title: Synergistic effect of local endothelial shear stress and systemic hypercholesterolemia on coronary atherosclerotic plaque progression and composition in pigs.
abstract: BACKGROUND
  Systemic risk factors and local hemodynamic factors both contribute to coronary atherosclerosis, but their possibly synergistic inter-relationship remains unknown. The purpose of this natural history study was to investigate the combined in-vivo effect of varying levels of systemic hypercholesterolemia and local endothelial shear stress (ESS) on subsequent plaque progression and histological composition.
  
  
  METHODS
  Diabetic, hyperlipidemic swine with higher systemic total cholesterol (TC) (n=4) and relatively lower TC levels (n=5) underwent three-vessel intravascular ultrasound (IVUS) at 3-5 consecutive time-points in-vivo. ESS was calculated serially using computational fluid dynamics. 3-D reconstructed coronary arteries were divided into 3mm-long segments (n=595), which were stratified according to higher vs. relatively lower TC and low (<1.2Pa) vs. higher local ESS (≥1.2Pa). Arteries were harvested at 9months, and a subset of segments (n=114) underwent histopathologic analyses.
  
  
  RESULTS
  Change of plaque volume (ΔPV) by IVUS over time was most pronounced in low-ESS segments from higher-TC animals. Notably, higher-ESS segments from higher-TC animals had greater ΔPV compared to low-ESS segments from lower-TC animals (p<0.001). The time-averaged ESS in segments that resulted in significant plaque increased with increasing TC levels (slope: 0.24Pa/100mg/dl; r=0.80; p<0.01). At follow-up, low-ESS segments from higher-TC animals had the highest mRNA levels of lipoprotein receptors and inflammatory mediators and, consequently, the greatest lipid accumulation and inflammation.
  
  
  CONCLUSIONS
  This study redefines the principle concept that "low" ESS promotes coronary plaque growth and vulnerability by demonstrating that: (i.) the pro-atherogenic threshold of low ESS is not uniform, but cholesterol-dependent; and (ii.) the atherogenic effects of local low ESS are amplified, and the athero-protective effects of higher ESS may be outweighed, by increasing cholesterol levels. Intense hypercholesterolemia and very low ESS are synergistic in favoring rapid atheroma progression and high-risk composition.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Harvard-MIT Division of Health Sciences & Technology, Massachusetts Institute of Technology, Cambridge, MA, United States.
authors.forename: Konstantinos C
authors.initials: KC
authors.lastname: Koskinas
authors.forename: Yiannis S
authors.initials: YS
authors.lastname: Chatzizisis
authors.forename: Michail I
authors.initials: MI
authors.lastname: Papafaklis
authors.forename: Ahmet U
authors.initials: AU
authors.lastname: Coskun
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Baker
authors.forename: Petr
authors.initials: P
authors.lastname: Jarolim
authors.forename: Antonios
authors.initials: A
authors.lastname: Antoniadis
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
authors.forename: Peter H
authors.initials: PH
authors.lastname: Stone
authors.forename: Charles L
authors.initials: CL
authors.lastname: Feldman
mesh_terms: D000818:Animals; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000473:pathology* / Q000503:physiopathology; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000473:pathology* / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D058226:Plaque, Atherosclerotic / Q000473:pathology* / Q000503:physiopathology; D033081:Shear Strength / Q000502:physiology; D013552:Swine
keywords: Coronary atherosclerosis; Endothelial shear stress; Histology; Hypercholesterolemia; Intravascular ultrasound