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 3 mm-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. 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: 0.24 Pa/100 mg/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.