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

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.

[1]  Zuhier Awan,et al.  Inflammation modulation and cardiovascular disease prevention , 2015, European journal of preventive cardiology.

[2]  What do carotid intima-media thickness and plaque add to the prediction of stroke and cardiovascular disease risk in older adults? The cardiovascular health study. , 2014, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[3]  Hisashi Adachi,et al.  Inflammation, atherosclerosis, and coronary artery disease. , 2005, The New England journal of medicine.

[4]  R. Sacco,et al.  Changes in Clinical and Microbiological Periodontal Profiles Relate to Progression of Carotid Intima‐Media Thickness: The Oral Infections and Vascular Disease Epidemiology Study , 2013, Journal of the American Heart Association.

[5]  Andrew D. Johnson,et al.  Multiethnic Meta-Analysis of Genome-Wide Association Studies in >100 000 Subjects Identifies 23 Fibrinogen-Associated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease , 2013, Circulation.

[6]  R. Sacco,et al.  Traditional Risk Factors Are Not Major Contributors to the Variance in Carotid Intima-Media Thickness , 2013, Stroke.

[7]  C. Cricelli,et al.  C-reactive protein distribution and correlation with traditional cardiovascular risk factors in the Italian population. , 2013, European journal of internal medicine.

[8]  G. Sangiorgi,et al.  Sex-related differences in carotid plaque features and inflammation. , 2013, Journal of vascular surgery.

[9]  M. Nahrendorf,et al.  Leukocyte Behavior in Atherosclerosis, Myocardial Infarction, and Heart Failure , 2013, Science.

[10]  Yu Xu,et al.  Increased C-reactive protein associates with elevated carotid intima-media thickness in Chinese adults with normal low density lipoprotein cholesterol levels. , 2013, Journal of atherosclerosis and thrombosis.

[11]  J. Gallacher,et al.  C-reactive protein, fibrinogen, and cardiovascular disease prediction. , 2012, The New England journal of medicine.

[12]  Giel Nijpels,et al.  Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis. , 2012, JAMA.

[13]  Lu Gao,et al.  Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data , 2012, The Lancet.

[14]  E. Ortega,et al.  White blood cell count is associated with carotid and femoral atherosclerosis. , 2012, Atherosclerosis.

[15]  P. Libby,et al.  Progress and challenges in translating the biology of atherosclerosis , 2011, Nature.

[16]  T. Vahlberg,et al.  High-Sensitivity C-Reactive Protein and Ankle Brachial Index in a Finnish Cardiovascular Risk Population , 2011, The International journal of angiology : official publication of the International College of Angiology, Inc.

[17]  J. Danesh,et al.  Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data , 2011, BMJ : British Medical Journal.

[18]  J. Després,et al.  Inflammatory biomarkers, physical activity, waist circumference, and risk of future coronary heart disease in healthy men and women. , 2011, European heart journal.

[19]  Holger Poppert,et al.  Individual progression of carotid intima media thickness as a surrogate for vascular risk (PROG-IMT): Rationale and design of a meta-analysis project. , 2010, American heart journal.

[20]  S. Humphries,et al.  Cross-sectional analysis of baseline data to identify the major determinants of carotid intima-media thickness in a European population: the IMPROVE study. , 2010, European heart journal.

[21]  R. Sacco,et al.  Infectious Burden and Carotid Plaque Thickness: The Northern Manhattan Study , 2010, Stroke.

[22]  M. Rizzo,et al.  An update on the role of markers of inflammation in atherosclerosis. , 2010, Journal of atherosclerosis and thrombosis.

[23]  J. Danesh,et al.  C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis , 2010, The Lancet.

[24]  B. Gersh.  C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis , 2010 .

[25]  Paul M Ridker,et al.  Inflammation in atherosclerosis: from pathophysiology to practice. , 2009, Journal of the American College of Cardiology.

[26]  Børge G Nordestgaard,et al.  Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial , 2009, The Lancet.

