Integrated microscopy techniques for comprehensive pathology evaluation of an implantable left atrial pressure sensor.

The safety and efficacy of an implantable left atrial pressure (LAP) monitoring system is being evaluated in a clinical trial setting. Because the number of available specimens from the clinical trial for histopathology analysis is limited, it is beneficial to maximize the usage of each available specimen by relying on integrated microscopy techniques. The aim of this study is to demonstrate how a comprehensive pathology analysis of a single specimen may be reliably achieved using integrated microscopy techniques. Integrated microscopy techniques consisting of high-resolution gross digital photography followed by micro-computed tomography (micro-CT) scanning, low-vacuum scanning electron microscopy (LVSEM), and microground histology with special stains were applied to the same specimen. Integrated microscopy techniques were applied to eight human specimens. Micro-CT evaluation was beneficial for pinpointing the location and position of the device within the tissue, and for identifying any areas of interest or structural flaws that required additional examination. Usage of LVSEM was reliable in analyzing surface topography and cell type without destroying the integrity of the specimen. Following LVSEM, the specimen remained suitable for embedding in plastic and sectioning for light microscopy, using the positional data gathered from the micro-CT to intersect areas of interest in the slide. Finally, hematoxylin and eosin (H&E) and methylene blue staining was deployed on the slides with high-resolution results. The integration of multiple techniques on a single specimen maximized the usage of the limited number of available specimens from the clinical trial setting. Additionally, this integrated microscopic evaluation approach was found to have the added benefit of providing greater assurance of the derived conclusions because it was possible to cross-validate the results from multiple tests on the same specimen.

A porcine coronary stent model of increased neointima formation in the left anterior descending coronary artery.

BACKGROUND: Clinical trials suggest an increased frequency of restenosis after coronary intervention in left anterior descending (LAD) compared to the left circumflex or right coronary arteries. Experimental studies correlate stent-induced arterial injury and the extent of neointima formation. This study investigates whether the coronary artery affects the relationship between arterial injury and neointima hyperplasia in the porcine stent model. METHODS: Non-lipemic farm pigs underwent stent placement in the LAD (n = 26) and the right coronary artery (RCA; n = 30). Quantitative coronary angiography (QCA) was performed before and after stent placement, and at follow-up; quantitative histomorphometry and injury score were analyzed at 30-day follow-up. RESULTS: Initial procedure balloon/artery ratios (LAD 1.17 +/- 0.11 vs RCA 1.17 +/- 0.09, P = NS), and minimal stent lumen diameters (MLD; LAD 2.91 +/- 0.31 vs RCA: 2.93 +/- 0.28 mm, P = NS) were similar suggesting no difference in deployment technique. At follow-up there was more restenosis in the LAD (diameter stenosis: 55.0 +/- 26.4% vs 37.3 +/- 18.1%, and MLD: 1.24 +/- 0.78 mm vs. 1.71 +/- 0.57 mm, P < 0.05 for both comparisons). No differences were seen for injury score (1.09 +/- 0.51 vs 1.01 +/- 0.57; LAD vs RCA) or stent area (6.13 +/- 0.99 vs 6.55 +/- 1.42 mm2). Histomorphometry demonstrated smaller lumen area (2.15 +/- 0.94 vs 2.96 +/- 1.29 mm2) and thicker neointima (0.63 +/- 0.25 vs 0.51 +/- 0.17 mm; all P < 0.05) in the LAD. Multiple linear regression analysis identified the LAD as an independent predictive factor for increased neointima formation. CONCLUSIONS: These observations establish an animal model that is consistent with clinical experience showing that restenosis after stenting is more common in the LAD. The findings may be useful for understanding and developing systemic and local antirestenotic strategies.

Usefulness of intracoronary brachytherapy for in-stent restenosis with a 188Re liquid-filled balloon.

The objective of this randomized pilot trial with 21 patients was to evaluate the effectiveness of a rhenium-188 liquid-filled balloon system to prevent recurrent restenosis after percutaneous transluminal coronary angioplasty for in-stent restenosis. A significant benefit from brachytherapy was seen at 6-month repeat angiography, as well as during the clinical follow-up of 12 months.

