title: Thin-capped atheromata with reduced collagen content in pigs develop in coronary arterial regions exposed to persistently low endothelial shear stress.
abstract: OBJECTIVE
  The mechanisms promoting the focal formation of rupture-prone coronary plaques in vivo remain incompletely understood. This study tested the hypothesis that coronary regions exposed to low endothelial shear stress (ESS) favor subsequent development of collagen-poor, thin-capped plaques.
  
  
  RESULTS
  Coronary angiography and 3-vessel intravascular ultrasound were serially performed at 5 consecutive time points in vivo in 5 diabetic, hypercholesterolemic pigs. ESS was calculated along the course of each artery with computational fluid dynamics at all 5 time points. At follow-up, 184 arterial segments with previously identified in vivo ESS underwent histopathologic analysis. Compared with other plaque types, eccentric thin-capped atheromata developed more in segments that experienced lower ESS during their evolution. Compared with lesions with higher preceding ESS, segments persistently exposed to low ESS (<1.2 Pa) exhibited reduced intimal smooth muscle cell content; marked intimal smooth muscle cell phenotypic modulation; attenuated procollagen-I gene expression; increased gene and protein expression of the interstitial collagenases matrix-metalloproteinase-1, -8, -13, and -14; increased collagenolytic activity; reduced collagen content; and marked thinning of the fibrous cap.
  
  
  CONCLUSIONS
  Eccentric thin-capped atheromata, lesions particularly prone to rupture, form more frequently in coronary regions exposed to low ESS throughout their evolution. By promoting an imbalance of attenuated synthesis and augmented collagen breakdown, low ESS favors the focal evolution of early lesions toward plaques with reduced collagen content and thin fibrous caps-2 critical determinants of coronary plaque vulnerability.
authors: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Konstantinos C
authors: KC
authors: Koskinas
authors: Galina K
authors: GK
authors: Sukhova
authors: Aaron B
authors: AB
authors: Baker
authors: Michail I
authors: MI
authors: Papafaklis
authors: Yiannis S
authors: YS
authors: Chatzizisis
authors: Ahmet U
authors: AU
authors: Coskun
authors: Thibaut
authors: T
authors: Quillard
authors: Michael
authors: M
authors: Jonas
authors: Charles
authors: C
authors: Maynard
authors: Antonios P
authors: AP
authors: Antoniadis
authors: Guo-Ping
authors: GP
authors: Shi
authors: Peter
authors: P
authors: Libby
authors: Elazer R
authors: ER
authors: Edelman
authors: Charles L
authors: CL
authors: Feldman
authors: Peter H
authors: PH
authors: Stone
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006937:Hypercholesterolemia / Q000150:complications; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011347:Procollagen / Q000235:genetics / Q000378:metabolism*; D012422:Rupture, Spontaneous; D013314:Stress, Mechanical; D013552:Swine; D013997:Time Factors; D018084:Ultrasonography, Interventional
chemical_list: D024042:Collagen Type I; D011347:Procollagen; D020782:Matrix Metalloproteinases
keywords: atherosclerosis; collagen; endothelial shear stress; metalloproteinases; natural history
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