Mahomed Y. Salame

Reduced Thrombus Formation by Hyaluronic Acid Coating of Endovascular Devices

Biocompatible stent coatings may alleviate problems of increased (sub)acute thrombosis after stent implantation. Hyaluronic acid (HA), a ubiquitous, nonsulfated glycosaminoglycan, inhibits platelet adhesion and aggregation and prolongs bleeding when administered systemically. However, the effects of immobilized HA for reducing stent platelet deposition in vivo are unknown. We therefore quantified the antithrombotic effects of coating stainless steel stents and tubes with HA using an established baboon thrombosis model under physiologically relevant blood flow conditions. HA-coated and uncoated (control) stents (3.5 mm in diameter, n=32) and stainless steel tubes (4.0 mm in diameter, n=18) were deployed into exteriorized arteriovenous shunts of conscious, nonanticoagulated baboons. Accumulation of (111)In-radiolabeled platelets was quantified by continuous gamma-camera imaging during a 2-hour blood exposure period. HA coating resulted in a significant reduction in platelet deposition in long (4 cm) tubes (0.24+/-0.15 x 10(9) versus 6.12+/-0.49 x 10(9) platelets; P<0.03), short (2 cm) stainless steel tubes (0.18+/-0.06 x 10(9) versus 3.03+/-0.56 x 10(9) platelets; P<0.008), and stents (0.82+/-0.20 x 10(9) versus 1.83+/-0. 23 x 10(9) platelets; P<0.02) compared with uncoated control devices. Thus, HA coating reduces platelet thrombus formation on stainless steel stents and tubes in primate thrombosis models. These results indicate that immobilized HA may represent an attractive strategy for improving the thromboresistance of endovascular devices.

The Effect of Endovascular Irradiation on Platelet Recruitment at Sites of Balloon Angioplasty in Pig Coronary Arteries

BACKGROUND Endovascular irradiation (EI) inhibits balloon-induced neointima formation in animals and is now in clinical trials for restenosis prevention. However, little is known of the effect of EI on vessel thrombogenicity due to delayed arterial healing. We investigated EI effects on platelet recruitment in pig coronary arteries. METHODS AND RESULTS EI was performed using (90)Sr/Y at 0 Gray (Gy), 15Gy, or 30Gy at 2 mm after balloon overstretch injury. At 1 day, 1 week, and 1 month, platelet recruitment and thrombus formation were assessed using autologous (111)In-oxine-platelet labeling and light and scanning electron microscopy. In balloon-injured nonirradiated vessels, there was complete reendothelialization at 1 month, and platelet recruitment was similar to normal uninjured arteries. In irradiated vessels, scanning electron microscopy showed incomplete reendothelialization at 1 month, and these areas demonstrated attachment of activated platelets. Light microscopy of irradiated coronaries showed adherent partially organized thrombi and incomplete resolution of intramural hemorrhages. There was a significant increase in platelet recruitment at 1 month in arteries receiving EI at 15Gy (5.1+/-2. 8x10(6), P=0.02) or 30Gy (12.5+/-9.9x10(6), P=0.005) compared with nonirradiated controls (2.7+/-1.5x10(6)); 30Gy was also higher than 15Gy (P=0.05). Platelet recruitment was also increased for 30Gy compared with control at 1 day. CONCLUSIONS Endovascular irradiation at 15Gy or 30Gy after balloon angioplasty results in incomplete endothelial recovery, impaired resolution of intramural hemorrhage, and a dose-dependent increase in platelet recruitment at 1 month.

