title: Natural progression of atherosclerosis from pathologic intimal thickening to late fibroatheroma in human coronary arteries: A pathology study.
abstract: OBJECTIVE
  Smooth muscle cells, macrophage infiltration and accumulation of lipids, proteoglycans, collagen matrix and calcification play a central role in atherosclerosis. The early histologic changes of plaque progression from pathologic intimal thickenings (PIT) to late fibroatheroma lesions have not been fully characterized.
  
  
  METHODS
  A total of 151 atherosclerotic coronary lesions were collected from 67 sudden death victims. Atherosclerotic plaques were classified as PIT without macrophage infiltration, PIT with macrophages, and early and late fibroatheromas. Presence of macrophages and proteoglycans (versican, decorin and biglycan) were recognized by specific antibodies while hyaluronan was detected by affinity histochemistry. Lipid deposition was identified by oil-red-O, and calcification was assessed following von Kossa and alizarin red staining.
  
  
  RESULTS
  Lesion progression from PIT to late fibroatheroma was associated with increase in macrophage accumulation (p < 0.001) and decreasing apoptotic body clearance by macrophages (ratio of engulfed-to-total apoptotic bodies) (p < 0.001). Lipid deposition in lipid pool of PIT had a microvesicular appearance whereas those in the necrotic core were globular in nature. Overall, the accumulation of hyaluronan (p < 0.001), and proteoglycan versican (p < 0.001) and biglycan (p = 0.013) declined along with lesion progression from PIT to fibroatheromas. Microcalcification was first observed only within areas of lipid pools and its presence and size increased in lesions with necrotic core.
  
  
  CONCLUSIONS
  PIT to fibroatheroma lesions are accompanied by early lipid accumulation, followed by macrophage infiltration with defective clearance of apoptotic bodies along with decrease in proteoglycan and hyaluronan in lipid pools that convert to necrotic cores. Calcification starts in PIT and increases with plaque progression.
authors.affiliation: CVPath Institute, Inc., Gaithersburg, MD, USA.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Otsuka
authors.affiliation: Academic Medical Centre, University of Amsterdam, The Netherlands.
authors.forename: Miranda C A
authors.initials: MC
authors.lastname: Kramer
authors.affiliation: Academic Medical Centre, University of Amsterdam, The Netherlands.
authors.forename: Pier
authors.initials: P
authors.lastname: Woudstra
authors.affiliation: CVPath Institute, Inc., Gaithersburg, MD, USA.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yahagi
authors.affiliation: CVPath Institute, Inc., Gaithersburg, MD, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ladich
authors.affiliation: Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Aloke V
authors.initials: AV
authors.lastname: Finn
authors.affiliation: Academic Medical Centre, University of Amsterdam, The Netherlands.
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: de Winter
authors.affiliation: CVPath Institute, Inc., Gaithersburg, MD, USA.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Kolodgie
authors.affiliation: The Matrix Biology Program, Benaroya Research Institute, Seattle, WA, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.affiliation: CVPath Institute, Inc., Gaithersburg, MD, USA.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Davis
authors.affiliation: CVPath Institute, Inc., Gaithersburg, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Joner
authors.affiliation: CVPath Institute, Inc., Gaithersburg, MD, USA. Electronic address: rvirmani@cvpath.org.
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
mesh_terms: D000328:Adult; D017209:Apoptosis; D050197:Atherosclerosis / Q000473:pathology; D002114:Calcinosis; D003324:Coronary Artery Disease / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology*; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000473:pathology*; D015995:Prevalence; D011509:Proteoglycans / Q000378:metabolism; D012189:Retrospective Studies; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D008055:Lipids; D011509:Proteoglycans
keywords: Apoptosis; Atherosclerosis; Calcification; Extracellular matrix; Macrophage; Pathology; Proteoglycans