Abstract 1945: Low Endothelial Shear Stress (ESS)-Mediated Elastolytic Activity Promotes the Formation of High Risk Atherosclerotic Plaques in the Coronary Arteries
Objectives: Low ESS promotes the formation of thin cap fibroatheromas (TCFAs) in the coronary arteries. The pathobiologic mechanisms through which low ESS leads to TCFA formation are not well known. We investigated the molecular mechanisms which are regulated by low ESS and promote the formation of TCFAs.
Methods: In 12 swine IVUS based geometrically correct 3D reconstruction of the coronary arteries was performed at week 23 after initiation of diabetes and high-fat diet. Local ESS was calculated in plaque-free subsegments using computational fluid dynamics. Coronary arteries (n=31) were harvested at week 30 and 142 atherosclerotic lesions were identified and classified histopathologically into minimal lesions (n=26), intermediate lesions (n=56) and TCFAs (n=60). Internal elastic lamina (IEL) fragmentation in each lesion was assessed at follow up. Gene and protein expression of elastolytic proteases (MMP-9, -12, cathepsins K, L, S and neutrophil elastase) and their inhibitors (TIMP-1, -2, cystatin C) was assessed in each lesion with real time PCR and in situ zymography.
Results: Seventy percent of TCFAs developed in subsegments with low baseline ESS (<1 Pa). The magnitude of low ESS at week 23 was significantly associated with the severity of lipid accumulation, inflammation and fibrous cap thinning at week 30 (p<0.01). Gene expression and protein activation of MMP-9, -12, cathepsins K, S and neutrophil elastase was significantly upregulated relative to their endogenous inhibitors in lesions exposed to low baseline ESS compared to lesions exposed to higher ESS (p<0.001). Gene expression and activity of these enzymes was positively correlated with the severity of inflammation, IEL fragmentation and formation of TCFAs vs. intermediate lesions (r>0.4, p<0.01). In the setting of low ESS, the balance of MMPs and cathepsins with their endogenous inhibitors was shifted towards a more elastolytic state in TCFAs (p<0.01).
Conclusions: Through enhancement of inflammation, low ESS upregulates gene and protein expression of elastolytic proteases in coronary atherosclerotic plaques shifting the plaque to a more proteolytic state and promoting the formation of a TCFA.