Application of in vivo and ex vivo magnetic resonance imaging for evaluation of tranilast on neointima formation following balloon angioplasty of therat carotid artery

Objective: Recent studies suggest that tranilast inhibits a variety of agen ts implicated in neointimal growth and restenosis in experimental animal mo dels and humans. We report here a study evaluating the efficacy of tranilas t in the rat carotid artery balloon angioplasty model, a model that mimics many aspects of the percutaneous transluminal angioplasty procedure in huma ns. Efficacy was determined based on in vivo and ex vivo magnetic resonance imaging (MRI) as well as by histomorphometry. The utility of this study, u sing a reverse paradigm, is to investigate if agents successful in the clin ic can demonstrate efficacy in this animal model primary screen as measured by MRI and histomorphometry. Methods: Tranilast (300 mg/kg/day, p.o.) was administered to Sprague-Dawley rats 3 days prior to balloon injury and cont inued for 14 days after injury. Three methods of measuring the vascular inj ury that occurs in this model were employed: (1)in vivo MRI, used to measur e in vivo lumen volumes for the carotid artery once at baseline (pre-surger y) and again at 14 days post angioplasty; (2) ex vivo MRI (and histomorphom etry), used to evaluate the total arterial wall thickness and the intima-to -media ratio; and (3) analysis of collagen density, used to evaluate the ef ficacy of tranilast to abrogate collagen synthesis and deposition following vascular injury. Results: Tranilast provided 33% protection (P<0.05) from angioplasty-induced lumen narrowing as measured by MRI in vivo. The results of the ex vivo MR analysis of total wall thickness showed a 14% protection of angioplasty-induced narrowing (P<0.05), and the mean intima-to-media ra tio showed a 39% (P<0.006) protection for the tranilast-treated rats. Histo logical analysis of the mean intima-to-media ratio demonstrated that tranil ast provided 36% (P<0.01) protection in the intima-to-media ratio. Further, treatment with tranilast showed a 52% reduction in collagen density of the intimal layer and a 70% reduction in collagen density of the medial layer of the injured arteries. Conclusion: The data obtained by in vivo MRI, ex v ivo MRI, histology and collagen analysis demonstrate that tranilast provide d significant beneficial effects in inhibiting neointimal formation in the rat carotid artery model. Also this study, to the best of our knowledge, is the first to harness complimentary information from various technologies, including lumen patency by in vivo MRI, neointimal formation by ex vivo MRI and conventional histomorphometry, and histological analysis for collagen density, to provide a comprehensive understanding of the pathology in this disease model. (C) 2000 Elsevier Science B.V. All rights reserved.