Studying restenosis

Traditionally, animal models are the cornerstone to test strategies aimed at developing treatments for pathologic conditions and for understanding pathophysiologic mechanisms that may cause that particular condition. In this respect, restenosis is no exception and several animal models have been developed during the past decade in an attempt to reproduce restenotic lesions and find a therapeutical strategy to reduce neointimal formation. Unfortunately, although several models of restenosis have been evaluated in the past 15 years, there is no perfect animal model for human restenosis. Common models include the rat carotid air desiccation or balloon endothelial denudation model,30,31 the rabbit femoral or iliac artery balloon injury model with or without cholesterol supplementation,32 and the porcine carotid and coronary artery model.33

The rat model, based on elastic arteries, does not develop severe stenotic neointimal lesions, and is therefore very permissive in terms of efficacy of pharmacological interventions. The cholesterol-fed rabbit model has been criticized for the high level of hyperlipidemia required for the development of lesions. The latter results in a large macrophage foam cell component, resembling fatty streaks rather than human restenotic lesions. Conversely, the histopatho-logic features of neointima obtained in porcine models closely resemble the human neointima, and the amount of neointimal thickening is proportional to injury severity. This has allowed the creation of an injury-neointima relationship that can be used to evaluate the response to different therapies. However, the repair process in the pig coronary artery injury model using normal coronary arteries is certainly more rapid and may be different from the response to balloon angioplasty that characterizes human coronary atherosclerotic plaques.

The major limitation in the use of animal models of restenosis is that agents effective in reducing neointima in those models are ineffective when transferred into the clinical arena. Many explanations might support those differences. Different animal species, types of artery, degree of arterial injury, volume of neointima, drug dosages and timing regimens, and atherosclerotic substrate might be considered.

To address this concern, we believe that before transferring the results obtained in animal models into clinical trials, standardization of injury type, the method of measurement, and the dose and timing of drug administration among different animal models is necessary.

Other issues in the study of restenosis are the limitations in the design of restenosis clinical trials. Incomplete angio-graphic follow up leading to the occurrence of selection and withdrawal biases, followed by inadequate power due to small patient sample leading to the potential of (3 (type II) errors, are the most common problems. Non-uniform definitions of angiographic restenosis and poor correlation between angiographic and clinical outcome are other problems that need to be resolved when comparing different trial results. Future restenosis studies should utilize composite clinical outcomes as primary end points, with multiple, simultaneous treatment approaches and careful choice of the appropriate regimen. These studies should also include an angiographic or IVUS subset to allow assessment of mechanisms of action, and using these data can help limit sample size necessary to detect efficacy at reducing neointima.

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