Leakage of a liquid 188Re-filled balloon system during intracoronary brachytherapy. A case report.

We are reporting the first case of an accidental radioactive 188Re leakage of a liquid-filled balloon system. Different analytical methods estimated that approximately 4 mCi 188Re were released. The radiation burden was reduced considerably by the combined therapy with perchlorate and forced volume diuresis. Estimated exposures to all organs were very low with 1.8 rad. A total body nuclear scintigraphy demonstrated uniform 188Re distribution, without specific organ concentration.

Elevated troponin I level on admission is associated with adverse outcome of primary angioplasty in acute myocardial infarction.

BACKGROUND: In patients with acute myocardial infarction (AMI) undergoing thrombolytic therapy, an elevated troponin level on admission is associated with a lower reperfusion rate and a complicated clinical course. Whether an elevated troponin level on admission similarly predicts an adverse outcome in patients undergoing primary angioplasty is currently unknown and was investigated in the present study. METHODS AND RESULTS: Cardiac troponin I (cTnI) was determined on admission in 110 consecutive patients with AMI associated with ST-segment elevation or left bundle branch block who underwent primary angioplasty. Fifty-four patients (49%) had an elevated cTnI (>/=0.4 ng/mL) on admission. In patients with elevated cTnI, primary angioplasty was less likely to achieve TIMI 3 flow (as classified by the Thrombolysis in Myocardial Infarction trial) in univariate (76% versus 96%, P:=0.03) or in multivariate (odds ratio 0.1, 95% CI 0.02 to 0.54) analysis. Patients with elevated cTnI were more likely to develop congestive heart failure (23% versus 9%, P:<0.05) and death, heart failure, or shock (30% versus 9%, P:=0.006). Elevated cTnI remained a significant predictor of the composite end point after controlling for other clinical data that were available early in the course, including time to presentation and angiographic results (relative risk 5.2, 95% CI 1.03 to 26.3). During a follow-up of 426+/-50 days, elevated admission cTnI was a predictor of cardiac mortality (11% versus 0%, P:=0.012), adverse cardiac events (cardiac mortality or nonfatal reinfarction; 19% versus 5.4%, P:=0.04), and adverse cardiac events plus target vessel revascularization (32% versus 14%, P:=0.054). CONCLUSIONS: In patients with ST-segment elevation AMI, an elevated cTnI on admission is associated with an increased risk of primary angioplasty failure and a more complicated clinical course.

Effects of beta(-)-emitting (188)Re balloon in stented porcine coronary arteries: an angiographic, intravascular ultrasound, and histomorphometric study.

BACKGROUND: Restenosis within stents may be prevented by ionizing radiation from an intravascular source. METHODS AND RESULTS: A liquid beta(-) radiation ((188)Re) balloon was evaluated in a randomized and blinded porcine coronary model of stent restenosis. Group A pigs (n=17) received 0,16, 22, or 29 Gy at 0.5-mm depth, followed by stenting. Restenosis was quantified by angiography, ultrasound, and histomorphometry at 30 days. Group B (n=7) was stented first and then treated with 0 or 29 Gy with follow-up at 60 days. There was a measurable effect at 16 Gy, which improved with increasing doses. At 29 Gy, the histological stenotic area was reduced by 67% (22% versus 66% in controls, P<0.001). Radiation after stenting was equally effective; the stenotic area was reduced (21% versus 65%, P<0.001). At 16 Gy, the vessel just distal to the stent was significantly smaller than control vessels because of intimal thickening (P=0.003). Radiated vessels had distinctive histology consisting of neointimal fibrin and reduced smooth muscle cells and matrix (P<0.0001). CONCLUSIONS: (188)Re balloon brachytherapy in porcine coronary arteries results in dose-dependent and injury-independent inhibition of stent restenosis for up to 60 days. Restenosis at the borders of the irradiated zone is a potential limitation and may be related to underdosing. Brachytherapy with the (188)Re balloon appears to be safe and feasible for clinical studies.

In vitro and in vivo studies of PEO-grafted blood-contacting cardiovascular prostheses.

