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Background: The arterial placement of (32)P beta-particle-emitting stents in various experimental animal models results in discordant effects on neointimal formation. We studied the vascular effects of beta-particle-emitting stents in normal canine coronary arteries because compared with pigs and rabbits, the canine model may more closely mimic the vascular response of humans., Methods and Results: Thirty stents (control nonradioactive, n=10; low-activity (32)P, 3.5 to 6.0 microCi, n=11; high-activity (32)P, 6.5 to 14.4 microCi, n=8) were implanted in normal canine coronary arteries through the use of a single balloon inflation at nominal pressure. Histological analysis after 15 weeks included the measurement of neointimal and adventitial area and thickness. Neointimal fibrin area was measured with the use of computer-assisted color segmentation on Movat pentachrome sections. Luminal stenosis was significantly increased in (32)P stents compared with control stents (44.6+/-16.8% versus 32.7+/-10.8%; P=0.05) and was highest in the high-activity group (45.5+/-24.3%). No evidence of an "edge effect" was seen in adjacent, nonstented coronary segments. All (32)P stents showed incomplete vascular healing as indicated by a dose-dependent increase in fibrin area with increasing stent activity. Arterial radiation resulted in a decrease in adventitial size, which was maximal for high-activity (32)P stents, indicating an inhibitory effect on the adventitial response to injury., Conclusions: (32)P beta-particle-emitting stents have adverse vascular effects at 15 weeks in the canine normal coronary artery model. Vascular brachytherapy with this device causes increased neointimal formation and prominent, dose-dependent lack of healing.

Iridium-192 (gamma)-radiation is effective in preventing recurrent in-stent restenosis by reducing neointimal hyperplasia as illustrated by intravascular ultrasound study and plaque area-length plot. This analytic technique will further our understanding of vessel behavior to radiant energy source both inside and outside the stented coronary artery segments.

Purpose: To determine the prevalence and severity of asymptomatic carotid arterial disease in young patients following neck radiation therapy for Hodgkin lymphoma and to compare the prevalence of carotid arterial disease following radiation therapy alone with that following radiation therapy and chemotherapy., Materials and Methods: Forty-two survivors of childhood or early adult Hodgkin lymphoma aged 18-37 years who had undergone radiation therapy more than 5 years earlier underwent carotid arterial ultrasonography. Common carotid intima-media thickness was measured; carotid vessels were assessed for intima-media abnormalities. Results were compared with those from 33 control subjects., Results: Patients had a significantly greater number of abnormal scans than did control subjects (11 [26%] vs one [3%]; P < .01). Ten patients (24%) had intima-media abnormalities that did not cause significant stenosis; one patient had diffuse bilateral intima-media thickening (mean, 1.99 mm) with greater than 70% stenosis of both common carotid arteries. Intima-media thickness was significantly greater in patients (0.51 mm) than in control subjects (0.43 mm; P < .005). The number of abnormalities in patients with radiation therapy plus chemotherapy (six [19%] of 31 patients) did not differ significantly from the number in patients with only radiation therapy (five [45%] of 11 patients; P = .12); there was no significant difference between median intima-media thicknesses (0.50 mm vs 0.51 mm, P > .2)., Conclusion: Asymptomatic carotid arterial disease occurs frequently in young patients following neck radiation therapy for Hodgkin lymphoma. No difference in prevalence was shown between only radiation therapy and radiation therapy plus chemotherapy.

To identify luminal dimension changes occurring within the stent alone and within the stent + margin segment, we reviewed the quantitative angiographic results obtained from the Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS) trial, a prospective randomized trial assessing the effect of iridium-192 (Ir-192) on the prevention of stent restenosis. Fifty-five patients were randomly assigned to receive Ir-192 or placebo sources after successful intervention. Procedural and 6-month follow-up cineangiograms were quantitatively reviewed in 52 patients to identify changes within the stent and the stent + margin segment. The percent diameter stenosis was lower within the stent than within the stent + margin segment after the procedure (6 +/- 22% vs 21+/- 15%, p <0.0001) and at follow-up (28 +/- 29% vs 42 +/- 21%, p <0.0001). As a result, a lower restenosis rate was found within the stent than within the stent + margin (25% vs 37%, p <0.0001); isolated stent margin restenosis occurred in 11.5% of lesions. Treatment with Ir-192 reduced restenosis within the stent (8% vs 39%; p = 0.010) and within the stent + margin segment (17% vs 54%; p = 0.010); the reduction in restenosis at the margin only (8.3% vs 14.3%, p = 0.503) was not significant. The lowest relative risk for restenosis resulting from Ir-192 occurred within the stent (0.21; 95% confidence interval [CI] 0.05 to 0.86) compared with the stent + margin segment (0.31; 95% CI 0.12 to 0.81) or the stent margin (0.58; 95% CI 0.12 to 2.91). In the SCRIPPS trial, 32% of restenosis occurred at the stent margins. Treatment with Ir-192 reduced restenosis primarily within the stent rather than the margin. Whether extending the treatment length to fully include the stent margins will further reduce restenosis requires further study.

A coronary stent was made radioactive by implantation of 133Xe ions for the purpose of suppressing the renarrowing of the part of blood vessel in which the stent is implanted. Electrons of relatively low energies emitted in the decay of 133Xe may give an antiproliferative effect of ionizing radiation to the intimal cells within a limited range of 1 mm. A 133Xe+ beam accelerated at 40 or 60 keV was directed to several stainless steel stents mounted on a target-holder table that could revolve and move up and down to distribute the 133Xe+ ions within a stent as well as among the stents. The radioactive stents produced contained up to 100 kBq of 133Xe and were implanted into the abdominal aortas of rabbits. Neointimal thickening was analyzed by histomorphometry for samples taken 4 weeks after stent implantation. The results indicate that the radioactive stents have a potential to suppress neointimal hyperplasia in rabbits.

Objectives: We sought to examine the effects of high volume external beam radiation (EBR) after stent implantation on neointimal hyperplasia, smooth muscle cell (SMC) proliferation, presence of inflammatory cells and expression of extracellular matrix (ECM)., Background: Endovascular irradiation has been shown to reduce restenosis rates after angioplasty in preliminary trials, but conflicting results have been reported for the effects of external beam irradiation., Methods: Forty-three Palmaz-Schatz stents were implanted into iliac arteries of New Zealand White rabbits. The arteries were externally irradiated after stent implantation with a single dose of 8 Gy (at day 3) or 16 Gy in two fractions (8 Gy at days 3 and 4) by means of a linear accelerator. In the control rabbits, no radiation was applied after stent implantation. Smooth muscle cells, macrophages and ECM were studied by immunohistochemistry at one and 12 weeks after stent implantation. Collagen type I and biglycan messenger ribonucleic acid (mRNA) levels were assessed by Northern blot analysis at one week. Neointimal cell densities and arterial lumen stenosis were measured by histomorphometry at 12 weeks., Results: At 1 week, SMC proliferation at the site of stent implantation was increased after EBR with 8 and 16 Gy (26 +/- 5%, 32 +/- 3% vs. 17 +/- 8%; p < 0.01, 16 Gy vs. control). External beam radiation with 8 and 16 Gy augmented SMC proliferation proximal and distal to the angioplasty site (11 +/- 3%, 14 +/- 3 vs. 6 +/- 1%; p < 0.01, 16 Gy vs. control). Collagen type I and biglycan mRNA levels were elevated in stented arteries after EBR with 16 Gy. At 12 weeks, a marked decrease in neointimal cell density (248 +/- 97 vs. 498 +/- 117 SMCs/0.1 mm2 neointima; p < 0.005 vs. control) was noted after EBR with 16 Gy. Irradiation with 8 and 16 Gy increased arterial lumen stenosis compared with nonirradiated control rabbits (45 +/- 7%, 55 +/- 9% vs. 33 +/- 7%; p < 0.05, 8 Gy and p < 0.001, 16 Gy vs. control)., Conclusions: High volume external beam radiation at doses of 8 or 16 Gy causes restenosis by augmenting proliferative activity at and adjacent to the site of stent implantation, and by dose-dependent up-regulation of extracellular matrix expression. The study suggests that excessive matrix accumulation is an important determinant of failure of radiation therapy to prevent restenosis.

