A dilemma for the 1990s. Choosing appropriate experimental animal model for the prevention of restenosis.

Ferrell, Margaret; Fuster, Valentı́n; Gold, H.K.; Chesebro, James H.

doi:10.1161/01.cir.85.4.1630

Cited by 86 publications

(38 citation statements)

References 9 publications

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“…The porcine model shares similar cardiovascular anatomy and physiology and therefore may provide results more predictive of responses in humans. [36][37][38][39][40] On this basis, the animal model selected for the present study was balloon angioplasty of the pig coronary arteries.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Thrombin Inhibition Reduces Restenosis After Balloon Angioplasty in Porcine Coronary Arteries

et al. 1998

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Background-Arterial injury after percutaneous transluminal coronary angioplasty (PTCA) triggers acute thrombus formation and thrombin generation. Hirudin, a potent and direct thrombin inhibitor, prevents thrombus formation after arterial injury. Two large clinical trials showed marked reduction in acute clinical events but no long-term benefits in reducing restenosis during short-term administration of thrombin inhibitors. Our hypothesis is that adequate, maintained thrombin inhibition, by inhibiting all the thrombin-dependent mechanisms, will reduce neointima formation after PTCA. Methods and Results-Thirty-six pigs received three different regimens of hirudin: bolus (1 mg/kg), short-term (bolusϩ0.7 mg/kg per day for 2 days), and long-term (bolusϩ0.7 mg/kg per day for 14 days). The results on neointima formation at 4 weeks after coronary angioplasty were compared with the control group (100 IU heparin/kg bolus). Hirudin was continuously administered for 2 weeks through an infusion pump. In vivo thrombin generation was persistently increased up to 2 weeks after angioplasty. Inhibition of thrombin activity for 14 days reduced luminal narrowing by 40% (58Ϯ3% versus 35Ϯ3%; PϽ.001). No differences were observed among the bolus and short-term hirudin groups and the control group. Conclusions-Our results indicate that there is a continued, marked thrombin generation that lasts for at least 2 weeks after PTCA. Administration of r-hirudin for 2 weeks significantly reduces neointima formation after PTCA. This observation, if extrapolated to humans, could explain the lack of effect on restenosis observed in the clinical trials with antithrombin agents despite the clear benefits on reducing acute thrombotic complications after PTCA. Therefore an adequate and prolonged administration of thrombin inhibitors is needed to "passivate" the thrombogenic substrate (disrupted arterial wall) and achieve full benefit of this therapeutic approach. (Circulation. 1998;97:581-588.)

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Section: Discussionmentioning

confidence: 99%

Prolonged Thrombin Inhibition Reduces Restenosis After Balloon Angioplasty in Porcine Coronary Arteries

et al. 1998

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“…[1][2][3][4] Injury to the arterial wall triggers smooth muscle cell (SMC) proliferation, migration, and matrix secretion. 5,6 The resultant intimal hyperplasia is a common histological finding in restenosis after angioplasty, 7 vascular anastomotic strictures, 8 and other arterial occlusive diseases.…”

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confidence: 99%

Mouse Model of Femoral Artery Denudation Injury Associated With the Rapid Accumulation of Adhesion Molecules on the Luminal Surface and Recruitment of Neutrophils

Roqué

Fallon

Badimón

et al. 2000

ATVB

190

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Abstract-Techniques of arterial injury commonly used in animals to mimic endovascular procedures are not suitable for small mouse arteries. This has limited examination of the response to arterial injury in genetically modified mice. We therefore sought to develop a model of transluminal injury to the mouse femoral artery that would be reproducible and result in substantial levels of intimal hyperplasia. Mice of the C57BL/6 strain underwent bilateral femoral artery denudation by passage of an angioplasty guidewire. Intimal hyperplasia was observed in 10% of injured arteries at 1 week, in 88% at 2 weeks, and in 90% at 4 weeks. The mean intimal-to-medial area ratio reached 1.1Ϯ0.1 at 4 weeks. No intimal proliferation was found in control sham-operated arteries. One hour after injury, the denuded surface was covered with platelets and leukocytes, predominantly neutrophils. This was associated with the accumulation of P-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Expression of these adhesion molecules was not seen in the underlying medial smooth muscle cells. At 24 hours, few neutrophils remained on the denuded surface. At 1 week, macrophages and platelets were present in the vessel wall, partially covered by regenerated endothelium. Transluminal wire injury to the mouse femoral artery induces abundant intimal hyperplasia formation by 2 and 4 weeks and elicits the rapid accumulation of leukocytes and adhesion molecules on the denuded luminal surface. This model will be a valuable tool to study arterial injury in genetically modified mouse models.

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“…7,8 Conversely, various experimental models have demonstrated that the damage and removal of luminal endothelium results in arterial lesion formation with a severity proportional to the duration of endothelial denudation. 9,10 Furthermore, mechanical endothelial injury has been reported to be a key feature in coronary arteries of patients after percutaneous coronary intervention (PCI) and, together with other forms of endothelial damage, has been implicated in arterial lesion formation in patients. [11][12][13] To better understand the effects of endostatin on reendothelialization and neointima formation, we overexpressed the endostatin gene in a mouse model of arterial injury.…”

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confidence: 99%

Decreased Reendothelialization and Increased Neointima Formation With Endostatin Overexpression in a Mouse Model of Arterial Injury

et al. 2003

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Background-Impaired endothelial regeneration contributes to arterial lesion formation. Endostatin is a specific inhibitor of endothelial cell growth and induces endothelial cell apoptosis. We examined the effect of endostatin overexpression on reendothelialization and neointima formation in a mouse model of arterial injury. Methods and Results-Mice underwent femoral arterial denudation and received recombinant adenovirus, expressing either murine endostatin (nϭ19) or control adenoviral vector (nϭ12), by jugular vein injection. Endostatin gene transfer resulted in high serum levels of endostatin. Strong adenoviral gene expression of ␤-galactosidase-expressing control vector was detected in liver tissue and was absent in the injured arterial wall at 1 week. Deposits of endostatin protein were detected along the denuded arterial wall and were not seen in the noninjured contralateral artery at 1 week. Endostatin deposits were also absent in the injured artery of control vector-treated animals. Overexpression of endostatin led to decreased reendothelialization and increased apoptosis of luminal endothelial cells 2 and 4 weeks after arterial injury (PϽ0.05). In addition, endostatin overexpression resulted in increased neointima formation (PϽ0.05). Endothelial apoptosis and neointima area correlated positively with endostatin serum levels, whereas the degree of reendothelialization correlated negatively with endostatin serum levels (PϽ0.05). Furthermore, poor reendothelialization correlated with increased neointima formation (PϽ0.05). Conclusions-In summary, decreased reendothelialization and enhanced endothelial apoptosis, in response to endostatin overexpression, were associated with increased neointima formation. These findings demonstrate that high serum levels of endostatin are capable of inhibiting endothelial regeneration and promoting arterial lesion growth in conditions of endothelial injury.

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A dilemma for the 1990s. Choosing appropriate experimental animal model for the prevention of restenosis.

Cited by 86 publications

References 9 publications

Prolonged Thrombin Inhibition Reduces Restenosis After Balloon Angioplasty in Porcine Coronary Arteries

Prolonged Thrombin Inhibition Reduces Restenosis After Balloon Angioplasty in Porcine Coronary Arteries

Mouse Model of Femoral Artery Denudation Injury Associated With the Rapid Accumulation of Adhesion Molecules on the Luminal Surface and Recruitment of Neutrophils

Decreased Reendothelialization and Increased Neointima Formation With Endostatin Overexpression in a Mouse Model of Arterial Injury

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