Abstract-Atherosclerotic plaque rupture is the main cause of coronary thrombosis and myocardial infarcts. Currently, there is no animal model of plaque disruption. We have developed a rabbit model in which an atherosclerotic plaque can be ruptured at will after an inflatable balloon becomes embedded into the plaque. Furthermore, the pressure needed to inflate the plaque-covered balloon may be an index of overall plaque mechanical strength. The thoracic aorta of hypercholesterolemic rabbits underwent mechanical removal of endothelial cells, and then a specially designed balloon catheter was introduced into the lumen of the thoracic aorta. As early as 1 month after catheter placement, atherosclerotic plaque formed around the indwelling balloon. The plaques were reminiscent of human atherosclerotic lesions, in terms of cellular composition, patterns of lipid accumulation, and growth characteristics. Intraplaque balloons were inflated both ex vivo and in vivo, leading to plaque fissuring. The ex vivo strategy is designed to measure the mechanical strength of the surrounding plaque, while the in vivo scenario permits an analysis of the plaque rupture consequences, eg, thrombosis. In addition, our model allows local delivery of various substances into the plaque. The model can be used to study the pathogenesis of plaque instability and to design plaque stabilization therapy. (Circ Res. 1998;83:705-713.)Key Words: atherosclerosis Ⅲ catheter Ⅲ plaque Ⅲ rupture Ⅲ thrombus T he abrupt closure of an artery by an occlusive thrombus is the main cause of myocardial infarcts and other thrombotic sequelae of atherosclerosis. This thrombosis is often associated with a fissure that develops in the underlying atherosclerotic plaque. [1][2][3][4][5][6] Therapy that prevents plaque rupture may significantly decrease the incidence of heart attack and stroke, while treatment that reduces blood clot formation associated with plaque disruption may reduce mortality after such catastrophic events. Currently, there is no specific therapy for plaque rupture.2 Research on the mechanisms of plaque destabilization and development of "stabilization therapy" have been hampered by lack of an appropriate animal model. 6 Our aim was to develop an animal model of atherosclerosis, in which the plaque could be ruptured at will under controlled conditions. Atherosclerotic plaque rupture occurs as a result of interactions between external mechanical triggers and vulnerable regions of the plaque, when forces acting on the plaque exceed its tensile strength. [7][8][9] The exact nature of these external forces is still unknown, thus making it difficult to design specific treatments to prevent plaque rupture. However, plaque tissue properties undoubtedly determine the mechanical strength/vulnerability of plaques and may be realistic targets for therapeutic intervention. Therefore, we focused on designing a model to evaluate plaque mechanical strength/vulnerability characteristics. The admittedly important problem of clinically relevant triggers of plaque di...

Abstract-Hypercholesterolemia may render atherosclerotic plaques prone to rupture. To test this hypothesis, catheters with matrix-covered balloons were implanted into the aorta of rabbits fed standard or 0.5% cholesterol chow (nϭ70). In 1 month, fibrous plaques developed around the balloon. Time-dependent accumulation of cholesteryl esters and free cholesterol was detected in the plaques of the cholesterol-fed group only. The pressure needed to rupture the plaque by balloon inflation was used as an index of plaque strength. Three months after the catheter implantation, the breaking pressure was 2.1 times lower (PϽ0.05) in cholesterol-fed rabbits. It was accompanied by collagen loss, as measured by plaque hydroxyproline content, but not with deficiency of collagen cross-linking. Sirius red staining showed preservation of collagen originally covering the balloon and accumulation of nascent collagen in the lesions of standard chow-fed rabbits. In the cholesterol-fed group, both mature and new collagen underwent degradation predominantly in the plaque shoulders. Collagen breakdown was associated with local accumulation of foamy macrophages. Gel zymography demonstrated relative enhancement of gelatinolytic activity at 92 and 72 kDa, as well as caseinolytic activity at 57, 45, and 19 kDa in the lipid-laden plaques. Lipid accumulation in the plaque was also associated with a loss of smooth muscle cells, the cellular source of the collagen fibers. The remaining smooth muscle cells showed increased collagen synthesis, although it was insufficient to counterbalance collagen degradation and cell loss. The following mechanism has been proposed 4 : hypercholesterolemia induces macrophage accumulation and activation in the atheroma; macrophages synthesize and secrete proteolytic enzymes, matrix metalloproteinases (MMPs); MMPs destroy collagen, thereby weakening the plaque. Although this mechanism looks very plausible, several key questions remain. First, the changes in plaque mechanical properties have long been assumed, although never directly demonstrated. Second, the most convincing evidence of the link between lipids and collagen was obtained in reverse sequence, when lipid lowering led to collagen accumulation in rabbit atheroma. 5 It still remains to be seen whether lipid accumulation induces collagen breakdown. Third, collagen content is a net result of its degradation and synthesis. The role of collagen synthesis in plaque destabilization has not yet been addressed. Fourth, tissue mechanical properties depend not only on collagen content, but also on its cross-linking and distribution. 6 These factors have not been studied in the context of plaque rupture.We have recently described an animal model of atherosclerosis in which a plaque, formed around an inflatable balloon (Figure 1), can be ruptured at will. 7 In the current study, rupturing pressure was used to measure plaque mechanical strength. We have tested the hypothesis that hypercholesterolemia induces local collagen loss and subsequent plaque mechanical destabi...

No abstract

No abstract

No abstract