Purpose: To evaluate the ability of 32phosphorus intraluminal irradiation to reduce pseudointimal hyperplasia in a transjugular intrahepatic portosystemic shunt (TIPS)., Materials and Methods: TIPS were successfully placed in 11 swine with normal portal pressures. Six animals received 15.2 Gy intraluminal irradiation to the hepatic parenchyma and venous outflow tract at the time of TIPS placement with use of a NA32P-filled balloon angioplasty catheter. Five control animals underwent TIPS and balloon angioplasty with saline. All animals were followed up for 28 days, at which time percutaneous portography was performed, the animals were killed, and the tissue around the TIPS stent was processed for histologic analysis. Maximum pseudointimal hyperplasia as a percentage of estimated TIPS diameter was calculated for each animal., Results: At the time of euthanasia, all five control TIPS and all but one irradiated TIPS were occluded. Histologic analysis demonstrated considerable variability in the degree of pseudointimal hyperplasia within each TIPS and between animals. No statistically significant difference was found in the maximum pseudointimal hyperplasia, measured as a percentage of stent radius, between control (80.2%+/-17.4%) and irradiated animals (69.2%+/-25.2%)., Conclusions: Irradiation of TIPS with 15.2 Gy 32P delivered at the time of TIPS placement did not significantly improve TIPS patency or reduce the degree of pseudointimal hyperplasia in swine with normal portal pressures.

Purpose: Endovascular irradiation with either a gamma or a beta source has shown to reduce neointimal proliferation. However, the effect of external-beam radiation on neointimal hyperplasia is controversial. The objective of this study was to determine the effect of external-beam irradiation with different doses on neointimal hyperplasia in the rat carotid artery injury model., Methods and Materials: Twenty-seven Sprague-Dawley rats underwent endothelial denudation injury by 2F Fogarty balloons on carotid artery. Immediately after the injury, rats were irradiated externally using 6-MeV electrons. Rats were grouped according to the radiation doses, 0 Gy as controls (n = 5), 5 Gy (n = 5), 10 Gy (n = 5), 15 Gy (n = 6), and 20 Gy (n = 6). Then, rats were sacrificed after 2 weeks and the carotid arteries were perfusion-fixed in paraformaldehyde. External elastic lamina (EEL) area, lumen area, maximal intimal thickness (MIT), and intimal area (IA) of the injured segments were measured on the basis of histomorphometry., Results: In EEL and lumen area, there was no statistically significant difference between the irradiated groups and the controls. In MIT and IA, low-dose radiation (5 Gy and 10 Gy) did not induce any significant reduction. High-dose radiation (15 Gy and 20 Gy), however, reduced MIT and IA significantly., Conclusion: External electron beam reduced the intimal area, and the inhibition of neointimal proliferation was dependent upon radiation doses. This study suggests that the minimal effective dose for the inhibition of neointimal hyperplasia following denudation injury in the rat carotid model is between 10 Gy and 15 Gy.

Purpose: Endovascular radiation has reduced postangioplasty restenosis in preclinical and early clinical studies. External radiation treatment may have advantages over endovascular therapy. We examined vascular and perivascular tissue responses to endovascular and external irradiation in pig coronary arteries., Methods and Materials: Ninety-one animals received endovascular or external radiation following balloon injury and were sacrificed at 14, 30, or 180 days. Injured segments of coronary vessels including perivascular and myocardial tissues were evaluated with histochemistry., Results: Endovascular radiation was associated with delayed arterial wound healing as late as 6 months, evidenced by paucity of smooth muscle alpha-actin in neointimal cells compared to control. External treatment was associated with increased collagen in neointima and adventitia, and focal interstitial necrosis in adjacent myocardium., Conclusions: These investigations showed whole-heart 14 Gy external radiation treatment following coronary injury exacerbated certain aspects of arterial healing. In addition focal myocardial necrosis and fibrosis was observed following external but not endovascular irradiation. Endovascular radiation has some advantages over external irradiation; however the persistence of a synthetic smooth muscle cell phenotype in the neointima at 6 months suggests ionizing radiation in general may have profound effects on vessel architecture over the long term.

Purpose: Brachytherapy has been shown to inhibit neointima formation after vascular balloon injury. This study was done to test the feasibility of low dose external radiation for prevention of restenosis in a non-stented balloon injury model., Materials and Methods: Twelve red Duroc swine underwent balloon overdilation injury of both iliac arteries. Twelve Gy was delivered to one side using a Theratron T-1000 Cobalt unit with the other side used as the control. Twelve weeks post injury arteriograms were performed. The animals were then sacrificed and iliac arteries explanted. Histomorphometric analysis of arterial cross sections was performed., Results: Neointima formation was observed in all arteries. Unilateral thrombosis was noted in two animals. The mean neointimal thickness in the radiated and control arteries was 0.63 +/- 0.17 mm and 0.72 +/- 0.31 mm, respectively. The differences in minimal luminal diameter and the neointimal thickness between the two groups were not statistically significant. Complications included superficial hair loss in the radiation port in 4 animals, and 2 deaths prior to the completion date (1 of hemorrhagic enteritis possibly related to the radiation, and 1 of iliac rupture)., Conclusion: External radiation at this low dose is not effective in preventing vascular restenosis following balloon injury in this animal model.

Background: Endovascular radiation is emerging as a potential solution for the prevention and treatment of restenosis. Its effects on the morphology of unstented vessels cannot be determined by angiography and therefore require the use of intravascular ultrasound., Methods and Results: Through a 5F noncentered catheter for delivery of a 90Sr/Y source train, 12, 14, or 16 Gy at 2 mm was delivered to native coronary arteries after successful balloon angioplasty in 30 patients. Four patients required stent deployment in the first week. Quantitative coronary angiography and IVUS were performed during the initial procedure and at 6-month follow-up. Binary angiographic restenosis was present in 3 of 30 patients, with target lesion and vessel revascularization performed in 3 and 5 patients, respectively. Angiographic late loss was -0.02+/-0.60 mm, with a -0.09+/-0.46 loss index. IVUS demonstrated no significant reduction in lumen area (from 5.69+/-1.72 mm2 after treatment to 6. 04+/-2.63 mm2 at follow-up), with no significant change in external elastic membrane area (13.71+/-4.54 to 14.22+/-4.71 mm2) over the 6-month follow-up. Wall area was 8.01+/-3.85 mm2 after radiation therapy and 8.19+/-3.44 mm2 at follow-up (P=NS). No significant differences were noted between the different dose groups., Conclusions: beta-Radiation therapy resulted in a low restenosis rate with negligible late loss by angiography. By IVUS, beta-radiation was shown to inhibit neointima formation, with no reduction of total vessel area at 6-month follow-up.