The initial step of thrombus formation on blood-contacting biomaterials is known to be adsorption of blood proteins followed by platelet adhesion. Poly(ethylene oxide) (PEO) has been frequently used to modify biomaterial surfaces to minimize or prevent protein adsorption and cell adhesion. PEO was grafted onto a number of biomaterials in our laboratory. Nitinol stents and glass tubes were grafted with PEO by priming the metal surface with trichlorovinylsilane (TCVS) followed by adsorption of Pluronic and y-irradiation. Nitinol stents were also coated with Carbothane for PEO grafting. Chemically inert polymeric biomaterials, such as Carbothane, polyethylene, silicone rubber, and expanded polytetrafluoroethylene (e-PTFE), were first adsorbed with PEO-polybutadiene-PEO (PEO-PB-PEO) triblock copolymers and then exposed to gamma-irradiation for covalent grafting. For PEO grafting to Dacron (polyethylene terephthalate), the surface was sequentially treated with PEO-PB-PEO and Pluronics followed by gamma-irradiation. In vitro studies showed substantial reduction in fibrinogen adsorption and platelet adhesion to the PEO-grafted surfaces compared with control surfaces. Fibrinogen adsorption was reduced by 70-95% by PEO grafting on all surfaces, except for e-PTFE. The platelet adhesion corresponded to the fibrinogen adsorption. When the PEO-grafted surfaces were tested ex vivo/in vivo, however, the expected beneficial effect of PEO grafting was inconsistent. The beneficial effect of the PEO grafting was most pronounced on the PEO-grafted nitinol stents. Thrombus formation was reduced by more than 85% by PEO grafting on metallic stents. Only moderate improvement (i.e. 35% decrease in platelet deposition) was observed with PEO-grafted tubes of polyethylene, silicone rubber, and glass. For PEO-grafted heart valves made of Dacron, however, no effect of PEO grafting was observed at all. It appears that the extent of thrombus formation on PEO-grafted biomaterials was directly related to the extent of tissue damage during implantation surgery. Platelets can be activated and form aggregates in the bulk blood, and the formed platelet aggregates may be able to deposit on the PEO monolayer overcoming its repulsive property. Our studies indicate that the testing of in vitro platelet adhesion should include adhesion of large platelet aggregates, in addition to adhesion of individual platelets. Furthermore, the surface modification methods should be improved over the current monolayer grafting concept so that the repulsive force by the grafted PEO layers is large enough to prevent adhesion of platelet aggregates formed in the bulk blood before arriving at the biomaterial surface.

Leakage of a liquid 188Re-filled balloon system during intracoronary brachytherapy. A case report.

We are reporting the first case of an accidental radioactive 188Re leakage of a liquid-filled balloon system. Different analytical methods estimated that approximately 4 mCi 188Re were released. The radiation burden was reduced considerably by the combined therapy with perchlorate and forced volume diuresis. Estimated exposures to all organs were very low with 1.8 rad. A total body nuclear scintigraphy demonstrated uniform 188Re distribution, without specific organ concentration.

Effect of glycoprotein IIb/IIIa inhibition without thrombolytic therapy on reperfusion in acute myocardial infarction: results of ReoMI pilot study.

The efficacy of abciximab and moderate dose heparin in attaining reperfusion in acute MI was tested in a multicenter pilot study. Patients with acute MI of less than 6-hr onset triaged to primary PTCA received intravenous abciximab bolus and infusion and heparin (70 u/kg) in the emergency room. Mean time to angiography from administration of abciximab was 34 +/- 23 min. TIMI flow rates were: grade 0-62%, grade I-20%, grade II-9%, and grade III-9%. Primary PTCA was performed with 100% success rate. Access site bleeding occurred in 10% of patients with no incidence of intracranial bleeding. TIMI II/III flow rates were 50% in a patient subset where angiography was delayed by 45 min. While not an alternative to thrombolytics in AMI, abciximab administration in the emergency room in patients triaged to PTCA may be beneficial in situation where door to needle time is delayed as TIMI II/III flows may be attained in some patients. Cathet. Cardiovasc. Intervent. 48:430-434, 1999.

