Coronary Restenosis: Prospects for Solution and New Perspectives From a Porcine Model

Schwartz, Robert S.; Edwards, William D.; Huber, Kenneth C.; Antoniades, Loizos; Bailey, Kent R.; Camrud, Allan R.; Jorgenson, Michael A.; Holmes, David R.

doi:10.1016/s0025-6196(12)60019-6

Cited by 66 publications

(24 citation statements)

References 23 publications

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“…Sections from each segment were stained with Accustain (Sigma Diagnostics) and examined with a Leica Quantimet 600S digital analysis system. The areas bounded by the luminal surface (lumen area), by the internal elastic lamina (IEL area: at IEL fracture sites, fractured ends were linked by a line describing the boundary between neointima and media), and by the external elastic lamina (EEL area) were measured in the segment with minimum luminal area (MLA) from each vessel along with IEL fracture length and injury score 17 by a blinded operator. Neointimal and medial areas were calculated as IEL area minus lumen area and EEL area minus IEL area, respectively.…”

Section: Morphometric Analysismentioning

confidence: 99%

Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-β Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition

et al. 2001

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Background-Extracellular matrix (ECM) remodeling is central to the development of restenosis after coronary angioplasty (PTCA). As a regulator of ECM deposition by vascular cells, substantial evidence implicates transforming growth factor-␤1 (TGF-␤1) in the pathogenesis of restenosis. We investigated the effects of intracoronary expression of a transgenic antagonist of TGF-␤1 on luminal loss after PTCA. Methods and Results-Porcine coronary arteries were randomized to receive a recombinant adenovirus expressing a secreted form of TGF-␤ type II receptor (Ad5-RIIs), an adenovirus expressing ␤-galactosidase (Ad5-lacZ), or vehicle only by intramural injection at the site of PTCA. Computerized morphometry 28 days after angioplasty revealed a greater minimum luminal area in Ad5-RIIs-injected arteries (1.71Ϯ0.12 mm 2 ) than in the Ad5-lacZ (1.33Ϯ0.13 mm 2 ) or vehicle-only (1.08Ϯ0.17 mm 2 ; Pϭ0.010 by ANOVA) groups. This was accompanied by greater areas within the internal (Pϭ0.013) and external (Pϭ0.031) elastic laminae in Ad5-RIIs-treated vessels. Adventitial collagen content at the site of injury was increased in the Ad5-RIIs group, in contrast to decreases in the Ad5-lacZ and vehicle-only groups (Pϭ0.004). Conclusions-Adenovirus-mediated

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Section: Morphometric Analysismentioning

confidence: 99%

Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-β Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition

et al. 2001

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“…6,7 Local transfer of genes encoding antiproliferative proteins has been effective in animal models of neointima formation. 14 -16 In rat carotid and in rabbit and porcine iliac arteries, local adenovirus-mediated transfer of genes encoding herpes simplex virus thymidine kinase, [17][18][19] p21, 20 a constitutively active form of the retinoblastoma gene product, 21 and hirudin 22 significantly reduced neointima formation after arterial injury.…”

mentioning

confidence: 99%

“…Despite its overall value in achieving immediate symptomatic relief, arterial restenosis still occurs in 20% to 50% of patients within 6 months. 1 Restenosis after PTCA is characterized by progressive arterial remodeling, [2][3][4][5] extracellular matrix formation, 6,7 and intimal hyperplasia at the site of angioplasty. Most pharmacological agents have failed to demonstrate a beneficial effect on restenosis in randomized clinical trials.…”

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confidence: 99%

“…9 -11 Platelet activation results in the release of a variety of vasoactive and mitogenic factors that stimulate vascular smooth muscle cell (SMC) proliferation and migration, 12,13 matrix formation, and the late fibroproliferative response. 6,7 Local transfer of genes encoding antiproliferative proteins has been effective in animal models of neointima formation. 14 -16 In rat carotid and in rabbit and porcine iliac arteries, local adenovirus-mediated transfer of genes encoding herpes simplex virus thymidine kinase, [17][18][19] p21, 20 a constitutively active form of the retinoblastoma gene product, 21 and hirudin 22 significantly reduced neointima formation after arterial injury.…”