Background: Although endovascular radiotherapy inhibits neointimal hyperplasia, the exact cellular alterations induced by beta irradiation remain to be elucidated., Methods and Results: We investigated in vitro the ability of 32P-labeled oligonucleotides to alter (1) proliferation of human and porcine vascular smooth muscle cells (VSMCs) and human coronary artery endothelial cells (ECs), (2) cell cycle progression, (3) cell viability and apoptosis, (4) cell migration, and (5) cell phenotype and morphological features. beta radiation significantly reduced proliferation of VSMCs (ED50 1.10 Gy) and ECs (ED50 2.15 Gy) in a dose-dependent manner. Exposure to beta emission interfered with cell cycle progression, with induction of G0/G1 arrest in VSMCs, without evidence of cell viability alteration, apoptosis, or ultrastructural changes. This strategy also proved to efficiently inhibit VSMC migration by 80% and induce contractile phenotype appearance, as shown by the predominance of alpha-actin immunostaining in beta-irradiated cells compared with control cells., Conclusions: 32P-labeled oligonucleotide was highly effective in inhibiting proliferation of both VSMCs and ECs in a dose-dependent fashion, with ECs showing a higher resistance to these effects. beta irradiation-induced G1 arrest was not associated with cytotoxicity and apoptosis, thus demonstrating a potent cytostatic effect of beta-based therapy. This effect, coupled to that on VSMC migration inhibition and the appearance of a contractile phenotype, reinforced the potential of ionizing radiation to prevent neointima formation after angioplasty.

Purpose: Restenosis after catheter-based revascularization has been demonstrated to be primarily caused by smooth muscle cell proliferation. This study examines the effects of external beam irradiation on neointimal proliferation after external injury to the central artery of the rabbit ear., Methods and Materials: Thirty male New Zealand White rabbits were used in this study. Crush lesions were performed on each ear under general anesthesia and bilateral auricular nerve blockade. A single dose of 1200 cGy (n = 10), 1600 cGy (n = 10), or 2000 cGy (n = 10) gamma radiation was delivered to the left or right central artery of the ear 24 hours after injury; the contralateral central artery served as control. All rabbits were sacrificed after 21 days and the central arteries of both ears were fixed for morphometric measurements., Results: Mean (+/-SD) neointimal area was 0.062 +/- 0.005 mm2 (1200 cGy), 0.022 +/- 0.005 mm2 (1600 cGy), and 0.028 +/- 0.006 mm2 in irradiated arteries compared with 0.081 +/- 0.009 mm2 in the control group. Mean (+/-SD) luminal area was 0.049 +/- 0.004 mm2 (1200 cGy), 0.059 +/- 0.002 mm2 (1600 cGy), and 0.072 +/- 0.006 mm2 (2000 cGy) in irradiated arteries compared with 0.043 +/- 0.008 mm2 in the control group. The differences in neointimal and luminal area between control and irradiated arteries were significant (p < 0.05) for the 1600 and 2000 cGy group only., Conclusion: We conclude that in this model, external beam X-ray irradiation was successful in reducing neointimal proliferation after injury of the central artery of the rabbit ear. Marked reductions in neointimal proliferation were demonstrated in vessels subject to 1600 and 2000 cGy radiation; a less prominent effect was noted for 1200 cGy. Whether this approach can be used successfully to inhibit restenosis in the clinical setting requires further investigation.

Intimal hyperplasia represents a serious complication limiting the long-term benefits of vascular interventions such as balloon angioplasty and stent placement. Although pharmacological interventions have attempted to curtail restenosis, they have not been shown to be effective to date. Radiotherapy is one alternative that has shown promise as an inhibitor of intimal hyperplasia in several animal models. Irradiation causes cell death by producing irreparable damage to DNA. This is believed to be the mechanism of inhibition of VSMC proliferation. Delivery of irradiation can be either intraluminal via an angiographically directed catheter or extraluminal using an external radiation source such as an x-ray device. Intraluminal irradiation has generally utilized either gamma or beta-emitting sources. Both have been effective in producing a dose response, although some studies advocate the use of beta-type irradiation as a safer, more efficient means of delivery. Extraluminal irradiation also has been an effective inhibitor of intimal hyperplasia. Studies suggest that this form of irradiation provides a more even-dose distribution to vessel walls than an intravascular delivery system. The use of radiotherapy has more recently been extended to clinical trials, and initial studies have shown promising results. The success of irradiation must be balanced with its potential complications including radiation-induced arteritis, coronary artery stenosis, and secondary development of malignancy. Although these have been associated with irradiation, the dose used in these cases was often considerably higher than those used in the treatment of intimal hyperplasia. Finally, with the advent of gene therapy, irradiation may provide an additional means of supplementing this new type of therapy through radiation-inducible gene therapy.

The occurrence of coronary artery disease following mediastinal radiation for malignancies has long been debated. However, the development of coronary pathology in young individuals following radiation who lack risk factors for atherosclerosis is highly suggestive of a cause-and-effect relationship. By far the most convincing pathologic changes are adventitial scarring and medial atrophy with severe intimal atherosclerotic disease consisting of necrotic core, fibrous tissue, and calcification. Initial clinical studies in patients with coronary atherosclerosis treated with intraluminal radiation following stenting hold great promise in the treatment and prevention of restenosis. There are little or no data, however, on long-term effects of intra-coronary radiation therapy in man. Therefore, it may be important to study the chronic effects of radiation in animal models in order to predict what is likely to occur in humans. We evaluated the effects of varying doses (0.15-23.0 microCi of 32P) of beta-particle-emitting radioactive stents in pig coronary arteries at 1 and 6 months. At 1 month, there were dose-dependent changes in the morphology of the intima and media. High activities (>3 microCi) caused medial necrosis with fibrin deposition in the media and intima, with interspersed red cells most marked in regions surrounding the stent struts. Only rare smooth muscle cells (SMCs) and inflammatory cells were seen away from the stent struts. In the intermediate (1 microCi) stent activity group, the neointima was expanded by SMCs and a proteoglycan-rich matrix with focal endothelialization of the luminal surface. Neovascular capillaries and extravascular red cells were present adjacent to stent struts. At low activities (<0.5 microCi), the neointima was significantly smaller than control stents and consisted of SMCs and matrix with complete endothelialization of the luminal surface. The neointimal cell density of the media and intima decreased with increasing doses of radiation. In pigs 6 months after radioactive stenting (activities ranging from 0.5-12 microCi 32P), >3.0 microCi radioactive stents induced marked neointimal thickening, with changes similar to atherosclerosis, consisting of necrotic debris containing cholesterol clefts surrounded by macrophage collections, fibrosis, and focal calcification. There was increased adventitial thickening in the radiated vs non-radiated arteries. The intermediate stent activity (1.0 microCi) also showed greater neointimal thickening (vs control stents) and consisted mostly of SMCs in a proteoglycan-rich matrix. At <1.0 microCi, there were minimal differences seen between radiated and control non-radiated stented arteries. The media was unevenly injured in all stent activities and varied from less than to significantly greater than controls. These data suggest that radiation-induced coronary atherosclerosis seen in man is partially simulated in normal porcine coronary arteries 6 months following high-dose beta-particle-emitting radioactive stent placement. There is greater fibrosis and thickness of the adventitia and focal attenuation of the media in man and severe luminal narrowing in pig coronary arteries treated with high doses of radiation. Only long-term clinical follow up and careful autopsy studies will determine if endoluminal or intra-arterial radiation is a viable means of reducing restenosis in man.

