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: Konstantinos C Koskinas, Yiannis S Chatzizisis, Michail I Papafaklis, Ahmet U Coskun, Aaron B Baker, Petr Jarolim, Antonios Antoniadis, Elazer R Edelman, Peter H Stone, Charles L Feldman
• Journal: International journal of cardiology (Int J Cardiol) Vol. 169 Issue 6 Pg. 394-401 (Nov 30 2013) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 24148915 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Topics

• Animals
• Cohort Studies
• Coronary Artery Disease (pathology, physiopathology)
• Disease Progression
• Endothelium, Vascular (pathology, physiopathology)
• Hypercholesterolemia (pathology, physiopathology)
• Male
• Plaque, Atherosclerotic (pathology, physiopathology)
• Shear Strength (physiology)
• Swine