Preclinical Restenosis Models: Challenges and Successes

Abstract

Coronary artery disease remains a major problem for Western societies. The advent of percutaneous interventions, including stents has brought clinical care to a new level of efficacy, yet problems remain. Restenosis following stenting in human coronary arteries appears at last to be yielding to therapeutic strategies, especially drug eluting stents. Because therapeutic percutaneous coronary intervention is widely dominated by the intracoronary stent, restenosis therapies must include the stented coronary artery. Animal models and in particular the porcine coronary model seem to represent the human coronary artery reaction to stenting. It mimics several clinical conditions including thrombosis and neointimal formation. A key question in the era of intravascular technologies is how well this and other models can predict clinical events. This paper discusses the models and their application.Keywords. Neointima; restenosis; stent; vascular injury INTRODUCTION Research in human coronary atherosclerosis is limited by an inability to control experiments and by the slow temporal lesion development. Fortunately, animal arterial injury models appear to yield comparable results to clinical trials, and can teach about the arterial response to injury. These models have become indispensable for understanding the interaction of the coronary artery with medical devices, and toward understanding neointimal genesis. They can likely function to test safety and efficacy of new devices. In these models the pathophysiologic aspects of disease can be simulated, variables can be controlled, and statistical data accrued in short time periods.Many animal models have been used for restenosis studies. This variety comes because an ideal animal model does not exist. Each animal model has advantages and disadvantages. This chapter discusses the principal animal models described for restenosis studies, their characteristics, advantages and disadvantages compared with humans, and the considerations necessary for proximity to and ideal animal model and study design.

Inhibition of In-Stent Stenosis by Oral Administration of Bindarit in Porcine Coronary Arteries

“…Although the porcine coronary model seems to represent the human coronary artery response to stenting, mimicking several clinical conditions, including thrombosis and neointimal formation, 20 it does not precisely simulate human in-stent restenosis. 18,20 An important point in the present model is that stent implantation was performed in normal porcine coronary arteries, whereas in humans, much of the stent would be in contact with atheromatous plaque and not with media. Furthermore, in the present study the extent of in stent stenosis was examined only at 28 days after stent implantation; for example, longer follow-up should be performed to assess the effect of bindarit on arterial healing.…”

Preclinical Models of Restenosis and Their Application in the Evaluation of Drug-Eluting Stent Systems

“…These approximations tend to be prolonged for drug-eluting stent systems and vary according to system design and elution or bioabsorption profiles. 160,186,199 atherosclerotic plaque is a contributory factor in vessel injury, given that compression and/or strut penetration of the plaque has been documented in up to 90% of angioplasties, which can further the potential for subsequent inflammation and cellular proliferation. 44,45 Concurrent with the initiating injury and in the following hours to days, thrombus formation occurs where there is endothelial denudation, exposed subintimal components, and exposed surfaces of the device.…”

“…Atherosclerotic and diabetic models are on the forefront of development, becoming more desirable for evaluating DES performance, although their standardization is lacking. Despite the inherent lesion variability that occurs with these models, 140,186 it is of value to evaluate DESs in an environment in which the primary cause for the vascular intervention, the underlying atherosclerotic lesion, is present. Furthermore, DES systems may affect not only the development of ISR but they also may impact the formation or progression of the local atherosclerotic lesion and, thereby, long-term device efficacy.…”

“…75,79,133 The rates of vascular healing in rat carotid arterial and aortic models appear to parallel those of models utilizing larger species qualitatively; however, the vascular response in the rat has similar salient features as mice, including only sparse thrombus formation and fibrin deposition, minimal inflammation, and a lack of remodeling. 11,77,104,105,186 Murine models have promise for elucidating pathophysiologic mechanisms related to atherosclerosis and ISR; nonetheless, the cumulative shortcomings of these models warrant their careful application and critical interpretation. First, murine arteries suitable for the evaluation of ISR are mostly elastic, which are less prone to injury and have only modest neointimal responses following vascular injury when compared to muscular arteries.…”

“…30,57,192 Nonetheless, the paucity of studies in nonhuman primate models utilizing either balloon angioplasty or stent implantation and the relative inconsistencies among studies are further shortcomings. 64,186 Model Selection, Application, and Limitations Each preclinical model of ISR has a unique set of attributes, assumptions, and limitations. Given that there is no single model that serves as a blanket ideal for investigations into ISR and drugs or devices designed for its treatment, each model discussed herein is appropriate in its own right for application to answer targeted questions relative to ISR.…”