Purpose: To evaluate in a pilot study the feasibility and efficacy of endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty (PTA) without stent implantation in a group of patients with a high risk of restenosis., Materials and Methods: Ten patients (six women, four men; mean age, 68 years) with long-segment (mean length, 16 cm; range, 9-22 cm) restenosis underwent PTA followed by endovascular irradiation with high-dose-rate afterloading of an iridium-192 rod. A dose of 12 Gy was targeted to the inner intimal layer of the vessel. Follow-up examinations until 12 months after PTA included measurement of the ankle-brachial index, color duplex ultrasonography (US) with calculation of the peak velocity ratio, and intraarterial angiography when recurrence was suspected., Results: Irradiation was technically feasible in all patients without complications. In six patients, the dilated and irradiated segment remained widely patent at color US, with corresponding excellent hemodynamic and clinical results after 12 months. In four patients, clinical and laboratory findings indicated recurrence and arteriography demonstrated restenosis with a diameter reduction of 60%, 70%, 80%, or 90%., Conclusion: Considering the negative selection of patients with a high risk of restenosis, the results of our pilot study are promising concerning the possibility of reduction of restenosis by means of endovascular brachytherapy after long-segment femoropopliteal PTA without stent implantation. The value of this approach should now be determined definitively in randomized trials.

Endovascular radiation therapy has proved to be safe and effective in preventing restenosis after coronary intervention both in animal studies and in pilot feasibility studies in humans. The rationale for such therapy is that radiation prevents neointimal proliferation and vessel constriction after vascular injury. Two forms of endovascular radiation therapy are available: catheter-based systems and radioactive stenting. However, several practical issues related to this technique still need to be addressed, such as questions about dosimetry, shielding, expense, handling and disposal of radioisotopes, certification for potential users, and-above all-safety and efficacy. In their pivotal studies, investigators and industry need to focus on prioritizing the clinical applications of this form of treatment. The clinical trials must attempt to determine the cost-effectiveness of this therapy as well as its risk versus benefit. For example, brachytherapy may prove to be of great benefit to patients with in-stent restenosis, and favorable results of studies examining this application should expedite the approval of endovascular radiation therapy for clinical use.

In animal studies, beta and gamma radiation delivered via catheter-based systems to sites of angioplasty after arterial injury has decreased the neointimal proliferation that is a part of the restenotic process. Extending radiotherapy to the clinical setting, results of the double-blind, placebo-controlled, randomized Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS) study showed dramatic reductions in the rate of restenosis after coronary stenting when catheter-based gamma radiotherapy (with iridium-192) was used. In the Beta Energy Restenosis Trial (BERT), angiographic, intravascular ultrasound, and clinical outcomes were better than expected with beta brachytherapy. Strontium-90/yttrium-90 seeds were delivered via a unique catheter system in 35 patients who underwent coronary angioplasty. Future trials are being planned to confirm these promising results.

Purpose: The major radiobiological issue in determining the rationale for the use of radiation to inhibit vascular restenosis is the identification of the target cell(s) and/or cytokine(s) responsible for neointimal hyperplasia and vascular remodeling. The central hypothesis of this report is that the macrophage/monocyte and PDGF are key elements in the process of neointimal hyperplasia seen following angioplasty, similar to their role in lesion formation and progression found in atherosclerotic thickening. Specific immunohistochemical and cytochemical stains were applied to a rat carotid model in a temporal series after balloon angioplasty to determine macrophage activity vs. smooth muscle cell proliferation, the latter being classically thought to be the cell responsible for restenosis., Methods and Materials: Neointimal hyperplasia was created in an established rat carotid artery model by a balloon catheter technique. Immediately following injury, treatment groups received irradiation via high dose rate (HDR) brachytherapy, the 192Ir source being placed externally to the vessel. Radiation was delivered to a length of 2 cm of the injured vessel at doses of 5, 10, and 15 Gy, and the animals were sacrificed at various time points following treatment (24 h to 6 months). Serial sections of tissue were stained immunohistochemically with the primary antibodies CD11b, mac-1, anti-PDGF, and alpha-smooth muscle actin., Results: Immediately (24 h) postinjury, there is an apparent migration of macrophages seen in the adventitia; after 1 week, proliferation and migration of macrophages could be seen clearly within all the vessel layers, especially in the intima; by 3 weeks, when there was evidence of neointimal hyperplasia, macrophages could still be seen, mainly in the intima scattered among the smooth muscle cells and myofibroblasts, and to a lesser degree at 6 months. There was corresponding expression of PDGF, whenever and wherever there were zones of activation/neointimal hyperplasia. Alpha-smooth muscle actin staining identified the smooth muscle cells distinct from the macrophages, and these SMCs exhibited activation in the neointimal hyperplasia zones at all later time points. Furthermore, we showed that radiation significantly reduced the macrophage population, while the onset of neointimal hyperplasia was accompanied by a return of the macrophage population., Conclusion: Our results suggest that the activated adventitial macrophage/monocyte are the key cells responsible for initiating the arterial neointimal hyperplasia and vascular remodeling developing postangioplasty as they are in the initiation and perpetuation of atheromatous thickening. Irradiation delivered immediately postinjury is, therefore, highly effective, because the macrophage population is exquisitely radiosensitive.

Background: Ionizing radiation has been shown to reduce vascular lesion formation after balloon overstretch injury of pig coronary arteries. The present series of experiments examines the mechanism by which this occurs., Methods and Results: Balloon injury was performed on porcine coronary arteries, followed immediately by ionizing radiation using either a source train of 90Sr/Y or 192Ir seeds designed to deliver 14 or 28 Gy at a depth of 2 mm from the source. The animals were killed 3, 7, or 14 days after injury. Bromodeoxyuridine was administered 24 hours before euthanasia to label proliferating cells. Cell proliferation was significantly reduced on day 3 in the adventitia and media of the irradiated vessels compared with controls. Two weeks after injury, there were fewer alpha-actin-positive myofibroblasts in the adventitia of the irradiated vessels than in nonirradiated controls, and morphometric analysis indicated that the vessel perimeter of the irradiated vessels was significantly larger than in controls. Together, these results suggest a positive effect of intravascular irradiation on vascular remodeling. Apoptosis was estimated by terminal transferase dUTP-biotin nick-end labeling (TUNEL) 3 and 7 days after injury. TUNEL-labeled cells were found primarily in the adventitia at the medial tear, but no differences were detected between irradiated and control vessels., Conclusions: These studies suggest that intracoronary radiation primarily inhibits the first wave of cell proliferation in the vessel wall and demonstrates a favorable effect on late remodeling by preventing adventitial fibrosis at the injury site.

