Implications for Restenosis Models

Neointimal hyperplasia occurs in the coronary arteries after percutaneous revascularization procedures and is a reparative response that frequently causes recurrent stenosis. Prior animal studies have shown that neointimal tissue thickness is proportional to the depth of arterial injury. Because animal models are increasingly used to test therapeutic strategies against restenosis, the purpose of this study was to evaluate the degree of neointimal thickening formed in the coronary arteries of pigs compared with dogs in response to severe injury. Fourteen coronary arteries in six mongrel dogs and 18 coronary arteries in nine pigs underwent severe arterial injury using tantalum metal coils delivered on oversized angioplasty balloons. Animals were killed after 4 weeks, and all coronary arteries were pressure perfusion fixed. Mean histological injury scores and neointimal thicknesses for dogs were 1.9±0.3 and 0.30±0.11, respectively, compared with 2.1±0.7 and 0.71 ±0.36 for pigs. Thus, there was significantly less Coronary artery restenosis remains a major unsolved limitation for interventional cardiology. It results from arterial injury incurred during the revascularization of coronary atherosclerosis and is caused in large part by neointimal hyperplasia at the injury site. Little progress has been made against restenosis despite much investigative work in both patients and animal models. The relevance of animal models to restenosis in humans is unclear yet of paramount importance to clinical trials. Neointima develops in most animal models but to varying degrees and with variable histopathologic appearance. In the porcine coronary model, large amounts of neointima develop with histopathology identical to that in humans. The depth and extent of arterial injury appear to determine the thickness of neointimal response. In other models, less neointima may form in response to injury. If this suspicion is true, comparative study of animal models resulting in less neointima might be useful for understanding the mechanisms of neointimal growth and possibly for suggesting new therapeutic approaches to restenosis. Thus, the purpose of this study was to Received March 30, 1993; revision accepted December 7, 1993. From the Division of Cardiovascular Diseases and Internal Medicine (R.S.S., A.R.C., M.AJ., D.R.H.), the Division of Pathology (W.D.E.), and the Section of Biomedical Statistics (K.R.B.), Mayo Graduate School of Medicine, Mayo Clinic and Foundation, Rochester, Minn. Reprint requests to Robert S. Schwartz, MD, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905. neointimal thickening in dogs compared with pigs (P<.001) despite no differences in injury (P=NS). The neointimal thickening differences translated into significantly different percent area stenoses: 55 ±24% for pigs versus 27 ±13% for dogs (P<.001). Linear regression modeled neointimal thickness versus injury assessed by an ordinal injury score proportional to the depth of injury for each species. This analysis confirmed the differences across multiple injury levels. The slope of the regression line for dogs was small, suggesting that no relation may exist between injury and neointimal thickness in this species. The pig may be a more appropriate model for the study of the genesis of stenosing neointima. If the lack of response in dogs could be better understood, insight into more effective restenosis therapies might be possible. (Arterioscler Thromb. 1994;14J95-400.)