Synergistic effect of local endothelial shear stress and systemic hypercholesterolemia on coronary atherosclerotic plaque progression and composition in pigs

INTERNATIONAL JOURNAL OF CARDIOLOGY

卷:169

Article

Koskinas, Konstantinos C.^1,2  Chatzizisis, Yiannis S.^1,2  Papafaklis, Michail I.^1,2  Coskun, Ahmet U.³  Baker, Aaron B.²  Jarolim, Petr¹  Antoniadis, Antonios¹  Edelman, Elazer R.^1,2  Stone, Peter H.¹  Feldman, Charles L.¹ 

[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA

[2] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA

[3] Northeastern Univ, Boston, MA 02115 USA

关键词: Coronary atherosclerosis;    Endothelial shear stress;    Hypercholesterolemia;    Intravascular ultrasound;    Histology;   

DOI  :  10.1016/j.ijcard.2013.10.021

来源: Elsevier

【 摘 要 】

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 3 mm-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 9 months, and a subset of segments (n=114) underwent histopathologic analyses. Results: Change of plaque volume (Delta PV) 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 Delta PV 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: 0.24 Pa/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 cholesteroldependent; 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. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

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