Chimeric DNA-RNA hammerhead ribozyme to proliferating cell nuclear antigen reduces stent-induced stenosis in a porcine coronary model.

BACKGROUND: Stent-induced coronary restenosis is a major clinical and public health problem. Proliferating cell nuclear antigen (PCNA) is an important regulator of cell division, and blocking of its expression after angioplasty may limit intimal proliferation. METHODS AND RESULTS: We cloned the porcine PCNA gene and constructed a chimeric hammerhead ribozyme to a segment of the gene with human homology. In vitro studies with both cultured porcine and human vascular smooth muscle cells demonstrated uptake of ribozyme within the nucleus and significant inhibition of cellular proliferation. The ribozyme was then delivered locally into pig coronaries in a stent model. At 30 days, histomorphometric analysis showed neointimal thickness of 0.51+/-0.20 mm in the ribozyme group versus 0.71+/-0.27 and 0.66+/-0.25 mm in stent controls and scrambled ribozyme control, respectively (P=0.002, P=0.03). Quantitative angiographic analysis showed late loss of 1.4+/-0.5 mm for ribozyme versus 1.9+/-0.4 and 2.0+/-0.4 mm for the controls (P=0.05 and P=0. 02). CONCLUSIONS: Chimeric hammerhead ribozyme to PCNA inhibits smooth muscle cell proliferation in vitro and reduces both histomorphometric and angiographic restenosis in the porcine coronary stent model when delivered locally.

Effects of a positron-emitting vanadium-48 nitinol stent on experimental restenosis in porcine coronary arteries: an injury-response study.

BACKGROUND: The major limitation of coronary stenting is restenosis due to exaggerated neointimal thickening. We evaluated a positron-emitting V48 nitinol stent in a porcine coronary model of restenosis. METHODS AND RESULTS: Pigs (n = 16) received a control nonradioactive and a V48 stent (1.5 or 10.6 muCi) randomized to the left anterior descending artery (LAD) and right coronary artery (RCA). Histology, morphometric variables, and strut injury scores were evaluated after 32 days. Peristrut fibrinoid deposits were greater in the high-dose group (p < 0.0001). Control stent area stenosis (AS) and mean neointimal thickness (NIT) correlated with injury (r = 0.81 and 0.79, respectively). Higher-dose stents reduced AS by 20% (0.57 +/- 0.13 vs. 0.71 +/- 0.16; p = 0.029) and mean NIT by 35% (0.44 +/- 0.16 vs. 0.71 +/- 0.24mm; p = 0.001) compared with controls. Lower-dose 1.5-muCi stents did not differ from controls. NIT over individual struts was reduced in the high-dose group compared with controls by 0.18 mm for grade 1 injury, 0.31 mm for grade 2, and 0.38 mm for grade 3 (p < 0.02 for all comparisons). CONCLUSIONS: 1.5-muCi V48 nitinol stents did not influence vessel histology or restenotic parameters in pig coronary arteries. In contrast, 10.6-muCi stents created a distinctive histological picture consisting of increased fibrinoid deposits on the neointimal-facing side of the struts without cellular organization. Higher dose radioactive stents significantly reduced AS and mean NIT. The reduction in neointimal thickening was greatest when the depth of strut penetration into the vascular wall was most severe.

Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis.

AIMS: Use of ticlopidine in coronary stenting is limited by delayed onset of action. We studied the effects of clopidogrel, a rapidly acting analog of ticlopidine alone, and in combination with aspirin, in inhibiting stent thrombosis. METHODS: Unpolished nitinol stents were deployed in a porcine ex vivo arteriovenous shunt and exposed to flowing arterial blood at a shear rate of approximately 1500. s-1. Stent thrombus, platelet aggregation and bleeding times were measured at baseline and after treatment. RESULTS: Intravenous clopidogrel produced a rapid (within 30 min) and dose-dependent inhibition of stent thrombosis, with 87% reduction at a dose of 10 mg.kg-1 (P < 0.001). Aspirin alone (10 mg.kg-1) was minimally effective (20% inhibition P > 0.05) in inhibiting stent thrombosis. Combined treatment with clopidogrel and aspirin produced 95-98% inhibition of stent thrombosis, even at low doses of clopidogrel (2.5-5.0 mg.kg-1) (P < 0.0001). At effective doses both clopidogrel and combined therapy produced significant prolongation of bleeding time (P < 0.05) and inhibition of platelet aggregation (P < 0.05). CONCLUSION: Clopidogrel, either alone or combined with aspirin, may have a potential role in preventing stent thrombosis in high-risk clinical situations.

