Effect of clopidogrel on neointimal formation and inflammation in balloon-denuded and radiated hypercholesterolemic rabbit iliac arteries.

BACKGROUND: Platelet-derived peptide and nonpeptide growth factors are known to play pivotal roles in neointimal proliferation. Along with its antiplatelet activity of reducing P-selectin and hs-CRP, clopidogrel has also been shown to have anti-inflammatory properties. The aim of this study is to find out by modulating inflammation if clopidogrel can affect neointima formation in balloon-denuded iliac arteries of hypercholesterolemic rabbits. METHODS AND RESULTS: Rabbits were fed with 1% cholesterol diet with (n = 20) or without (n = 20) clopidogrel (10 mg/kg body weight) for 7 days followed by balloon-denudation of endothelial layer in both the iliac arteries and continued on 0.15% cholesterol diet with or without clopidogrel. Four weeks later, the denuded area in both iliac arteries was radiated (n = 11, cholesterol-only group; n = 9, clopidogrel group) or sham treated (n = 10 from each group). Four weeks after radiation, animals were sacrificed and arterial segments were processed for morphometry. In the sham-treated clopidogrel group, neointimal area, percent stenosis, and macrophage score were 39% (P = 0.01), 32% (P = 0.02), and 50% (P = 0.02) smaller, respectively, when compared to the cholesterol-only group (0.48 +/- 0.18, 32.42 +/- 13.04, and 1.5 +/- 0.83). There were no differences in the radiated group (0.89 +/- 0.32, 50.34 +/- 13.00, and 1.88 +/- 1.27 vs. 0.93 +/- 0.38, 59.41 +/- 11.41, and 2.00 +/- 0.74, respectively). CONCLUSION: This study demonstrates that clopidogrel reduces inflammation and neointimal formation in balloon-denuded iliac arteries of hypercholesterolemic rabbits.

32P liquid sources--comparison of the effectiveness of postangioplasty versus poststenting intravascular brachytherapy in hypercholesterolemic rabbits. Adjunctly implanted titanium stent does not attenuate the effect of endovascular irradiation.

PURPOSE: Endovascular application of ionizing radiation is a promising but still not sufficiently studied means of restenosis prevention. To test the effects of radiation on restenosis, and especially their dependence on whether the angioplasty was followed by stent implantation or not, we performed an in-stent versus no-stent intravascular brachytherapy study in an animal model. Balloon-based, continuous and self-centering, liquid 32P sources seemed the most convenient for the purpose. METHOD: The radial dose distribution around angioplasty balloons filled with solutions of Na(2)H32PO(4) was calibrated by thermoluminescence dosimetry, both in the absence and presence of stents. The animal experiments were performed on rabbits with induced hypercholesterolemia. The balloons containing 32P were introduced into iliac artery immediately after stent implantation or after angioplasty alone. Radiation effects were evaluated postmortem by comparing thickness of various components of the artery wall. RESULTS: In the presence of titanium stents (TTS), irradiation with 16 Gy dose at 1.0 mm from the balloon surface was no less effective in reducing hypertrophy in every active layer of the artery wall than without a stent. CONCLUSION: In the animal model, IVBT basing on P(32) liquid sources was no less effective in the stented arteries than in the nonstented ones.

Prophylactic gamma radiation of unaffected vein grafts failed to prevent vein graft disease in a chronic hypercholesterolemic porcine model.

OBJECTIVE: The value of prophylactic brachytherapy on vein graft disease is unknown. METHODS AND RESULTS: Vein bypass grafts in 23 hypercholesterolemic pigs after ex vivo gamma irradiation of the vein grafts (10, 20, and 40Gy) and 16 control veins were analyzed regarding: (1) expression of platelet-derived growth factor (PDGF-AA and -BB, ELISA); (2) smooth muscle cell (SMC) proliferation/cell death (double-immunohistochemistry Mib-1/TUNEL/SMC alpha-actin); and (3) vessel wall dimensions. Planimetric data on vessel wall dimensions revealed no positive effect of gamma radiation on neointima formation and inner lumen diameter. On the contrary, vein grafts subjected to 40Gy were significantly more likely to be occluded and to have reduced inner lumen and increased neointima formation. Radiation therapy had no effect on PDGF expression and SMC proliferation/cell death. The mean inner lumen diameter decreased as PDGF-AA expression increased. CONCLUSIONS: Prophylactic gamma radiation of unaffected vein grafts failed to prevent vein graft disease in a hypercholesterolemic porcine model. High-dose radiation (40Gy) resulted in more frequent graft occlusion and vein sclerosis.

