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.

Intracoronary beta-radiation exacerbates long-term neointima formation in balloon-injured pig coronary arteries.

BACKGROUND: Long-term biological effects of ionizing radiation on coronary arteries remain poorly defined. We examined late arterial responses 6 months after balloon angioplasty and beta-radiation in normal pig coronary arteries. METHODS AND RESULTS: Coronary arteries of 25 adult pigs were randomized to receive 20 Gy (n=8) or 30 Gy (n=9) of (186)Re beta-radiation or sham radiation (n=8) immediately after balloon angioplasty. Aspirin was given daily during follow-up. The study vessels were analyzed histopathologically at 6 months. beta-Radiation decreased lumen area (20 Gy, 1.55+/-0.99 mm(2); 30 Gy, 1.03+/-0.82 mm(2); and 0 Gy, 2.05+/-0.80 mm(2); P<0.05) but not overall vessel area. The neointimal area was significantly larger within the injured segment with beta-radiation (20 Gy, 1.92+/-1.23 mm(2); 30 Gy, 1.51+/-0.97 mm(2); and 0 Gy, 0.89+/-0.31 mm(2); 0 Gy versus 20 Gy, P<0.05), and a significant increase of edge stenosis was observed with beta-radiation. Irradiated vessels also had larger thrombus areas within the neointima (30 Gy, 0.24+/-0.61 mm(2); 20 Gy, 0.98+/-1.57 mm2; and 0 Gy, 0.00+/-0.01 mm(2); P<0.05) and larger adventitial areas (20 Gy, 2.25+/-0.75 mm(2); 30 Gy, 2.38+/-0.98 mm(2); and 0 Gy, 1.23+/-0.29 mm(2); 0 Gy versus 20 or 30 Gy, P<0.05) that showed substantial collagen accumulation. CONCLUSIONS: Intracoronary beta-radiation did not inhibit neointima formation in balloon-injured normal pig coronary arteries 6 months after the interventional procedure. Unresorbed thrombus contributed to, but was not the sole component of, augmented neointima formation. Irradiated vessels demonstrated more adventitial thickening and fibrosis. These observations may have relevance for long-term clinical outcomes after intracoronary beta-radiation.

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.

Expression of the plasminogen activator system in the human vascular wall.

In this paper we describe the expression of the tissue plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) and the uPA receptor (uPAR), in normal and atheromatous human vascular tissue obtained at coronary and peripheral vascular surgery. tPA, uPA, PAI-1 and uPAR antigens were localised by immunohistochemistry. Vessel homogenates were used to quantitate tPA, uPA and PAI-1 antigens as well as uPA and PAI-1 activities using immunoassay and immunoactivity assays, respectively. Quantitative reverse transcription polymerase chain reaction assays (PAI-1 and uPA) were developed and used to quantify PAI-1 and uPA mRNA. In-situ hybridisation (tPA, uPA and PAI-1) was used to localise mRNA. In normal saphenous vein or internal mammary artery, expression of tPA, uPA and PAI expression is associated with endothelium and with intimal or medial smooth muscle cells, but expression is at a low level. uPAR protein was seen on the endothelium of normal saphenous vein or internal mammary artery but absent on the smooth muscle cells. In complex atheroma tPA, uPA, PAI and uPAR proteins were associated with the endothelium, groups of smooth muscle cells (in the intima and around vascular channels, but not with the media), infiltrating mononuclear cells, and also with acellular areas. PAI-1, tPA and uPA mRNA were demonstrated in atheroma in endothelial cells and smooth muscle cells, as well as in areas rich in macrophages. In stenosing saphenous vein grafts there was strikingly increased tPA and uPA (but not PAI-1) expression in neointimal smooth muscle cells and migrating SMC at the intima/media border. A major difference between complex atheroma and either normal vessel or saphenous vein grafts was greatly increased expression of PAI-1 mRNA associated with smooth muscle cells (SMC) in the former. In spite of the greatly increased PAI-1 mRNA expression in atheromatous lesions, the immunoactivity assay showed PAI-1 activity to be low compared to normal internal mammary artery. Our findings would be compatible with previous reports implicating the plasminogen activator/inhibitor system in the initiation and control of matrix remodelling during normal and pathological vessel growth and repair, but also emphasize the complexity of this process in human vessels.

