Late Arterial Responses (6 and 12 Months) After
            <sup>32</sup>
            P β-Emitting Stent Placement

Farb, Andrew; Shroff, Sweta; John, Michael C.; Sweet, William L.; Virmani, Renu

doi:10.1161/01.cir.103.14.1912

Cited by 42 publications

(15 citation statements)

References 29 publications

(24 reference statements)

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“…33 These findings imply that endothelial recovery was inhibited by the antiproliferative approach, a hypothesis documented in animal studies that revealed protracted deendothelialization in irradiated arteries. 36 Moreover, recent data have revealed direct inhibition of reendothelialization by paclitaxel 2 and inhibition of endothelial cell (EC) proliferation by rapamycin. 21 In this context, we have considered the alternative hypothesis that stents that develop intimal thickening, as well as a portion of restenosis lesions that originate in nonstented arteries after percutaneous transluminal coronary angioplasty, may result in part from belated reendothelialization.…”

Section: Discussionmentioning

confidence: 99%

Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

et al. 2004

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Background— Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. Methods and Results— phVEGF 2-plasmid (100 or 200 μg per stent)–coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7±1% versus 79.0±6%, P <0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2±0.4 versus 2.27±0.3 mm 2 , P <0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4±6 versus 51.2±10, P <0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production. Conclusions— Acceleration of reendothelialization via VEGF-2 gene–eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene–eluting stents may be considered as a stand-alone or combination therapy.

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Section: Discussionmentioning

confidence: 99%

Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

et al. 2004

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“…Brachytherapy intensively inhibits neointimal formation at early time points (ie, 28 days), whereas delayed arterial healing and "late catch up" had been documented in rabbit iliac artery model at 90 and 180 days. 19,20 Incomplete endothelial coverage and persistent fibrin deposition were demonstrated even at later time points. Clinically, brachytherapy was also associated with late stent thrombosis, which was documented in both clinical trials and in autopsy studies.…”

Section: Sirolimus and Paclitaxel And Their Effects On The Arterial Wallmentioning

confidence: 99%

Vascular Responses to Drug Eluting Stents

Finn

Nakazawa

Joner

et al. 2007

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Abstract-Polymer-based sirolimus-(Cypher) and paclitaxel-eluting (Taxus) drug eluting stents have become the treatment of choice for patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention (PCI).Although these stents reduce rates of restenosis compared with bare metal stents (BMS), late thrombosis, a life threatening complication, has emerged as a major safety concern. Our understanding of the pathophysiology of late DES thrombosis is derived from animal and human pathologic samples taken after implantation of these devices. These data indicate that both DES cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared with BMS. This delayed healing is the primary substrate underlying all cases of late DES thrombosis at autopsy. Several additional risk factors for late stent thrombosis such as penetration of necrotic core, malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions represent additional barriers to healing and should be avoided if DES are to be used to minimize the risk of late thrombosis.Because the time course of complete healing with DES in man is unknown, the optimal duration of antiplatelet treatment remains to be determined. Key Words: stents Ⅲ thrombosis Ⅲ endothelium P olymer-based sirolimus (Cypher) and paclitaxel (Taxus) drug eluting stents (DES) have reduced rates of restenosis and target lesion revascularization (TLR) compared with bare metal stents (BMS) and launched a revolution in the interventional treatment of symptomatic coronary artery disease. However, enthusiasm for this technology has recently been dampened by concerns about late thrombosis (ie, stent thrombosis occurring more than 30 days after percutaneous coronary intervention), an event with oftencatastrophic consequences.Our understanding of the pathophysiology of late DES thrombosis is derived from the histological examination of animal and human arteries containing these devices. This review will focus on the cellular response that occurs when the drug and polymer contained in these devices interact with the vessel wall, especially as it relates to the process of late stent thrombosis. Preclinical Evaluation of DESPreclinical testing in both the porcine and rabbit models is an important part of the regulatory process used to determine the safety and efficacy of devices before human use. Comparative preclinical histological studies remain the most effective method of assessing the vascular responses to these devices before their introduction into humans. Although it is wellrecognized that arterial repair after stent placement in animals occurs more rapidly than in man, the sequence of biological events associated with healing are remarkably similar. 1 We will discuss below why the predictive value of the vascular healing responses for humans has for the most part not been shown. Sirolimus and Paclitaxel and Their Effects on the Arterial WallDrug choice and release kin...

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“…22 Preclinical studies of arterial brachytherapy have demonstrated delayed neointimal healing characterized by persistent fibrin and platelet deposition with nonconfluent areas of matrix, incomplete endothelialization, and increased intimal cellular proliferation. 23,24 …”

Section: Radiation Therapymentioning

confidence: 99%

Pathological Mechanisms of Fatal Late Coronary Stent Thrombosis in Humans

et al. 2003

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Background-Coronary stent deployment is associated with a low incidence of acute thrombosis. However, late stent thrombosis (LST) has likely been underrecognized clinically, and pathological descriptions are lacking. Methods and Results-LST was defined as an acute thrombus within a stent that had been in place Ն30 days. Cases of LST were selected from a registry of human coronary stents submitted for analysis. Thirteen cases of LST (9 men, 4 women) were identified. The mean duration from implantation to thrombosis was 3.6Ϯ3.5 months (range, 1 to 11.9 months). The causes of death were sudden cardiac death (nϭ10), acute myocardial infarction (nϭ2), and heart failure (nϭ1). The pathological mechanisms of LST were as follows: (1) stenting across ostia of major arterial branches (5 cases); (2) exposure to radiation therapy (3 cases); (3) plaque disruption in the nonstented arterial segment within 2 mm of the stent margin (2 cases); (4) stenting of markedly necrotic, lipid-rich plaques with extensive plaque prolapse (2 cases); and (5) diffuse in-stent restenosis (1 case). Twelve cases demonstrated a failure to form a completely healed neointimal layer overlying stent struts. Underlying in-stent restenosis was present in only 4 (31%) of 13 cases. Conclusions-LST is a potentially fatal complication of coronary stenting. Stenting across branch ostia, disruption of adjacent vulnerable plaques, radiation therapy, and extensive plaque prolapse can precipitate LST. Impaired intimal healing (ie, the failure to form a complete neointimal layer over stent struts) extends the window during which stents are prone to thrombosis.

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Late Arterial Responses (6 and 12 Months) After ³² P β-Emitting Stent Placement

Cited by 42 publications

References 29 publications

Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

Vascular Responses to Drug Eluting Stents

Pathological Mechanisms of Fatal Late Coronary Stent Thrombosis in Humans

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Late Arterial Responses (6 and 12 Months) After 32 P β-Emitting Stent Placement

Cited by 42 publications

References 29 publications

Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

Vascular Responses to Drug Eluting Stents

Pathological Mechanisms of Fatal Late Coronary Stent Thrombosis in Humans

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Product

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Late Arterial Responses (6 and 12 Months) After ³² P β-Emitting Stent Placement