Purpose: Repeat balloon angioplasty is likely to induce intimal proliferation, which is associated with a higher restenosis rate. This study examined the effect of intracoronary ionizing radiation on restenotic lesions using repeat balloon injury in a normolipemic swine., Methods and Materials: Eight domestic normolipemic pigs underwent overstretch balloon angioplasty with a 3.5 mm balloon in the LAD and LCX, followed by repeat balloon injury at the same sites 4 weeks after the initial injury. At that time a high activity 192Iridium source was introduced immediately after the angioplasty by random assignment to deliver 14 Gy at 2 mm in eight of the injured coronary arteries (LAD and LCX). One month later the animals were killed and the coronary arteries pressure perfusion fixed. Serial sections were stained with H&E and VVG, then evaluated by histopathologic and morphometric techniques. Maximal intimal thickness (MIT), intimal area (IA), and intimal area corrected for the extent of injury (IA/FL) were measured in the irradiated and control arteries and were compared to control arteries with single injuries from previous studies., Results: Repeat balloon injury induced significant additional medial damage, which was associated with marked intimal hyperplasia in a concentric pattern. Intracoronary irradiation significantly decreased the total of neointima area formation (IA 93 + 0.35 mm2 compared to control 1.38 + 0.33 mm2 p < 0.01) and the MIT was also significantly reduced in the irradiated vessels (0.57 + 0.18 mm vs. 0.71 + 0.08 mm, p = 0.05)., Conclusions: Intracoronary irradiation immediately after the second balloon dilatation inhibits the intimal hyperplasia due to that injury. However, there was no effect on the existing neointima from the initial injury.

Purpose: Restenosis after percutaneous transluminal coronary angioplasty represents, in part, a proliferative response of vascular smooth muscle at the site of injury. We have previously shown that high-dose radiation (20 Gy), delivered via an intracoronary 192Ir source, causes focal medial fibrosis and markedly impairs the restenosis process after balloon angioplasty in swine. This study sought to delineate the dose-response characteristics of this effect., Methods and Materials: Forty juvenile swine underwent coronary angiography; a segment of the left coronary artery was chosen as a target for balloon injury. In 30 swine, a 2 cm ribbon of 192Ir was positioned at the target segment and 20, 15, or 10 Gy were delivered to the vessel wall (10 animals/dose). Subsequently, overdilatation balloon angioplasty was performed at the irradiated segment. In 10 control swine, overdilatation balloon angioplasty was performed without previous irradiation. Thirty-eight animals survived until sacrifice at 30 +/- 3 days. Histopathological analysis was performed by a pathologist in a blinded manner. The area of maximal luminal compromise within the target segment was analyzed via computer-assisted planimetry., Results: Neointimal area was decreased by 71.4% at 20 Gy and by 58.3% at 15 Gy compared with control animals (p < 0.05 for both). A stimulatory effect on smooth muscle cell proliferation was noted at 10 Gy, with a 123% increase in neointimal area compared with controls (p < 0.05). Mean percent area stenosis was also reduced by 63% at 20 Gy and by 74.8% at 15 Gy compared with controls (p < 0.05 for both)., Conclusions: Intracoronary irradiation prior to overstretch balloon angioplasty markedly reduces neointima formation; this effect is dose dependent, with evidence of a significant stimulatory effect at 10 Gy. The effective therapeutic dose range for the prevention of restenosis in this model begins at approximately 15 Gy delivered to the vessel wall.

Purpose: We examined the effects of intracoronary irradiation delivered at a high dose rate on neointimal hyperplasia after injury induced by two methods: balloon overstretch injury, and stent implantation in a porcine model of coronary restenosis., Methods and Materials: In 34 Hanford miniature swine, a segment of each coronary artery was targeted for injury and treatment. The artery segments were treated with 192Ir at doses of 10 Gy over 4 min (eight animals), 15 Gy over 6 min (nine animals), 25 Gy over 10 min (nine animals) or control (simulation wire only; eight animals). The treated segments were subjected to stent implantation (left anterior descending and right coronary artery) or balloon overstretch (circumflex) injury. Twenty-eight days later, repeat coronary angiography and sacrifice were done. Quantitative coronary angiography, morphometry, and extensive histopathologic analyses were carried out in a blinded fashion., Results: The change in minimal lumen diameter from postinjury to presacrifice in the stent-injured left anterior descending was -0.79 +/- 0.34 (mean: +/- SD) mm in the control group, compared to -0.43 +/- 0.35 mm in the 15 Gy (p = 0.04) and -0.21 +/- 0.50 mm in the 25 Gy (p = 0.01) groups; and in the balloon-injured circumflex was -0.31 +/- 0.22 mm in the control group compared to -0.03 +/- 0.18 mm in the 10 Gy (p = 0.05) and 0.00 +/- 0.33 in the 15 Gy (p = 0.01) groups. Percent area stenosis in the left anterior descending was 36 +/- 9% in the control group compared to 18 +/- 12% in the 15 Gy (p = 0.003) and 11 +/- 11% in the 25 Gy (p < 0.001) groups; and in the circumflex was 16 +/- 10% in the control groups, compared to 5 +/- 5% in the 15 Gy (p = 0.02) and 2 +/- 2% in the 25 Gy (p = 0.009) groups. Histopathology showed a striking reduction in the amount of neointima in the irradiated arteries compared with control vessels. Other radiation effects were stromal fibrin exudate, thinning of the media, and adventitial fibrosis and leukocyte infiltration in the radiated arterial segments., Conclusions: High dose rate intracoronary irradiation with 192Ir effectively inhibits intimal proliferation after stent-induced as well as balloon-overstretch injury. This shorter treatment time (4 to 10 min) may provide a clinically practical approach to the prevention of restenosis after angioplasty.

Purpose: Percutaneous transluminal angioplasty (PTA) with or without stent implantation is the accepted standard in the therapy of occlusive arterial disease. Despite improvements in the technique and medical equipment, there is still a restenosis rate of up to 40%. A high-dose-rate afterloading technique to avoid vascular stenosis or occlusion after PTA and subsequent stent implantation caused by intimal hyperplasia is presented with long-term results., Methods and Materials: Intravascular brachytherapy with a 10-Ci 192Ir source was performed in cases of recurrent vascular occlusion or stenosis which appeared within 6 months after a previous PTA. After recanalization by PTA and stent implantation, a 9-Fr ReKa catheter was positioned within the stent to center the applicator with its tip 2 cm below the stent. This catheter served as a guide for a 5-Fr flexible applicator. After this procedure the isodose was calculated and a 12-Gy to 3-mm source distance was applied. The procedure was followed by 72 h of heparinization., Results: From May 1990 to June 1996, 28 patients (21 male and seven female) were treated with endovascular brachytherapy. All patients had a clinically relevant restenosis or reocclusion of the arteria femoralis. Follow-up time ranged from 1 to 71 months. Twenty-eight patients had a sufficient follow-up time; 25 of these patients were examined. Twenty-one patients had treated vessel segments; four patients had no flow in the treated area. Two patients moved away with unknown addresses, and one patient died without any follow-up examination. Radiation-associated side effects were not notable., Conclusion: Intraluminal brachytherapy with 192Ir is a safe and useful procedure to avoid endovascular hyperplasia after transluminal percutaneous angioplasty.