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.

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.

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 pig's 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.

Predicting mitral regurgitation following percutaneous mitral valvotomy with the Inoue balloon: comparison of two echocardiographic scoring systems.

BACKGROUND: Percutaneous balloon mitral valvotomy (PBMV) has become the procedure of choice for many patients with symptomatic mitral stenosis. However, the development of significant mitral regurgitation (MR) remains an infrequent but very important complication. The echocardiographic scoring system described by Padial et al. has been successful in predicting the development of severe MR following PBMV using the double balloon technique. HYPOTHESIS: We aimed to assess the applicability of this new scoring system in predicting a significant increase in MR with the Inoue balloon and to compare it with the established Wilkins score. METHODS: The echocardiograms of 23 patients who had undergone PBMV for symptomatic mitral stenosis were analyzed retrospectively using both scoring systems, and the severity of MR was determined from pre- and postprocedural studies. RESULTS: Post PBMV, significant MR occurred in four patients (17%) while severe MR occurred in two patients (9%). Padial scores [mean (standard error of the mean)] in the group of patients with and without significant MR were [9.1 (0.8)] and [6.0 (0.3)], respectively (p = 0.002), while the Wilkins score was [7.5 (1.0)] and [6.4 (0.5)], respectively (p = 0.3). Using 8 as a cutoff point, the sensitivity and specificity of the newer scoring system was 83 and 100%, respectively, while the sensitivity and specificity of the Wilkins score was 50 and 50%, respectively. The positive predictive value > 8 was 100% (4/4) for the Padial and 25% (1/4) for the Wilkins system. Accordingly, the negative predictive value < 8 was 89% (17/19) for the Padial and 73% (14/19) for the Wilkins system. CONCLUSION: The newer scoring system is better at reliably identifying patients at risk of developing significant MR from PBMV with the Inoue balloon.

Comparison of Iotrolan 320 and Iohexol 350 in cardiac angiography: a randomised double-blind clinical study.

OBJECTIVE: A double-blind randomised study was conducted in two British centres, to evaluate the safety, tolerance and efficacy of the new dimeric non-ionic contrast medium Iotrolan 320 in comparison with the monomeric non-ionic compound Iohexol 350 in coronary angiography. METHODS AND MATERIAL: 120 patients were randomised to receive either Iotrolan at a concentration of 320 mgI/ml or Iohexol at a concentration of 350 mgI/ml, during selective coronary angiography and left ventriculography. The variables measured were: maximum increase of the left ventricular end-diastolic pressure up to 6 min after ventriculography, haemodynamic and electrocardiographic variables, arrhythmogenicity, clinical laboratory parameters, tolerance, adverse events and efficacy. RESULTS: Iotrolan resulted in a smaller change of left ventricular end-diastolic pressure compared to Iohexol, but the difference was not statistically significant. Transient changes in left ventricular systolic pressure, intra-arterial systolic pressure, intra-arterial diastolic pressure, and in electrocardiographic parameters, occurred after the injections, but they were not clinically significant. Changes in the clinical laboratory markers from baseline values were comparable between the two groups and confirmed good renal and hepatic tolerance. During the left ventriculogram, Iotrolan resulted in less symptoms compared to Iohexol (P = 0.002). Adverse events, which were mild or moderate in most cases, were observed with no statistical difference between the two agents. The contrast quality of both agents was good with no statistical difference. CONCLUSION: This study did not show a significant difference between Iotrolan 320 and Iohexol 350 with regard to cardiovascular safety or patient tolerance, except for a minor difference in the intensity of heat/warmth sensation.