Biocompatibility of polyurethane-coated stents: tissue and vascular aspects.

To assess the arterial injury triggered by polyurethane-coated vs. uncoated stents, six polyurethane-coated and six bare nitinol stents were implanted in rabbit carotid arteries. All animals were sacrificed 4 wk after stent placement. Sections were evaluated by histology and morphometric analysis. At 4 wk, both the coated and uncoated stent struts were entirely endothelialized. The spaces between the struts showed a relatively mild proliferative response, with a few sections demonstrating neovascularization around the struts. Polyurethane coating was associated with an inflammatory tissue response consisting of lymphocytic infiltration and foreign-body reaction, with the appearance of multinucleated giant cells. Lumen, intimal, and medial cross-sectional areas varied little between coated and uncoated stented vessels (2.45+/-0.19 vs. 2.47+/-0.47 mm2, 1.17+/-0.52 vs. 0.78+/-0.30 mm2, and 0.66+/-0.18 vs. 0.58+/-0.27 mm2, respectively). In the rabbit carotid artery model, polyurethane coating does not affect the degree of neointimal proliferation after endovascular stenting compared with the conventional stenting approach. However, the inflammatory tissue response may indicate a low intrinsic biocompatibility of this stable polymer, so that it may not be an ideal material for coating intravascular devices.

Characterization of a positron emitting V48 nitinol stent for intracoronary brachytherapy.

Percutaneous transluminal coronary angioplasty (PTCA) is currently one of the most common treatments for obstructive coronary artery disease. The long term success of the treatment, however, is severely limited by restenosis. Recently, different investigators have begun to study the possibility of radiation therapy in restenosis prevention and have shown promising results. However, an optimal radiation delivery device for delivering a highly localized radiation dose to the arterial medial layer while preserving the viability of the artery has yet to be established. In this article, we discuss the development of a unique mixed gamma/beta brachytherapy source capable of delivering high radiation dose to a 0.5 mm thick vessel wall by proton-beam activating an existing nickel titanium stent to produce vanadium-48. The dose distribution of the activated stent is determined by computer simulation using MCNP Monte Carlo code and is verified by radiochromic film measurement.

Long-term follow-up of a high risk cohort after stent implantation in saphenous vein grafts.

OBJECTIVES: We sought to provide short- and long-term clinical outcomes of a high risk cohort treated with stents in saphenous vein grafts (SVGs). BACKGROUND: Data on the long-term outcome of SVG stenting in high risk patients are limited. METHODS: Johnson & Johnson stents were implanted in the SVGs of 186 patients (302 stents, 244 lesions). Ninety percent of patients presented with myocardial infarction (MI) or unstable angina (mean +/- SD ejection fraction [EF] 44 +/- 11%, patient age 71 +/- 9 years, graft age 9.4 +/- 5 years). Using a risk score classification, 155 patients (83%) were defined as high risk for repeat surgical repair or angioplasty. RESULTS: The procedural success rate was 97.3%, with 2.7% major complications (death, Q wave MI, coronary artery bypass graft surgery [CABG]). Clinical follow-up was obtained in 177 patients (mean 19.1 +/- 13.5 months, range 7 to 59). Event rates were 10% for death; 9% for MI; 11% for repeat CABG; and 15% for repeat angioplasty (total events 45%). Kaplan-Meier estimated survival and event-free survival at 4 years were 0.79 +/- 0.06 and 0.29 +/- 0.07, respectively. Predictors of death were congestive heart failure (p < 0.01) and EF <44% (p < 0.05). Predictors of combined events of death, MI and CABG were low EF (p < 0.01) and high SVG age (>10 years, p < 0.01). There were 66 revascularization procedures (35% of patients), 24% of which were in nontarget lesions. Fifty-three percent of the cardiac events occurred during the first year of follow-up. Of the 160 survivors, 36% were free of angina, 49% were in Canadian Cardiovascular Society functional class I or II, and 15% were in class III or IV. Sixty-nine percent of patients were in class I or II according to the Specific Activity Scale, and 31% of patients were in class III or IV. CONCLUSIONS: Balloon-expandable stent implantation in the SVGs of high risk patients is associated with a low early complication rate. Expected survival rates are good, as are the anginal and functional classifications, but there is a high rate of recurrent events and need for repeat revascularization. Vein graft stenting is an acceptable palliative option in many high risk patients.

