Abstract 3565: Nox4 Overexpression is Associated with Thin Fibrous Cap in a Swine Model of Carotid Atherosclerosis

Purpose: The NADPH oxidases (Nox) are a family of reactive oxygen species generating enzymes, which play an important role in the pathophysiology of atherosclerosis. The relationship of Nox expression with carotid plaque vulnerability has not well been described. Vulnerable plaque with thin fibrous cap may be associated with the feature of distal emboli in a swine model of carotid atherosclerosis. The purpose of this study is to assess the association of Nox4 expression in vulnerable carotid plaque with thin fibrous cap in a swine model. Materials and Methods: Carotid atherosclerosis was induced in miniswines using the combination of partial ligation and high cholesterol diet, and a minimum 70% stenosis was confirmed by Doppler ultrasonography immediately post-ligation. Carotid artery sections were obtained for histopathological examination and immunohistochemical study for Nox4 at three months. Distal embolism was determined by the presence of atheroemboli in the ipsilateral rete mirabile. The atherosclerotic lesions of AHA stage type IV to VI were defined as vulnerable plaques. The association of distal embolism in the rete mirabile with vulnerable carotid plaque was analyzed. The association of Nox4 expression in the plaque with the morphological features of plaque vulnerability was analyzed. Results: One hundred ninety-one carotid segments from ten carotid artery models were assessed. One hundred two segments had vulnerable plaque. Vulnerable atherosclerotic plaques were found more frequently in the vessel wall proximal to the partial ligation than distal. Distal embolism was found in all 10 rete mirabilis, and deemed to be from the ipsilateral vulnerable carotid plaques. Areas positive for Nox4 tended to be greater in the plaques with the vulnerability features, including necrosis core, marked foam cells, plaque rupture, intraplaque hemorrhage and surface thrombus. The positive expression of Nox4 was associated with the feature of a large lipid core (p=0.035). Forty-eight segments were considered as thin fibrous cap plaques with the minimal thickness of fibrous cap less than 200 μ m. Areas positive for Nox4 were significantly greater in the plaque with thin fibrous cap than in the plaque with thick fibrous cap (p=0.005). On multivariate analysis, positive expression of Nox4 was an independent predictor of thin fibrous cap. Conclusion: Vulnerable carotid plaques with distal embolism were created in a swine model of carotid atherosclerosis. Increased expression of Nox 4 is associated with the feature of thin fibrous cap in vulnerable carotid plaques and may be used as a target for reducing the risk of distal embolism.