Recent reports suggest that intraluminal irradiation of coronary arteries in conjunction with balloon angioplasty reduces proliferation of smooth muscle cells and neointima formation, thereby inhibiting restenosis. One possible irradiation technique is to inflate the balloon dilitation catheter with a radioactive solution. This has advantages over other proposed irradiation procedures, in that accurate source positioning and uniform dose to the vessel wall are assured. Several high-energy beta-minus emitters may be suitable for this application. We present experimental measurements and analytical calculations of the dose distribution around a 3-mm-diam by 20-mm-long balloon filled with 90Y-chloride solution. The dose rate at the surface of the balloon is approximately 0.14 cGy/s per mCi/ml (3.78 x 10(-11) Gy/s per Bq/ml), with the dose decreasing to 53% at 0.5 mm, and < 5% at 3.5-mm radial distance. 90Y and other possible isotopes are currently available at specific concentrations > or = 50 mCi/ml (1.85 x 10(9) Bq/ml), which enables the delivery of 20 Gy in less than 5 min. The dosimetric and radiation safety advantages of this system warrant further feasibility studies. Issues of concern include incorporating the beta-emitter into a suitable chemical form, and assessing organ and whole body doses in the (< 1 in 10(3)) event of balloon failure.

Purpose: To study the effects of single-dose radiation on the porcine rete mirabile, a tangle of microvessels that mimics human arteriovenous malformations of the brain., Methods: Eight retia mirabilia received a single dose of radiation under stereotactic location with digital angiography and CT. The following doses were applied: 20, 30, 40, 50, 60, 70, 80, and 90 Gy. The animals were followed up for a period of 7 months. Findings at neurologic examination, serial angiography, and histopathologic examination were analyzed., Results: Progressive occlusion as observed by angiography corresponded to the histopathologic finding of intimal hyperplasia; that is, marked thickening of the vessel wall, progressing to occlusion of the vascular lumen, and associated thrombosis. A direct dose response was noted for these changes. Neurologic findings were related to the dose distribution and to histologic findings in structures adjacent to the rete mirabile., Conclusion: The rete mirabile is an excellent model by which to study the radiologic and histologic effects of single-dose radiation to the microvasculature of the central nervous system.

Radiation delivered by intravascular stent is an appealing approach to prevent neointimal hyperplasia, since it nonselectively kills dividing cells. In particular, beta-particle-emitting radioisotope stents may prove to be an ideal means of local irradiation in that 95% of the dose is delivered within 4 mm of the stent edge and the dose drops off rapidly to < 1/1,000 of the original dose at 5 months postimplantation. In the in vitro smooth muscle cell model, one can observe a zone of growth inhibition around radioactive stent wires that averages about 6 mm at very-low-activity levels (0.006 microCi/cm of wire). In vivo studies in animal models, including porcine iliac and coronary arteries and rabbit iliac arteries, have shown the effectiveness of radioisotope stents in inhibiting neointimal proliferation. Proliferating endothelial cells appear to be relatively radioresistant. A computer model was employed to look at the radiation dose delivered as a function of distance from the stent. With very-low-activity stents, presumably, DNA of the smooth muscle cells is damaged as they migrate through the "electron fence" on the way to the neolumen, diminishing the population of myofibroblasts and reducing hyperplasia. Catheter-based radiation therapies may disable these cells before they migrate, although such an approach may not inhibit early recoil or late contraction. Based on the characteristics of beta emissions (i.e., rapid drop-off, minimal leaching), radioisotope stents containing phosphorus-32 appear to be safe. A randomized triple-blind clinical trial is planned to assess restenosis at 6 months in native coronary arteries treated with radioisotope stents.

Background: Restenosis after successful percutaneous transluminal coronary angioplasty is the major factor limiting the long-term effectiveness of this procedure. Neointimal proliferation in response to arterial injury is an important contributor to restenosis. The use of radiation for the treatment of malignant and benign proliferative conditions has been well established. External beam irradiation and endovascular irradiation by use of an after-loading technique have been shown to inhibit neointimal proliferation in experimental models of restenosis. The objective of this study was to investigate whether low-dose irradiation from a beta-particle-emitting stent would inhibit neointimal proliferation after placement in porcine iliac arteries., Methods and Results: Fourteen titanium-mesh stents were implanted in the iliac arteries of nine NIH miniature swine. There were seven beta-particle-emitting radioisotope stents (32P, activity level 0.14 microCi) and seven control stents (31P, nonradioactive). Treatment effect was assessed by angiography and histomorphological examination of the stented iliac segments 28 days after implantation. There was a significant reduction in neointimal area (1.76 +/- 0.37 mm2 versus 2.81 +/- 1.22 mm2, P = .05) and percent area stenosis (24.6 +/- 2.9% versus 36.0 +/- 10.7%, P = .02) within the beta-particle-emitting stents compared with the control stents. Neointimal thickness, which was assessed at each wire site, was also significantly less within the treatment stents (0.26 +/- 0.04 mm versus 0.38 +/- 0.10 mm, P = .012). Scanning electron microscopy was performed on sections from four stents. This demonstrated endothelialization of both the treatment and control stents. There was no excess inflammatory reaction or fibrosis in the media, adventitia, or perivascular space of vessels treated with the beta-particle-emitting stent compared with control vessels. At 28 days, there was no difference in smooth muscle cell proliferation as measured by the proliferating cell nuclear antigen index., Conclusions: A local, continuous source of low-dose endovascular irradiation via a beta-particle-emitting stent inhibits neointimal formation in porcine arteries. This low dose of local irradiation did not prevent endothelialization of the stents. This novel technique offers promise for the prevention of restenosis and warrants further investigation.

Objectives: We investigated the effects of Photodynamic therapy (PDT) using Aluminium disulphonated phthalocyanine (AlS2Pc) on experimental intimal hyperplasia (FCIH)., Materials and Methods: (a) Pharmacokinetics: Normal rats were injected with Als2Pc and carotid artery fluorescence was measured. (b) Normal artery PDT: Sensitised rats underwent carotid artery laser irradiation (50J/cm2, 675nm) and were assessed after 3 and 14 days and 1-6 months. (c) PDT: Rats underwent standard carotid artery balloon injury immediately prior to PDT and arteries were assessed at 2 to 26 weeks, together with laser, AlS2Pc, and untreated controls., Chief Outcome Measures: (a) Fluorescence intensity in different arterial layers. (b) Medial smooth muscle cell counts per high power field (light microscopic). (c) Percentage amount of FCIH (area of intimal hyperplasia) as a ratio of the IEL (area enclosed by the internal elastic lamina)., Results: (a) AlS2Pc fluorescence intensity increased with increasing dosage, with maximal fluorescence in the arterial media at 30 min. (b) PDT produced medial cell depletion at 3 days and persisted over 6 months without loss of vessel integrity. (c) PDT completely inhibited FCIH at 2 and 4 weeks. This was partial at 6 to 26 weeks (51% of untreated level). PDT inhibition of FCIH was significantly greater than in any of the control groups. p < 0.0001. Mann-Whitney Test., Conclusion: Adjunctive AlS2Pc sensitised photodynamic therapy inhibits experimental intimal hyperplasia, by causing medial smooth muscle cell depletion. This offers a new approach to the management of angioplasty restenosis in patients.