Inhibition of neointima formation by tranilast in pig coronary arteries after balloon angioplasty and stent implantation

OBJECTIVES We evaluated the effect of orally administered tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, on histologic and histomorphometric changes after angioplasty or stent implantation in pig coronary arteries. BACKGROUND Tranilast, which has antikeloid and antiallergic properties and therefore may modulate the fibrotic and inflammatory tissue responses to angioplasty and stenting, has been shown to inhibit angiographic restenosis in small clinical trials. However, its effect on histomorphometric changes in coronary arteries after angioplasty and stenting is unknown. METHODS Following initial pharmacokinetic studies in two pigs to determine desirable plasma levels of orally administered tranilast, 36 crossbred juvenile pigs were randomized to placebo or tranilast before undergoing balloon angioplasty in both the left anterior descending and left circumflex plus stent implantation in the right coronary artery. Oral tranilast was administered at 3 g/day starting 3 days before coronary injury and continued for 28 days until euthanasia. Injured vessels were harvested and sections analyzed by computer-assisted microscopic planimetry. RESULTS In balloon-injured vessels, tranilast was associated with a 37% reduction in neointimal area normalized to fracture length (0.47 +/- 0.01 vs. 0.74 +/- 0.03 mm; p < 0.001) and a 23% reduction in adventitial area normalized to vessel size (0.43 +/- 0.02 vs. 0.56 +/- 0.03; p = 0.003). In stented arteries, neointimal area normalized to injury score was 32% lower in the tranilast-treated group compared to control (1.94 +/- 0.17 vs. 2.86 +/- 0.29; p = 0.01). CONCLUSIONS In pig coronary arteries, tranilast was associated with a reduction in neointima formation and adventitial reaction after balloon injury. In stented vessels, tranilast was associated with a reduction in neointima formation normalized to injury score.

Short‐ and long‐term histopathologic evaluation of stenting using a self‐expanding nitinol stent in pig carotid and iliac arteries

Stenting is increasingly being used to treat carotid artery disease. However, complications including distal embolization, stent thrombosis, stent collapse from external compression, the need for high‐pressure inflation with increased neointimal response, or balloon rupture during stent expansion and stent loss are all potential problems and of concern. To address each of these specific concerns, a new stent was designed, which is self‐expandable, made of nitinol, with temperature‐dependent superelastic properties, and with high vessel wall surface coverage. Since this device has a number of novel characteristics, we aimed to assess the short‐ and long‐term histopathologic response in pig carotid and iliac arteries. Single stents were deployed in pig carotid and iliac arteries after overstretch balloon injury. Angiograms were performed pre‐ and poststenting and prior to sacrifice. Intravascular ultrasound was used before implantation to determine vessel size. Vessels were examined histologically at 1 month (n = 6) and 6 months (n = 6) for morphometric analysis, hemorrhage and thrombus, endothelialization, and inflammatory and fibrotic responses. There was a 100% angiographic success rate at implantation. In one case, it was determined histologically that a single stent was implanted in a dissection plane of a pigs left iliac artery and was occluded by organized thrombus, with the true lumen being patent. At 6‐month follow‐up, this was the only evidence of a single stent occlusion, with flow adjacent to the stent in the true lumen. In the other vessels, the stents showed good vessel wall–stent apposition and the lumens were patent with a concentric and thin neointima. Inflammatory cells were rare and there were no mural thrombi. Coverage of the vessel wall by endothelial‐like cells was complete at 1 month. The novel nitinol EndoStent appears to have favorable biocompatibility with minimal thrombus deposition or inflammatory response, and its use is feasible for clinical application in carotid and iliac arteries. Cathet. Cardiovasc. Intervent. 48:316–323, 1999.

High-dose external beam irradiation inhibits neointima formation in stented pig coronary arteries

PURPOSE To evaluate high-dose external beam irradiation (EBRT) in a pig coronary stent preparation because low and intermediate-dose EBRT failed to show inhibition of neointima formation in stented animal models. METHODS AND MATERIALS Thirty-five stents were implanted in the coronary arteries of 17 pigs. Seven pigs were exposed to a single dose of 21 Gy EBRT immediately after stenting. Ten stented, nonirradiated pigs served as controls. After 4 weeks, the study arteries and myocardium were examined by light and scanning electron microscopy. RESULTS Compared with controls, 21 Gy EBRT resulted in a larger lumen area (7.57 +/- 1.67 mm2 vs. 4.00 +/- 1.63 mm2, p <0.001), a smaller neointima area (0.47 +/- 0.43 mm2 vs. 3.36 +/- 2.26 mm2, p <0.001) and a smaller maximal intimal thickness (0.16 +/- 0.09 mm vs. 0.68 +/- 0.31 mm, p <0.001). Unresorbed intramural hemorrhages and adherent mural thrombi were present in the irradiated vessels, which also showed incomplete re-endothelialization. The irradiated hearts demonstrated diffuse interstitial and perivascular inflammation and fibrosis. CONCLUSIONS EBRT at 21 Gy to the entire heart significantly inhibited neointima formation in stented pig coronary arteries but also resulted in incomplete re-endothelialization, myocardial inflammation, and fibrosis. Improvements in localization and delivery techniques are required to allow clinical implementation of this technique.