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confidence: 99%

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Local Adenovirus-Mediated Transfer of Human Endothelial Nitric Oxide Synthase Reduces Luminal Narrowing After Coronary Angioplasty in Pigs

et al. 1998

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Background-Nitric oxide, synthesized from L-arginine by nitric oxide synthase (NOS), is a vasodilator and inhibits vascular smooth muscle cell (SMC) proliferation and migration. The effects of local NOS gene transfer on restenosis after experimental balloon angioplasty were investigated. Methods and Results-Left anterior descending coronary artery angioplasty was performed in 25 pigs. Animals received an intramural injection of adenovirus (1.5ϫ10 9 pfu) carrying either the NOS cDNA (AdCMVceNOS) or no cDNA (AdRR5) via the Infiltrator. Local gene transfer efficiency and bioactivity of recombinant protein were assessed after 4 days. Indices of restenosis were evaluated by computerized planimetry on coronary artery sections prepared 28 days after angioplasty. Adenoviral vectors permitted efficient gene delivery to medial SMCs and adventitial cells of coronary arteries. Vascular cGMP levels were depressed after angioplasty from 1.30Ϯ0.42 to 0.33Ϯ0.20 pmol/mg protein (PϽ0.05) but were restored after constitutive endothelial (ce) NOS gene transfer to 1.82Ϯ0.98 pmol/mg (PϽ0.05 versus injured group and PϭNS versus control). The ratio of the neointimal area to the internal elastic lamina fracture length, maximal neointimal thickness, and percent stenosis were all reduced in AdCMVceNOS-versus AdRR5-transduced pigs (0.59Ϯ0.14 versus 0. Arterial restenosis is a complex biological process initiated by platelet adhesion and aggregation at the site of arterial injury.9 -11 Platelet activation results in the release of a variety of vasoactive and mitogenic factors that stimulate vascular smooth muscle cell (SMC) proliferation and migration, 12,13 matrix formation, and the late fibroproliferative response. 6,7 Local transfer of genes encoding antiproliferative proteins has been effective in animal models of neointima formation. 14 -16 In rat carotid and in rabbit and porcine iliac arteries, local adenovirus-mediated transfer of genes encoding herpes simplex virus thymidine kinase, [17][18][19] p21, 20 a constitutively active form of the retinoblastoma gene product, 21 and hirudin 22 significantly reduced neointima formation after arterial injury. 23PTCA-induced injury to the endothelial protective barrier also results in the loss of constitutively expressed endothelium-derived vasoactive factors, including NO, prostacyclin, and bradykinin, which play an important role in vascular homeostasis. 24 Loss of endothelial NO production after PTCA and subsequent loss of guanylate cyclase stimulation in medial SMCs is most likely the predominant factor responsible for the loss of vascular cGMP production. In animal Received October 30, 1997; revision received March 18, 1998; accepted March 26, 1998. From the Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (O.V., H.G., R.D.G., P.Z., D.C., S.P.J.), and the Cardiac Unit (S.P., N.V., F.V., S.P.J.), KU Leuven, Belgium.Correspondence to S.P. Janssens, Cardiac Unit and Center for Transgene Technology and Gene Therapy, 49 Herestraat, B-3000 ...

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“…These adjusted means were calculated by ANCOVA for each outcome variable, with injury score as a covariate. 9,10 The probability values calculated from comparison of regression slopes and from comparison of adjusted means are necessarily equal. Data are expressed as meanϮSEM.…”

Section: Data Analysis and Statisticsmentioning

confidence: 99%

An Iron-Binding Exochelin Prevents Restenosis Due to Coronary Artery Balloon Injury in a Porcine Model

et al. 2001

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Background-Vascular smooth muscle cell (VSMC) proliferation is a critical factor in the neointima formation that causes restenosis after coronary angioplasty (PTCA). Desferri-exochelin 772SM (D-EXO), a highly diffusible, lipophilic iron chelator secreted by Mycobacterium tuberculosis, inhibits proliferation of VSMCs in culture. We hypothesized that treatment with D-EXO would inhibit neointima formation in balloon-injured vessels in vivo. Methods and Results-We subjected 24 pigs to overstretch coronary artery injury with standard PTCA balloons and then administered intramural injections of either D-EXO (nϭ14) or vehicle (nϭ10) through an Infiltrator catheter. Treatments were randomized, and the investigators were blinded with regard to treatment group until data analysis was completed. One month later, we euthanized the pigs, excised the injured coronary segments, made multiple sections of each segment, and identified the site of maximal neointima formation. An injury score based on the degree of disruption of the internal or external elastic lamina or media was assigned. D-EXO reduced stenosis index (neointima area divided by the area within the internal elastic lamina), adjusted for injury score, by 47%. Neointima thickness was also reduced. Conclusions-D-EXO, injected intramurally, substantially inhibited formation of neointima in a porcine vascular injury model.

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Coronary Restenosis: Prospects for Solution and New Perspectives From a Porcine Model

Cited by 66 publications

References 23 publications

Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-β Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition

Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-β Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition

Local Adenovirus-Mediated Transfer of Human Endothelial Nitric Oxide Synthase Reduces Luminal Narrowing After Coronary Angioplasty in Pigs

An Iron-Binding Exochelin Prevents Restenosis Due to Coronary Artery Balloon Injury in a Porcine Model

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