medicine, SHIP/Clinical-Epidemiological Research, Greifswald, Germany.
³⁴ Department of Internal Medicine, National Taiwan University, Taipei, Taiwan Health Management Centre, National Taiwan University Hospital, Taipei, Taiwan.
³⁵ INSERM, U970, Université Paris Descartes, France Gerontology Department, Broca Hospital, Paris, France.
³⁶ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA, and the École des Hautes Études en Santé Publique, and INSERM U738, Paris, France.
³⁷ Department of Neurology, Benedictus Krankenhaus Tutzing and Feldafing, Tutzing, Germany and Technische Universität München, Germany D.Sander@mac.com.

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Atherosclerosis / blood*
Biomarkers / blood
C-Reactive Protein / analysis*
Carotid Intima-Media Thickness
Disease Progression*
Fibrinogen / analysis*
Humans
Inflammation / blood
Leukocyte Count*

Substances

Biomarkers
Fibrinogen
C-Reactive Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding