title: Carotid plaque vulnerability: a positive feedback between hemodynamic and biochemical mechanisms.
abstract: OBJECTIVE
  Rupture of atherosclerotic plaques is one of the main causes of ischemic strokes. The aim of this study was to investigate carotid plaque vulnerability markers in relation to blood flow direction and the mechanisms leading to plaque rupture at the upstream side of carotid stenoses.
  
  
  METHODS
  Frequency and location of rupture, endothelial erosion, neovascularization, and hemorrhage were determined in longitudinal sections of 80 human carotid specimens. Plaques were immunohistochemically analyzed for markers of vulnerability. Plaque geometry was measured to reconstruct shape profiles of ruptured versus stable plaques and to perform computational fluid dynamics analyses.
  
  
  RESULTS
  In 86% of ruptured plaques, rupture was observed upstream. In this region, neovascularization and hemorrhage were increased, along with increased immunoreactivity of vascular endothelial and connective tissue growth factor, whereas endothelial erosion was more frequent downstream. Proteolytic enzymes, mast cell chymase and cathepsin L, and the proapoptotic protein Bax showed significantly higher expression upstream as compared with the downstream shoulder of atherosclerotic lesions. Comparison of geometric profiles for ruptured and stable plaques showed increased longitudinal asymmetry of fibrous cap and lipid core thickness in ruptured plaques. The specific geometry of plaques ruptured upstream induced increased levels of shear stress and increased pressure drop between the upstream and the downstream plaque shoulders.
  
  
  CONCLUSIONS
  Vulnerability of the upstream plaque region is associated with enhanced neovascularization, hemorrhage, and cap thinning induced by proteolytic and proapoptotic mechanisms. These processes are reflected in structural plaque characteristics, analyses of which could improve the efficacy of vascular diagnostics and prevention.
authors: Laboratory of Molecular Cardiology, Department of Cardiology and Angiology, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany. Iwona_Cicha@yahoo.com
authors: Iwona
authors: I
authors: Cicha
authors: Anja
authors: A
authors: Wörner
authors: Katharina
authors: K
authors: Urschel
authors: Kamen
authors: K
authors: Beronov
authors: Margarete
authors: M
authors: Goppelt-Struebe
authors: Eric
authors: E
authors: Verhoeven
authors: Werner G
authors: WG
authors: Daniel
authors: Christoph D
authors: CD
authors: Garlichs
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology*; D002340:Carotid Artery Diseases / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology; D058226:Plaque, Atherosclerotic / Q000473:pathology / Q000503:physiopathology*; D012422:Rupture, Spontaneous / Q000473:pathology / Q000503:physiopathology; D013314:Stress, Mechanical