Samarium-153 for intravascular irradiation therapy with liquid-filled balloons to prevent restenosis: acute and long-term results in a hypercholesterolemic rabbit restenosis model.

BACKGROUND: It has been shown that irradiation with either beta and gamma sources inhibit neointimal formation. Samarium-153 ((153)Sm) is an isotope with 0.8 MeV, subdivided in three different beta energies and 103 keV of gamma energy. This compound has been tested and used in humans for palliation of pain from bone metastases. The aim of the present study was to evaluate the feasibility and efficacy of brachytherapy with (153)Sm-filled balloon to inhibit neointimal formation in rabbits after balloon overstretch injury. METHODS: Nineteen rabbits underwent balloon injury in their iliac arteries. In 12 animals (control), oversized balloons filled with saline solution were inflated up to 5 atm for a period of 5 min. In 7 rabbits, the same procedure was performed but using balloons filled with (153)Sm. In all cases, both iliac arteries were treated. The prescribed radiation dose was 15 Gy at 1 mm depth. After 30 days, the animals were sacrificed and their arterial segments were analyzed. Radiation exposure at the animal chest to the table and at a distance of 1 m from the table was measured. RESULTS: Histopathologic analysis showed a striking reduction in the amount of neointima in the irradiated arteries compared with control vessels (0.36+/-0.21 vs. 1.07+/-0.56 mm(2), P<.01). The dose delivered to the animal chest was 21.5 mR/h, whereas only 1.9 mR/h was measured at the table and virtually no radiation could be detected at a distance of 1 m from the table. CONCLUSIONS: Brachytherapy with (153)Sm was feasible with minimal personnel exposure radiation and effectively inhibited neointimal formation in this experimental model. These results warrant further experimental and clinical investigations.

[Behavior of lipids, other serum parameters and cardiovascular functions in ultraviolet therapy]. / Untersuchungen zum Verhalten von Lipiden, weiteren Serumparametern sowie Kreislauffunktionen unter UV-Einwirkung.

During a period of 3 years, four controlled clinical studies in 34 patients with hypercholesterolaemia and 40 healthy persons--in some cases with stratification of the basic cholesterol levels and matched pair formation--were performed to find out the effects of serial sun-like UV irradiation on various serum parameters and blood circulation functions. The following significant effects were observed. Patients with hypercholesterolaemia: increase of HDL cholesterol after termination of the serial UV irradiation, increase of serum 25(OH)D3 levels, decrease of serum triiodothyronine, decrease of serum lactate; healthy persons: decrease of resting pulse rate, decrease of recovery pulse rate, decrease of systolic blood pressure. All effects were induced by application of suberythematous UV doses, i.e. amounts of UV with a relatively low risk of side effects.

[Is cholesterol lowering following UVA blood irradiation an effect of citrate?]. / Ist die Cholesterolsenkung nach UVA-Blutbestrahlung (UVAB) eine Zitratwirkung?

On 92 patients the effect of the UV irradiation of blood on the blood parameters is studied. In the blood picture a decrease of leucocytes and reticulocytes is observed, in which case the latter is in connection with the decrease of blood and not with the UVA irradiation. In test persons with increased cholesterol level after UVA therapy as well as after a mere citrate infusion (anticoagulancy) during four weeks highly significant decrease of the cholesterol level, above all of the LDL-cholesterol appears. HDL cholesterol and triglycerides are not influenced. The decrease of cholesterol by citrate infusion is discussed and it is referred to possible therapeutic consequences.