Augmented Expression and Activity of Extracellular Matrix-Degrading Enzymes in Regions of Low Endothelial Shear Stress Colocalize With Coronary Atheromata With Thin Fibrous Caps in Pigs

Abstract

Background The molecular mechanisms that determine the localized formation of thin-capped atheromata in the coronary arteries remain unknown. This study tested the hypothesis that low endothelial shear stress augments the expression of matrix-degrading proteases and thereby promotes the formation of thin-capped atheromata. Methods and Results Intravascular ultrasound–based, geometrically correct 3-dimensional reconstruction of the coronary arteries of 12 swine was performed in vivo 23 weeks after initiation of diabetes mellitus and a hyperlipidemic diet. Local endothelial shear stress was calculated in plaque-free subsegments of interest (n=142) with computational fluid dynamics. At week 30, the coronary arteries (n=31) were harvested and the same subsegments were identified. The messenger RNA and protein expression and elastolytic activity of selected elastases and their endogenous inhibitors were assessed. Subsegments with low preceding endothelial shear stress at week 23 showed reduced endothelial coverage, enhanced lipid accumulation, and intense infiltration of activated inflammatory cells at week 30. These lesions showed increased expression of messenger RNAs encoding matrix metalloproteinase-2, -9, and -12, and cathepsins K and S relative to their endogenous inhibitors and increased elastolytic activity. Expression of these enzymes correlated positively with the severity of internal elastic lamina fragmentation. Thin-capped atheromata developed in regions with lower preceding endothelial shear stress and had reduced endothelial coverage, intense lipid and inflammatory cell accumulation, enhanced messenger RNA expression and elastolytic activity of MMPs and cathepsins, and severe internal elastic lamina fragmentation. Conclusions Low endothelial shear stress induces endothelial discontinuity and accumulation of activated inflammatory cells, thereby augmenting the expression and activity of elastases in the intima and shifting the balance with their inhibitors toward matrix breakdown. Our results provide new insight into the mechanisms of regional formation of plaques with thin fibrous caps.

Endothelial fluid shear stress sensing in vascular health and disease

“…Thus, it is unknown to what extent high blood pressure contributes to the vulnerable phenotype in the upstream low-flow region compared to the downstream, oscillatory, low-pressure regions. In other models, both low shear and transverse shear were strongly correlated with regions of vulnerability within plaques (77)(78)(79). Plaque rupture itself also depends on wall strain.…”

In Vivo Assessment of the Risk Profile of Evolving Individual Coronary Plaques

“…6 -8 Areas of moderate or physiological shear stress are generally vasculoprotective, with increased expression of atheroprotective molecules, such as nitric oxide and decreased expression of degrading enzymes. 8,9 Areas of high ESS may be associated with atrophy of smooth muscle cells, increased macrophages, matrix degradation, increased thrombogenicity, and high mechanical strain. 10 -14 Pilot serial studies of the anatomic natural history of coronary disease in humans using small numbers of patients have confirmed that areas of low ESS are indeed associated with an increase in plaque size over time and associated expansive or constrictive remodeling responses.…”

Flow patterns in externally stented saphenous vein grafts and development of intimal hyperplasia

“…To characterize the different flow patterns, several hemodynamic parameters have been developed and investigated. These parameters have been shown to strongly correlate with the development of vascular pathology, mainly in the arterial system (17)(18).…”

“…Several studies applied various methodologies in an effort to set a pathological threshold value for TAWSS (17)(18)30 Compared to non-stented SVGs, the failure rate of stented SVGs was significantly lower than in the left territory but significantly higher in the right territory. As previously described (15), the high failure rate in the right territory was observed when either metallic clips, rather than sutures, were used to ligate side branches (62% versus 20% respectively) or when the stent was fixated to the proximal and/or distal anastomoses although contra-indicated by the protocol (75% versus 33.3% respectively).…”