Cardiovascular radiation medicine最新文献

Background

The effectiveness of brachytherapy for the treatment of in-stent restenosis (ISR) has been established in a number of large randomized controlled trials. Efficacy of this therapy in general population is less well established.

Methods and materials

We report our experience of 207 patients, 236 coronary lesions, treated with brachytherapy between November 2000 and November 2002. All commercially available brachytherapy devices, as well as one investigational device, were utilized. This cohort was followed over 9 months and clinical outcomes were obtained with subsequent analysis of patient and lesion-specific characteristics.

Results

Average treatment age was 62.5 years; 73% were male and the most frequent presentation was unstable angina (74%). All patients had successful delivery of radiation, with no in-hospital deaths. Novoste BetaCath device was used for 163 (65%) lesions, Cordis Checkmate for 56 (24%) lesions, Interventional Therapies device in 13 (8%) lesions, and Guidant Galileo in 4 lesions (3%). At a mean follow-up of 9.1 months, 78.7% were free of major adverse cardiac event (MACE). Twenty-one patients required repeat PTCA (10.1%), 19 had CABG (9.2%), 3 had MI (1.4%), and there was 1 death (0.5%). Unadjusted MACE rates for each device were 21% for Novoste, 28% for Checkmate, 8% for Interventional Therapies, and 50% for Galileo. Lesion length, minimal lumen diameter, renal failure, diabetes, and smoking did not predict treatment failure; only age was inversely correlated with MACE (P=.002).

Conclusion

When applied across a spectrum of patients, lesions, and devices, brachytherapy retains its effectiveness with outcomes similar to those reported in randomized clinical trials.

Bone marrow stem cells have been shown to differentiate into various phenotypes including cardiomyocytes, vascular endothelial cells and smooth muscle. Bone marrow stem cells are mobilized and home in to areas of injured myocardium where they are involved in tissue repair. In addition, bone marrow secretes multiple growth factors, which are essential for angiogenesis and arteriogenesis. In some patients, these processes are not enough to avert clinical symptoms of ischemic disease. Therefore, in vivo administration of an adequate number of stem cells would be a significant therapeutic advance. Unfractionated bone marrow derived mononuclear stem cells, which contain both hematopoietic and nonhematopoietic cells may be more appropriate for cell therapy. Studies in animal models suggest that implantation of different types of stem cells improve angiogenesis and arteriogenesis, tissue perfusion as well as left ventricular function. Several unanswered questions remain. For example, the optimal delivery approach, dosage and timing of the administration of cell therapy as well as durability of improvements need to be studied. Early clinical studies have demonstrated safety and feasibility of various cell therapies in ischemic disease. Randomized, double blind and placebo-controlled clinical trials need to be completed to determine the effectiveness of stem cell.

Purpose: This experiment was designed to assess the feasibility of radio frequency energy delivered by a prototype radio frequency generator inductive heating device (REVAX) positioned external to the body, for transient heating of stents after arterial implant. Methods and Materials: Twenty-one New Zealand White rabbits underwent stenting of their infrarenal aorta. Nine rabbits were stented and immediately placed in the REVAX for external stent heating with internal temperature probes in place. Twelve rabbits were stented and 3 days later either heated or placed in the generator as a sham for 20 min. The animals were terminated 28 days later. Results: The REVAX was able to heat the aortic stents in a controlled fashion; in Phase II experiments, the stent temperature was raised to 42 °C for 20 min. In Phase I mild necrosis was noted at the stent struts. In Phase II, necrosis and mineralization of the media was seen at the stent struts, and evidence of neointimal suppression was observed. Conclusion: This study demonstrated that external heating of stents in a blood vessel in a live animal via radio frequency energy is feasible. Further studies will be needed to assess whether any specific heating regimen might inhibit fibrocellular neointimal hyperplasia.

Hypothesis

The antisense phosphorodiamidate morpholino oligomer (PMO), AVI-4126, has been effective in reducing neointimal formation in animal models following delivery by pluronic gels, local delivery catheters and coated stents. Greater flexibility of repeated-dosage regimens and reduced procedure complexity may be provided by systemic injection of AVI-4126 bound to perfluorobutane gas microbubble carriers. The purpose of this study was to investigate the effects of perfluorocarbon gas microbubble carrier (PGMC)-based systemic delivery of AVI-4126 on expression of the c-myc in vascular tissue and restenosis after stent implantation.

Methods

Seven pigs underwent stent implantation (3 stents/animal). Five pigs received IV injection of PGMC and 2 mg of AVI-4126 (AVI BioPharma). Two served as control. Four hours postprocedure, 3 pigs were sacrificed and stented segments analyzed by high-performance liquid chromatography (HPLC) and Western blot. In chronic experiments, 4 pigs (12 stent sites) were sacrificed at 28 days.

