title: Prevalence of M4 macrophages within human coronary atherosclerotic plaques is associated with features of plaque instability.
abstract: BACKGROUND
  The platelet chemokine CXCL4 induces monocyte differentiation resulting in a macrophage phenotype called "M4", which co-expresses CD68, MMP7, and S100A8. We hypothesized that M4 macrophages are associated with plaque destabilization.
  
  
  METHODS
  Atherosclerotic arteries were obtained from explanted hearts of patients with severe coronary artery disease (CAD, n = 32) and of patients with dilated cardiomyopathy and no or mild CAD (controls, n = 19). Coronary arteries were stained with H&E, and immuno-fluorescence was performed against CD68, MMP7, and S100A8.
  
  
  RESULTS
  Both CD68(+) macrophages representing the entire macrophage population and MMP7(+)S100A8(+)CD68(+) M4 macrophages could be reproducibly identified within all arterial layers. The average proportion of the M4 macrophage phenotype amongst all CD68(+) macrophages was 31.7 ± 16.2%. The highest number of M4 macrophages was found in the adventitia, followed by the intima. CD68(+) and M4 macrophage numbers were significantly higher in patients with severe CAD. The presence of M4 macrophages within the intima and the media was significantly associated with plaque instability as determined by Stary class. Multivariate analysis showed a highly significant contribution of cardiovascular risk factors (P = 0.008) to plaque instability, while only trends were observed for age (P = 0.060) and intimal prevalence of M4 macrophages (P = 0.098).
  
  
  CONCLUSIONS
  We demonstrate for the first time that M4 macrophages can be reproducibly found in coronary artery plaques. The prevalence of M4 macrophages is associated with indexes of plaque instability, most likely representing a surrogate marker of inflammatory activity. These findings suggest a pathogenetic role of M4 macrophages in vulnerable atherosclerotic plaques.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Erbel
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Linden
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Domschke
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Mohammadreza
authors.initials: M
authors.lastname: Akhavanpoor
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Germany.
authors.forename: Andreas O
authors.initials: AO
authors.lastname: Doesch
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Germany. Electronic address: christian.gleissner@med.uni-heidelberg.de.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Gleissner
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology*; D003331:Coronary Vessels / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology*; D010978:Platelet Factor 4 / Q000378:metabolism*; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D010978:Platelet Factor 4
keywords: Atherosclerosis; Coronary artery disease; Macrophage; Unstable plaque