Background: Neointima formation contributing to recurrent stenosis remains a major limitation of percutaneous transluminal angioplasty. Endovascular low-dose gamma-irradiation has been shown to reduce intimal thickening (hyperplasia) after balloon overstretch injury in pig coronary arteries, a model of restenosis. The objective of this study was to determine whether the use of a beta-emitting radioisotope for this application would have similar effects and to examine the dose-response relations with this approach., Methods and Results: Normal domestic pigs underwent balloon overstretch injury in the left anterior descending and left circumflex and coronary arteries. A flexible catheter was introduced by random assignment into one of these arteries and was afterloaded with a 2.5-cm ribbon of encapsulated 90Strontium/90Yttrium sources (90Sr/Y, a pure beta-emitter). It was left in place for a period of time sufficient to deliver one of four doses: 7, 14, 28, or 56 Gy, to a depth of 2 mm. Animals were killed 14 days after balloon injury, the coronary vasculature was pressure-perfusion fixed, and histomorphometric analysis of arterial cross sections was performed. All arteries treated with radiation demonstrated significantly decreased neointima formation compared with control arteries. The ratio of intimal area to medial fracture length was inversely correlated with increasing radiation dose: control (no radiation), 0.47; 7 Gy, 0.34; 14 Gy, 0.20; 28 Gy, 0.08; and 56 Gy, 0.02 (r = -.78, P < .000001). Scanning electron microscopy demonstrated a confluent layer of endothelium-like cells both in control and in 14 Gy-irradiated arteries. There was neither evidence of significant necrosis nor excess fibrosis in the media, adventitia, or perivascular space of the coronary arteries or adjacent myocardium in the irradiated groups. Furthermore, the exposure to the staff and the total body exposure to the pig with the beta source was a small fraction of the dose previously measured and calculated with 192Ir, a gamma-emitting radioisotope., Conclusions: Administration of endovascular beta-radiation to the site of coronary arterial overstretch balloon injury in pigs with 90Sr/Y is technically feasible and safe. Radiation doses between 7 and 56 Gy showed evidence of inhibition of neointima formation. A dose-response relation was demonstrated, but no further inhibitory effect was seen beyond 28 Gy. These data suggest that intracoronary beta-irradiation is practical and feasible and may aid in preventing clinical restenosis.

Background: Intra-arterial gamma irradiation has been shown to reduce restenosis after balloon angioplasty. The use of beta emitters should allow similar effects while inducing less undue tissue irradiation radioprotection problems., Methods and Results: Flexible 90-yttrium (90Y) coils inside a centering balloon were used to allow homogeneous intraarterial dose delivery. One carotid and one iliac artery of 21 hypercholesterolemic rabbits were deendothelialized and then irradiated. Four dose schedules were studied: (1) control (dilated, nonirradiated); (2) 6 Gy; (3) 12 Gy; and (4) 18 Gy. Arterial specimens were histologically evaluated at 8 days and at 6 weeks. For all radiation doses at 8 days compared with controls, there was a significant decrease in bromodeoxyuridine-labeled cells (245 +/- 93 cells/cm in control, 42 +/- 27 in 6 Gy, 72 +/- 107 in 12 Gy, and 2 +/- 2 in 18 Gy groups; P < .001) and in total neointimal cells (891 +/- 415 cells/cm in control, 79 +/- 43 in 6 Gy, 192 +/- 264 in 12 Gy and 22 +/- 13 in 18 Gy groups; P < .0002). At 6 weeks, computer-derived histological percent area stenosis was reduced from 26 +/- 10% in the control group to 1 +/- 1.3% in the 18 Gy group (P < .0001), but lower doses had no significant effect., Conclusions: Administration of intra-arterial beta irradiation with a 90Y source is technically feasible and compatible with an ordinary catheterization laboratory environment. A dose of 18 Gy effectively induces long-term inhibition of neointimal hyperplasia.

Objective: X-irradiation is known to enhance atherosclerotic change. We tested whether coronary vasoconstrictor responses are augmented at the sites of X-ray-induced intimal thickening in Göttingen miniature pigs., Methods: In 17 pigs, a major branch of the left coronary artery was denuded with a balloon catheter. In 10 pigs, the denuded portion of the left coronary artery was selectively irradiated with 15 Gy of X-rays twice at 3 and 4 months after denudation (group 1). The remaining 7 pigs were not irradiated (group 2). The effects of intracoronary administration of serotonin, histamine and phenylephrine on the coronary diameter were studied 3 (3M) and 5 months (5M) after denudation. After the angiographical study at 5M, the vessels were isolated and isometric tension was measured in an organ chamber., Results: The percent reduction in coronary diameter evoked with 10 micrograms.kg-1 of serotonin increased from 39(s.e.m. 4)% before X-irradiation (3M) to 75(6)% after X-irradiation (5M) in group 1 (P < 0.01), while it did not differ in group 2 [39(6)% at 3M vs. 33(8)% at 5M[ [39(6)% at 3M vs. 33(8)% at 5M]. In group 1, serotonin-induced coronary constriction was frequently accompanied by ischemic ECG changes. Histamine (10 micrograms.kg-1)-induced vasoconstriction was also augmented but to a smaller degree [47(6)% at 3M vs. 62(4)% at 5M; P < 0.05] in group 1, while it remained unchanged in group 2[52(5)% at 3M vs. 44(7)% at 5M]. Phenylephrine did not cause detectable contraction in either group at 3M or 5M. Methysergide and ketanserin attenuated serotonin-induced hypercontraction in a dose-dependent fashion. In the in vitro studies, endothelium-dependent relaxation to serotonin was impaired at the denuded site with (group 1) and without (group 2) X-irradiation to a similar extent. Isometric tension of medial smooth muscle developed by serotonin was significantly greater at the denuded site with X-irradiation (group 1) than the control site and the denuded site without X-irradiation (group 2) (P < 0.05). Intimal thickening was significantly greater at the denuded sites with X-irradiation [group 1, 238(45) microns] than at the denuded sites without X-irradiation [group 2, 58(5) microns] (P < 0.05)., Conclusions: These results indicate that X-irradiation augments the coronary vasoconstrictor responses to autacoids, predominantly to serotonin, and that this augmentation is accompanied by enhanced intimal thickening. Serotonin-induced hypercontraction after X-irradiation resulted mainly from the hyperreactivity of medial smooth muscle.

Purpose: We sought to determine whether low-dose radiation can inhibit neointimal hyperplasia immediately after balloon injury to the common carotid artery and to assess the extent of endothelial regeneration after treatment., Methods: Sprague-Dawley rats were subjected to balloon injury to the common carotid artery. Immediately after injury rats were treated with a single dose of iridium 192 radiation at 5 gy, 10 gy, and 15 gy or received no radiation (control). Three weeks after injury and treatment, vessels were harvested and compartment areas were measured on fixed specimens. Scanning and transmission electron microscopy, along with Evans blue dye uptake into injured vessels, was used to assess the effect radiation had on endothelial regeneration., Results: Rats receiving radiation at all three doses demonstrated no intimal thickening when compared with rats that were not treated (at 5 Gy 0.01 +/- 0.01 mm2; at 10 Gy 0.02 +/- 0.01 mm2; at 15 Gy 0.05 +/- 0.02 mm2; with balloon injury/no radiation 0.12 +/- 0.02 mm2; p < 0.01). In addition, the groups that were irradiated had no medial thickening when compared with control rats (at 5 Gy 0.22 +/- 0.02 mm2; at 10 Gy 0.21 +/- 0.02 mm2; at 15 Gy 0.22 +/- 0.07 mm2; with balloon injury/no radiation 0.37 +/- 0.03 mm2; p < 0.01). Endothelial regeneration, evaluated by transmission and scanning electron micrographs along with uptake of Evans blue dye, was significantly greater in animals that received radiation compared with controls., Conclusions: Low-dose radiation prevents the occurrence of neointimal hyperplasia after balloon injury and may have a future role in vascular grafting.

