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

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 (<1.2 Pa) vs. higher local ESS (≥1.2 Pa). Arteries were harvested at 9 months, and a subset of segments (n=114) underwent histopathologic analyses. © 2013 Elsevier Ireland Ltd. All rights reserved. Address for Correspondence: Peter H. Stone, M.D., Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, Tel: 857 307 1963, Fax: 857 307 1955, pstone@partners.org. *The first two authors contributed equally to this work All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation Conflicts of Interest: None The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [41]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Int J Cardiol. Author manuscript; available in PMC 2014 November 30. Published in final edited form as: Int J Cardiol. 2013 November 30; 169(6): 394–401. doi:10.1016/j.ijcard. 2013.10. 021. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript 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 timeaveraged 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 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 favouring rapid atheroma progression and high-risk composition.