Abstract 19592: Coronary Thin-Capped Atheromata Exhibit Increased Expression of Interstitial Collagenases in Regions of Persistently Low Endothelial Shear Stress: A Serial, in vivo Natural History Study in Pigs.
Background: The mechanisms underlying the focal formation of coronary thin cap atheromata (TCA) remain elusive. Endothelial shear stress (ESS) critically influences individual plaque progression. Interstitial collagen, the major structural component of the plaque's fibrous cap, contributes to the stability of the atheroma. We hypothesized that low ESS augments collagenase expression in vivo, favoring focal collagen degradation and promoting TCA formation.
Methods — Results: Five diabetic, hyperlipidemic pigs underwent serial, intravascular ultrasound-based 3D reconstruction of their coronary arteries (n=15) in vivo at weeks 4, 11, 16, 23 and 36. ESS was calculated at all time points using computational fluid dynamics. Coronary arteries were harvested at week 36, and 64 segments 3mm in length were identified and analyzed histopathologically. We assessed fibrillar collagen content by picrosirius red staining, and the expression of interstitial collagenases [matrix-metalloproteinase (MMP) -1, -8, -13] immunohistochemically and by RT-PCR. Collagenase activity was evaluated by in situ zymography. The analyzed segments exhibited substantial changes of local ESS over time, and marked histopathologic heterogeneity at week 36. TCA, defined as atheromata with cap thickness <65μm (n=26 of 64 segments; 41%) developed in segments that had experienced lower ESS at all time points compared to all other lesions (n=38 of 64 segments; 59%) (p<0.05; Fig A). TCA contained less intimal collagen (29% vs. 61%, p<0.01), and showed increased mRNAs encoding MMP-1 and -13 (p<0.05), and MMP-1, -8 and -13 protein (p<0.05) vs. all other lesions. The enzymatic activity of MMPs localized at sites with pronounced cap thinning (Fig B).
Conclusions: Coronary regions exposed to persistently low ESS exhibit augmented expression of interstitial collagenases, which may contribute to collagen depletion and the formation of rupture-prone plaques.
- © 2010 by American Heart Association, Inc.