Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model

Carter, Andrew J.; Laird, John R.; Farb, Andrew; Kufs, William M.; Wortham, Dale C.; Virmani, Renu

doi:10.1016/0735-1097(94)90126-0

Cited by 212 publications

(97 citation statements)

References 24 publications

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“…The degree of arterial injury induced at the time of angioplasty is a major predictor of the neointimal response. 41,42 Our experimental model of coronary angioplasty causes deep arterial injury and medial tears with exposure of the external elastic lamina. As shown in the Table, the degree of injury did not differ between coronary arteries taken from the two groups.…”

Section: -11mentioning

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: -11mentioning

confidence: 99%

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

et al. 1998

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“…3,4 Thrombus deposition and acute inflammation are followed by a granulation tissue response with neovascularization, SMC migration and proliferation, and the replacement of acute by chronic inflammatory cells. 5 ECM molecules are synthesized by neointimal SMCs. Experimental arterial injury studies demonstrate that the neointima remodels over time with changes in proteoglycans and replacement of type III collagen with type I collagen.…”

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confidence: 99%

Extracellular Matrix Changes in Stented Human Coronary Arteries

et al. 2004

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Background-Restenosis after stenting occurs secondary to the accumulation of smooth muscle cells (SMCs) and extracellular matrix (ECM), with the ECM accounting for Ͼ50% of the neointimal volume. The composition of the in-stent ECM has not been well characterized in humans. Methods and Results-Postmortem human coronary arteries (nϭ45) containing stents underwent histological assessment of neointimal proteoglycans, hyaluronan, collagen (types I and III), SMCs, and CD44 (a cell surface receptor for hyaluronan). The mean duration of stent implantation was 18.7 months; stents in place Ն3 to Ͻ9 months (nϭ17) were assigned to group 1, stents Ն9 to Ͻ18 months old (nϭ19) to group 2, and stents Ն18 months old (nϭ9) to group 3. In groups 1 and 2, neointimal versican and hyaluronan staining was strongly positive, colocalized with ␣-actin-positive SMCs, and was greater in intensity compared with group 3. Conversely, decorin staining was greatest in group 3. The neointima of both group 1 and 2 stents was rich in type III collagen, with reduced staining in group 3. Type I collagen staining was weakest in group 1 stents, with progressively stronger staining in groups 2 and 3. SMC density and stent stenosis were significantly reduced in group 3 stents compared with groups 1 and 2. CD44 staining colocalized with macrophages and was associated with increased neointimal thickness. Conclusions-The ECM within human coronary stents resembles a wound that is not fully healed until 18 months after deployment, followed by neointimal retraction. ECM contraction may be a target for therapies aimed at stent restenosis prevention.

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“…Many animal experiments showed that denudation or overstretch injuries led to neointimal hyperplasia (4,9,(35)(36)(37)(38). At the cellular level, SMC proliferation is an important factor for neointimal hyperplasia.…”

Section: Neointimal Hyperplasia Stimulated By Mechanical Injurymentioning

confidence: 99%

“…However, restenosis is a problem often encountered and is mainly due to neointimal hyperplasia and vascular remodeling (2)(3)(4)(5)(6)(7)(8)(9)(10). Stent insertion decreases the restenosis rate, probably by physically blocking negative vascular remodeling, but it cannot prevent neointimal hyperplasia that resulted from smooth muscle cell (SMC) proliferation (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

The effect of external electron beam on neointima in rat carotid artery injury model

Kim

Chun

et al. 1999

International Journal of Radiation Oncology*Biology*Physics

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Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model

Cited by 212 publications

References 24 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

Extracellular Matrix Changes in Stented Human Coronary Arteries

The effect of external electron beam on neointima in rat carotid artery injury model

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