[27]  P. Libby,et al.  Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. , 2008, The New England journal of medicine.

[28]  Elena Tremoli,et al.  Carotid intima‐media thickness and markers of inflammation, endothelial damage and hemostasis , 2008, Annals of medicine.

[29]  C. Sudlow,et al.  Association Between Apolipoprotein E Genotype and Carotid Intima-Media Thickness May Suggest a Specific Effect on Large Artery Atherothrombotic Stroke , 2008, Stroke.

[30]  H. Markus,et al.  Polymorphisms in MMP Family and TIMP Genes and Carotid Artery Intima-Media Thickness , 2007, Stroke.

[31]  D. Sander,et al.  High-Sensitivity C-Reactive Protein Is Independently Associated With Early Carotid Artery Progression in Women But Not in Men: The INVADE Study , 2007, Stroke.

[32]  H. Markus,et al.  High-Sensitivity C-Reactive Protein Is Not Associated With Carotid Intima-Media Progression: The Carotid Atherosclerosis Progression Study , 2007, Stroke.

[33]  T. Lehtimäki,et al.  Blood leukocyte count is a risk factor for intima-media thickening and subclinical carotid atherosclerosis in middle-aged men. , 2006, Atherosclerosis.

[34]  Qingbo Xu,et al.  Genetic and Acquired Inflammatory Conditions Are Synergistically Associated With Early Carotid Atherosclerosis , 2006, Stroke.

[35]  Peter Libby,et al.  Inflammation and cardiovascular disease mechanisms. , 2006, The American journal of clinical nutrition.

[36]  H Tunstall-Pedoe,et al.  Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. , 2005, JAMA.

[37]  O. Wagner,et al.  Prognostic Impact of Fibrinogen in Carotid Atherosclerosis: Nonspecific Indicator of Inflammation or Independent Predictor of Disease Progression? , 2005, Stroke.

[38]  O. Wagner,et al.  Inflammation and Carotid Artery—Risk for Atherosclerosis Study (ICARAS) , 2005, Circulation.

[39]  J. Beilby,et al.  Monocyte Count, But Not C-Reactive Protein or Interleukin-6, Is an Independent Risk Marker for Subclinical Carotid Atherosclerosis , 2004, Stroke.

[40]  S. Humphries,et al.  Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches , 2004, The Lancet Neurology.

[41]  B. Conrad,et al.  Progression of Early Carotid Atherosclerosis Is Only Temporarily Reduced After Antibiotic Treatment of Chlamydia pneumoniae Seropositivity , 2004, Circulation.

[42]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[43]  J. Paramo,et al.  Independent Association of Fibrinogen with Carotid Intima-Media Thickness in Asymptomatic Subjects , 2003, Cerebrovascular Diseases.

[44]  L. Csiba,et al.  Early-Onset Carotid Atherosclerosis Is Associated With Increased Intima-Media Thickness and Elevated Serum Levels of Inflammatory Markers , 2003, Stroke.

[45]  A. Hofman,et al.  C-Reactive Protein Predicts Progression of Atherosclerosis Measured at Various Sites in the Arterial Tree: The Rotterdam Study , 2002, Stroke.

[46]  M. Hanefeld,et al.  Leukocyte count and fibrinogen are associated with carotid and femoral intima-media thickness in a risk population for diabetes. , 2002, Cardiovascular research.

[47]  S. Blankenberg,et al.  Impact of Infectious Burden on Progression of Carotid Atherosclerosis , 2002, Stroke.

[48]  B. Conrad,et al.  Elevated C-Reactive Protein Is Associated with an Increased Intima to Media Thickness of the Common Carotid Artery , 2002, Cerebrovascular Diseases.

[49]  M. Hori,et al.  C-Reactive Protein Is an Independent Predictor of the Rate of Increase in Early Carotid Atherosclerosis , 2001, Circulation.

[50]  A G Babiker,et al.  Floating absolute risk: an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. , 1991, Statistics in medicine.