Background: Restenosis after percutaneous transluminal coronary angioplasty remains a major limitation of the long-term success of this procedure. Restenosis is a form of wound healing. Low-dose ionizing radiation has been effective in inhibiting exuberant wound healing responses in a variety of clinical situations., Methods and Results: Vascular neointimal lesions resembling human restenosis were created in the coronary arteries of normal pigs by overstretch balloon angioplasty injury. To test the effect of low-dose endovascular gamma radiation on lesion formation, a high-activity 192Ir source was introduced into one of the injured arteries in each animal and left in place for a period sufficient to deliver one of three doses: 350, 700, or 1400 cGy. To test potential benefits of delayed irradiation, 700 cGy was given in another group 2 days after injury. Animals were killed 14 days after balloon injury and the coronary vasculature was pressure-perfusion fixed. To test the late effect and safety of endovascular low-dose irradiation, 700 or 1400 cGy was given in miniswine coronary arteries after injury as well as in noninjured carotid arteries; this group was followed up for 6 months. Tissue sections were measured by computer-assisted planimetry. All arteries treated with radiation demonstrated significantly decreased neointima formation compared with control arteries. The ratio of intimal area-to-medial fracture length (IA/FL) was inversely correlated with the different radiation doses: control, 0.59; 350 cGy, 0.38; 700 cGy, 0.42; and 1400 cGy, 0.17 (r = -0.75, P < .0001). Delay of 700-cGy irradiation for 2 days after injury significantly decreased neointima formation compared with the same dose given immediately after injury. Analysis of long-term specimens showed reduction of IA/FL in the arteries irradiated with 700 cGy (0.3, P = .009) and 1400 cGy (0.31, P = .001) compared with control arteries (0.50). There was no excess fibrosis in the media, adventitia, or perivascular space of the coronary arteries or adjacent myocardium in pigs that received radiation compared with control animals., Conclusions: Low-dose intracoronary irradiation delivered to the site of coronary arterial overstretch balloon injury in pigs inhibited subsequent intimal thickening (hyperplasia). A dose-response relationship was demonstrated, and delay of treatment for 48 hours appeared to augment the inhibitory effect. Six months of follow-up without fibrosis or arteriosclerosis demonstrated the durability of the beneficial effect in the treated group. These data suggest that intracoronary irradiation therapy may aid in preventing clinical restenosis.

Restenosis is a serious problem limiting the long-term efficacy of percutaneous transluminal coronary angioplasty. Neointimal smooth muscle proliferation is the major process underlying restenosis. The objective of this study was to investigate the effects of external irradiation on neointimal hyperplasia following balloon angioplasty. We examined the ability of external X-ray irradiation to inhibit intimal hyperplasia following balloon angioplasty in a non-atherosclerotic rabbit model. Baseline quantitative angiography (day 0) was performed in all rabbits and balloon angioplasty was performed in the right (control) and the left iliac arteries. Five days after balloon angioplasty, the left iliac in each rabbit was irradiated with either 600 cGy (n = 5) or 1200 cGy (n = 5). Twenty-eight days following angioplasty final angiography was performed. All rabbits were sacrificed, and the iliac arteries were fixed for morphometric measurements. Comparison of baseline and final angiographic measurements revealed a significant decrease in average and minimum lumen dimensions for both control and irradiated segments (600 and 1200 cGy) [average: P (baseline vs. final) 0.008 (control), 0.001 (600 cGy); 0.05 (control), 0.007 (1200 cGy)]. Morphometric analysis showed no difference in neointimal cross-sectional area between control (0.29 +/- 0.05 mm2) and 600 cGy irradiated segments (0.32 +/- 0.07 mm2) (P = 0.82). However, there was a statistically significant reduction in neointimal hyperplasia in the 1200 cGy irradiated segments (0.09 +/- 0.02 mm2) compared to control (0.23 +/- 0.06 mm2, P = 0.02). There was no significant difference in medial cross-sectional area between control and irradiated segments (600 and 1200 cGy). We conclude that in this model, external beam X-ray irradiation (1200 cGy) was successful in reducing neointimal proliferation after balloon angioplasty. Whether or not this approach can be used successfully to inhibit restenosis in the clinical setting requires further investigation.

Purpose: Recurrent stenosis or occlusion by intimal hyperplasia occurs in up to 40% of patients with tantalum stent implantations in femoropopliteal arteries and greatly restricts their usefulness. We evaluated the effect of prophylactic endovascular radiotherapy on stenosed/occluded stents., Methods: We investigated prophylactic endovascular radiotherapy with a surface dose of 12 Gy using an iridium 192 source as a means to reduce or eliminate recurrent stenosis in 4 patients with stenosed/occluded stents, 6-8 months after the original implantation. Confirmatory diagnostic atherectomy, PTA or laser recanalization and endovascular radiotherapy were performed., Results: None of the four has developed recurrent obstruction within 23 to 30 months after this treatment, which up to now shows no short-term or long-term complications., Conclusion: We conclude that this limited experience is promising enough to warrant further study.

Excessive vascular damage causes excessive vascular repair, which results in restenosis. To limit the thickness of the coagulation layer in laser balloon angioplasty, we used a carbon monoxide (CO) laser, which has high tissue absorption, as a therapy laser source instead of a Nd: YAG laser. To investigate the benefit of short-penetration CO laser light to vascular tissue, excised human abdominal aorta was irradiated with a CO laser through a 30 microns polyethylene membrane. The temperature of the vascular tissue was continuously monitored during irradiation. CO laser irradiation of 20 W/cm2 was performed in either a continuous mode or an intermittent mode with various duty ratios (exposure/interval duration). With a total fluence of 200 J/cm2, the adventitial temperature decreased as the duty ratio was reduced. The adventitial temperature at a duty ratio of 1:2 was 43 degrees C. Microscopic examination of aorta which had been intermittently irradiated duty ratio of 1:2 showed thermal coagulation localized within the intima and a flattened intimal surface. These results suggest that intermittent laser irradiation with a CO laser can be used to limit the depth of thermal coagulation, and can selectively weld the intima without excessive thermal damage. Laser balloon angioplasty using a CO laser may help to prevent restenosis.

Vasoconstriction is a clinical problem associated with invasive vascular procedures, microvascular reconstruction and subarachnoid hemorrhage. We sought to characterize the ability of pulsed-dye laser irradiation to reverse and prevent vasoconstriction in an anesthetized rabbit model of surgically and pharmacologically induced vasoconstriction. Five groups of experiments were performed to study the effect of pulsed-dye laser irradiation delivered through a 320 microns core ball-tip fiber into the femoral artery. The studies demonstrated that pulsed-dye irradiation can reproducibly cause vascular dilatation. The zone of vasodilatation propagated equally proximal and distal to the site of irradiation within the vessel. When saline was infused into the vessel to replace flowing blood during delivery of laser irradiation, no significant vasodilatation occurred. After laser irradiation reversed surgical and pharmacologic vasoconstriction, the vessel was resistant to further pharmacologic vasoconstriction. This resistance to pharmacologic vasoconstriction did not occur if the vessel was pharmacologically predilated before delivery of laser irradiation. Pathologic analysis of the vessels revealed endothelial damage and mild to moderate medial necrosis, most significant at the site of energy delivery. These studies provide characterization of pulsed-dye laser-mediated vasodilatation in an in vivo model. Delivery of pulsed-dye laser energy has potential clinical application and warrants further investigation.