Highly localized arterial remodeling in patients with coronary atherosclerosis: an intravascular ultrasound study.

BACKGROUND: Preservation of luminal area and symmetry in the presence of irregular plaques necessitates local expansion of the artery wall. METHODS AND RESULTS: Cross-sectional dimensions of coronary arteries in 65 patients were measured with the use of intravascular ultrasound. A total of 104 arterial segments were studied, of which 88 had atherosclerosis; 16 served as nonatherosclerotic control segments. Three features of atherosclerotic arterial segments were classified: (1) plaque formation, (2) lumen shape, and (3) shape of arterial external elastic lamina. With our intravascular ultrasound-based three-level classification system, we identified three patterns that accounted for 89% of all atherosclerotic arterial segments: (1) concentric plaque with a circular lumen and a circular external elastic lamina (n= 17), (2) eccentric plaque with a circular lumen and an oval external elastic lamina (n=35), and (3) eccentric plaque with an oval lumen and a circular external elastic lamina (n=26). A circular lumen was preserved in 66% of all atherosclerotic arterial segments. Arterial segments with a circular lumen in the presence of an eccentric plaque had a significantly larger lumen area than the other two main groups (P<.05). CONCLUSIONS: With our intravascular ultrasound-based classification, we provided information regarding the local remodeling response in the coronary artery wall. In a majority of cases, a circular lumen is maintained. Failure of this highly localized response to be operative may contribute to the development of stenotic lesions at a specific site in the artery.

Sustained local drug delivery to the arterial wall via biodegradable microspheres.

This study was designed to evaluate the feasibility of applying locally delivered polylactic acid microspheres for drug delivery to the arterial wall. To study drug persistence, rhodamine-loaded microspheres were infused into one carotid artery of 14 rabbits and plain rhodamine solution into the other by using a porous balloon. To study tissue response, plain microspheres and dexamethasone-loaded microspheres were infused into the carotid arteries of another group of rabbits. To study the antiproliferative effects of locally delivered drug, 20 rabbits were subjected to overstretch balloon injury to both carotid arteries and divided into 4 groups: injury alone, plain microspheres, dexamethasone-loaded microspheres, and microspheres containing colchicine and dexamethasone. Fluorescent microspheres persisted in the vessel wall for 4 wk, whereas rhodamine without microspheres disappeared at 72 h. Histopathologic studies in arteries infused with unloaded microspheres showed inflammatory cell infiltrate with polymorphonuclear cells at 1 wk and macrophages and giant cells at 4 wk. Arteries infused with dexamethasone-loaded microspheres did not show any inflammatory cell infiltrate. Local delivery of dexamethasone or dexamethasone plus colchicine did not result in significant change in the intima-to-media ratio or in residual lumen following balloon injury. Polylactic acid microspheres may be used for prolonged delivery of drugs or other bioactive agents locally to the arterial wall. They induce an inflammatory reaction that is suppressable by dexamethasone in the microspheres. Dexamethasone or dexamethasone and colchicine delivered via this system, however, failed to reduce the degree of intimal hyperplasia after overstretch balloon injury to the rabbit carotid arteries.

Temporary arterial stenting: comparison to permanent stenting and conventional balloon injury in a rabbit carotid artery model.