Results

HPLC analysis of plasma samples of treated animals showed minimal presence of AVI-4126. HPLC of the treated arteries demonstrated easily detected concentrations of AVI-4126. Western blot analysis of the stented vessels demonstrated modest inhibition of c-myc. Morphometry showed that the neointimal area was significantly reduced in the AVI-4126/PGMC group compared with control (2.63±1.99 vs. 4.77±.1.71 mm², respectively, P<.05).

Conclusion

In the porcine coronary stent model, systemic targeted delivery of AVI-4126 using PGMC carrier significantly inhibited neointimal formation.

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 Na₂H³²PO₄ 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 P³² liquid sources was no less effective in the stented arteries than in the nonstented ones.

Purpose

Intramural delivery of a P-32 radiolabeled oligonucleotide (ODN) using an infiltrating catheter has been proposed recently to potentially reduce restenosis in coronary arteries and tested on a limited number of human subjects. However, because of the low efficiency of drug retention (∼2–5%) after the initial washout period from this technique, the dose levels to nontarget organs may be significant and thus may require a detailed investigation. The radiation dose distributions resulting from this technique is investigated using the MIRD formalism and Monte Carlo calculations.

Materials and Methods

The total activity of the P-32 ODN to be injected during treatment to deliver a therapeutic dose of ∼30 Gy to the arterial wall is estimated taking into account the drug delivery efficacy of the infiltrating device (∼2–5% typical). Using pharmacokinetic data for P-32 ODN, we estimate the dose to healthy organs resulting from the systemic fraction that is released into the circulatory system during washout (>95% typical). Variabilities in the biological parameters are also identified as important sources of error in the prescribed dose.

Results

A limitation to this technique is the poor accuracy in delivering the prescribed dose due to variability in the amount of drug delivered. Dose to organs is also an important limitation. For example, our calculation indicate that ∼37 MBq (1 mCi) of P-32 labeled ODN are needed to deliver 30 Gy to the arterial wall assuming a delivery efficiency of 2–5% and a 24-h residence time. This may result in doses of ∼1 Gy to the spleen and 0.2–0.4 Gy to the liver, kidneys and lungs (95% confidence interval).

Conclusions

This novel therapy suffers from serious limitations. It is doubtful that a therapeutic dose can be delivered accurately, safely and effectively to the arterial wall because of the poor delivery efficacy and extreme variability found in drug delivery experiments. Also, dose levels to healthy organs appears to be too high to recommend the use of this technique in human experiments.

Introduction

Initial events following vascular interventions include activation of platelets and coagulation cascade. Activated platelets release several vasoactive mediators including serotonin. Activation of coagulation cascade results in conversion of inactive zymogens such as factor X to its active form (factor Xa). So this study designed to examine the effect of factor Xa on rabbit vascular smooth muscle cell (VSMC) proliferation and its interaction with serotonin.

Methods

Growth-arrested VSMCs were incubated in a serum-free medium with different concentrations of factor Xa with or without serotonin. VSMC proliferation was examined by increase in incorporation of [³H]thymidine into DNA and by increase in cell number.

Results

Factor Xa and serotonin stimulated DNA synthesis in a dose-dependent manner. Factor Xa had a maximal effect at 100 nM (1180±110%) and serotonin at 50 μM (345±21%). When added together, at nonmitogenic concentrations, factor Xa (0.1 nM) and serotonin (1 μM) synergistically induced DNA synthesis (312±12%). These increases in DNA synthesis were paralleled by an increase in cell number. Serine protease inhibitors, active site blockers and platelet-derived growth factor receptor tyrosine kinase inhibitor blocked the mitogenic effect of factor Xa and its interaction with serotonin. Similarly, serotonin type 2 receptor inhibitor and Gi-protein-coupled receptor inhibitor inhibited the mitogenic effect of serotonin and its interaction with factor Xa. When used in combination, they blocked the interaction between factor Xa and serotonin.

Conclusion

Coagulation factor Xa and serotonin are mitogenic to VSMCs and also function as amplification factors to each other, suggesting that inhibition of neointimal proliferation after vascular injury may require the combined use of multiple growth factor inhibitors to simultaneously block several critical cellular activation pathways.

Vascular brachytherapy has been established as the standard of care for the treatment of in-stent restenosis (ISR). Both beta and gamma emitters are currently in use for the prevention of ISR recurrence. The use of beta sources for vascular application is attractive from both the radiation exposure and safety points of view, and a wide variety of beta sources are available for this application. This review is intended to summarize the clinical trials utilizing beta emitter systems for the treatment of ISR and de novo lesions and their subsequent results.