GPIIbIIIa inhibitors as adjunctive therapy in acute myocardial infarction

Thrombolytic therapy has proved useful in the treatment of acute myocardial infarction but is frequently associated with limited vessel reperfusion and early reocclusion. Local platelet aggregation and activation play a role in these pathological processes, explaining the benefit of aspirin, a weak antiplatelet agent. Recent interest has turned to GPIIbIIIa antagonists, a class of potent inhibitors of platelet aggregation. Their concomitant use with fibrinolytics, in rescue and primary angioplasty for acute myocardial infarction treatment is explored. Efficacy and safety issues are addressed and the potential pivotal role of these agents in the treatment of acute myocardial infarction is discussed.

The restenosis story: Is intracoronary radiation therapy the solution?

Restenosis remains a major limitation of percutaneous transluminal coronary intervention. Stenting made an important contribution in restenosis reduction, but in-stent restenosis is becoming a growing problem. Although radiation therapy was traditionally used to kill relatively fast-growing tumor cells, it has also been used to clinically treat benign but problematic hyperplastic conditions. In addition, in vitro studies have shown that radiation inhibits serum-stimulated growth of arterial smooth muscle cells and fibroblasts, and decreases collagen synthesis by fibroblasts. The effects of radiation on neointimal inhibition after vascular injury were investigated in animal models using various catheter- and stent-based endovascular approaches (brachytherapy) as well as externally delivered x-irradiation. These studies have consistently shown that ionizing radiation delivered by the endoluminal approach results in remarkable suppression of neointima formation. However, animal studies also demonstrate altered vessel wall healing with increased thrombogenicity. The catheter-based approach with gamma- or beta-emitters showed feasibility and appears promising in early human clinical trials, whereas the strategy of using radiation stents is more problematic in the clinical arena. A number of randomized multicenter trials have been initiated and the results are eagerly awaited. More work needs to be done to define the optimal dosage, and to study the short- and long-term vascular biologic effects of brachytherapy. Additionally, if this form of therapy proves efficacious in the large, randomized, clinical trials, its cost-effectiveness will then need to be established. This review touches on some of the basic concepts involved in using the strategy of endovascular irradiation therapy for restenosis prevention after percutaneous coronary intervention and reviews the evidence of clinical efficacy and safety.

Tirofiban in Coronary Intervention—The RESTORE Trial

Atheromatous plaque rupture, platelet activation with consequent thrombus formation and impairment of coronary arterial blood flow is a common theme in acute coronary syndromes (ACS) (1–4). The importance of antiplatelet therapy in the treatment of acute myocardial infarction (MI) was amply demonstrated in the second International Study of Infarct Survival (ISIS-2). At present, aspirin and to a lesser extent heparin, are used in nearly all patients with ACS. In spite of the improvements in prognosis that these treatments have brought, the incidence of adverse events in patients with ACS is still significant (5–8) and demonstrates the need for further improvement. There has been a rapid expansion of data from large multicenter trials on the use of IIb/IIIa receptor antagonists in the full spectrum of ACS. This is in part related to a recognition of the limitations of other antiplatelet agents, a better understanding of the mechanisms of platelet activation and aggregation. The realization that the GPIIb/IIIa platelet receptor is the final common pathway through which all the platelet agonists exhibit their effects on platelet aggregation make this receptor a promising target for antiplatelet therapy (9).