The objective was to assess the arterial wall response to temporary stenting with a removable nitinol stent in comparison with permanent stenting and balloon injury at 28 days in the rabbit carotid artery. Restenosis remains an important limiting factor after the implantation of permanent metallic stents and balloon angioplasty. We have developed a temporary nitinol stent that uses a bolus injection of warmed saline to collapse the stent for percutaneous removal. Vascular changes related to the thermal saline bolus injection required to remove a nitinol implanted stent were assessed in 12 rabbit carotid arteries at 7 and 28 days postinjection. Nitinol stents, inflated to 3.0 mm diameter, were implanted for 3 days (n = 6) and histology and quantitative histomorphometry examined at 28 days. Results were compared with permanently implanted stents (n = 5) and balloon injury (n = 9). Dual bolus injection of 10 ml at 70 degrees C created an acute necrotizing injury and chronic neointimal proliferation, whereas injections of 5 ml at 63 degrees C were minimally injurious. Temporary stenting resulted in the least neointimal proliferation measured by the intima to media ratio (0.22 +/- 0.10 vs. 1.59 +/- 0.31 for permanent stenting and; 0.49 +/- 0.14 for balloon injury; P < 0.001). Temporary stenting maintained a significantly larger lumen than balloon (1.53 +/- 0.72 mm2 vs. 0.64 +/- 0.14 mm2; P < 0.001), which could not be explained by absolute changes in intimal cross sectional area (0.14 +/- 0.07 mm2 vs. 0.21 +/- 0.06 mm2 respectively; P = 0.33). Temporary stenting resulted in a relatively larger vessel area within the external elastic lamina than with balloon (2.28 +/- 1.06 mm2 vs. 1.30 +/- 0.18 mm2; P = 0.007). The thermal stent recovery process can create necrotizing vascular injury and neointimal proliferation at higher temperatures and injectate volumes. Stent removal after 3 days using 63 degrees C saline bolus injection results in less neointimal proliferation than with permanent stents or balloon injury. In comparison to balloon injury, temporary stenting also may have a long-lasting beneficial effect on vessel recoil and remodeling, resulting in larger lumen size after stent removal.

Effects of GP IIb/IIIa receptor monoclonal antibody (7E3), heparin, and aspirin in an ex vivo canine arteriovenous shunt model of stent thrombosis.

BACKGROUND: Thrombosis is an important limitation of metallic coronary stents, especially in smaller vessels in which shear rates are high. Monoclonal antibody to platelet glycoprotein IIb/IIIa receptor (7E3) has been shown to inhibit shear-induced platelet aggregation. In this study, we compared the effects of 7E3, heparin, and aspirin on stent thrombosis in an ex vivo arteriovenous shunt model of high-shear blood flow. METHODS AND RESULTS: An ex vivo arteriovenous shunt was created in 10 anesthetized dogs. Control rough-surface slotted-tube nitinol stents (n = 72) expanded to 2 mm in diameter in a tubular perfusion chamber were interposed in the shunt and exposed to flowing arterial blood at a shear rate of 2100s-1 for 20 minutes. The animals were treated with intravenous murine 7E3 (Fab')2 (0.2, 0.4, and 0.8 mg/kg), heparin (100 U/kg), or aspirin (10 mg/kg). Effects of the test agents on thrombus weight, platelet aggregation, platelet P-selectin expression, bleeding time, and activated clotting time (ACT) were quantified. 7E3 reduced stent thrombosis by 95% (20 +/- 1 to 1 +/- 1 mg, P < .001) and platelet aggregation by 94% (14 +/- 2 to 1 +/- 1 omega, P < .001) at the highest dose (0.8 mg/kg). 7E3 significantly prolonged bleeding time but had no effect on ACT and platelet P-selectin expression. Heparin prolonged ACT but had no significant effect on stent thrombosis or platelet aggregation. Aspirin, although it inhibited platelet aggregation by 65%, had no effect on stent thrombosis (19 +/- 2 versus 20 +/- 1 mg in controls). CONCLUSIONS: 7E3 produced a dose-dependent inhibition of acute stent thrombosis under high-shear flow conditions. Stent thrombosis was resistant to heparin and aspirin. Thus, 7E3 may be an effective agent for preventing stent thrombosis.