Differential neointimal response to coronary artery injury in pigs and dogs. Implications for restenosis models.

Abstract

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 C oronary artery restenosis remains a major unsolved limitation for interventional cardiology. 13 It results from arterial injury incurred during the revascularization of coronary atherosclerosis 46 and is caused in large part by neointimal hyperplasia at the injury site. 79 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. 10 The depth and extent of arterial injury appear to determine the thickness of neointimal response.11 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. 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 r...

Selective ET A Receptor Antagonism Reduces Neointimal Hyperplasia in a Porcine Coronary Stent Model

“…This was performed as previously described. 20 Briefly, the three regressions were tested by use of the following equations. Note that the variables labeled Gp establish the treatment group.…”

“…The neointimal response was measured from the elastin-stained sections by calibrated digital microscopy as previously detailed. 20 Vessel injury at each stent wire site was scored with values 0 (endothelium denuded), 1 (internal elastic lamina lacerated), 2 (media lacerated), and 3 (external elastic lamina lacerated). The neointimal thickness was also measured at each wire site, and mean injury scores and neointimal responses were calculated for each stented coronary segment.…”

Growth Factors Stimulate Neointimal Cells In Vitro and Increase the Thickness of the Neointima Formed at the Neck of Porcine Aneurysms Treated by Embolization

“…3,22 This characteristic seems to be linked to exuberant thrombosis and thick neointimal formation in this animal, 2 phenomena also found after angioplasty. 31,32 In the present study we chose to aim at the complete obliteration of aneurysms to minimize asymmetries in residual blood flow between aneurysms. Angiography performed in the first 20 animals served to demonstrate that the surgical technique led to consistent results and that differences in neointimal thickness found at 2 weeks were not caused by asymmetries in blood flow.…”

“…The nature and origin of cells involved in neointima formation after vascular injury or in atherosclerosis remain a matter of debate. [31][32][33][34][35][36][37][38][39][40] Although circulating stem cells, 38,39 monocytes/ macrophages, 14,18,[35][36][37] and adventitial myofibroblasts 33,35 have been evoked as potential actors in neointima formation, migration and proliferation of vascular smooth muscle cells from the adjacent media is a commonly accepted mechanism. 8 -12 These cells are thought to undergo phenotypic modulation to switch from a quiescent contractile stage to a secretory phenotype, specialized in proliferation and extracellular matrix secretion.…”

Dose-Response Effects of 32 P Radioactive Stents in an Atherosclerotic Porcine Coronary Model

“…Others have demonstrated species differences in response to nonradioactive stent implantation that may be related to endothelial cell regeneration or the intrinsic fibrinolytic capacity of the animal. 15,16 Studies are currently under way to examine species differences in the response to stent-based irradiation that may have important implications for the selection of animal models used to evaluate radioactive stents.…”