Radiation Impacts Early Atherosclerosis by Suppressing Intimal LDL Accumulation.

RATIONALE: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT. OBJECTIVE: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms. METHODS AND RESULTS: Ldlr-/- mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of Ldlr-/- relative to Ldlr+/+ mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT. CONCLUSIONS: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.

Intimal sarcoma of the superficial femoral artery with osteosarcomatous differentiation.

Sarcomas of the large vessels usually present centrally in the aorta, pulmonary artery, and inferior vena cava. Peripheral arterial sarcomas are exceptionally rare. They have been reported in the iliac and common or profunda femoral arteries, and are frequently undifferentiated. In this study, we describe a differentiated intimal sarcoma of the superficial femoral artery with abundant osteosarcoma within the specimen. Before knowing the diagnosis, treatment was for a presumed pseudoaneurysm using excision and bypass. Postoperatively, the patient received palliative radiation therapy. The tumor's location and histopathology are unique. A differentiated intimal sarcoma has never been reported in the superficial femoral artery, and it represents the second peripheral arterial intimal sarcoma reported with osteosarcomatous differentiation.

Effects of external irradiation of the neck region on intima media thickness of the common carotid artery.

BACKGROUND: Several studies have shown that common carotid intima-media thickness (IMT) is increased after radiotherapy (RT) to the head and neck. However, further studies are needed to define the exact mechanism of radiation-induced injury in large vessels, investigate the relationship between radiation dose and large vessel injury and evaluate the rate of progress of atherosclerosis in irradiated vessels. OBJECTIVES: To investigate whether external irradiation to the carotid area has any effect on IMT of the common carotid artery in a group of patients who received RT vs control group matched for age, gender and race. METHODS: We studied 19 patients (10 male; 47.8 +/- 17.4 years) during a 5-month period (January 2009-July 2009); they had completed RT with a mean of 2.9 years before (range: 1 month-6 years) The mean radiation dose to the neck in the irradiated patients was 41.2 +/- 15.6 Gy (range: 25-70 Gy). Common carotid IMT was measured with echo-color Doppler. Nineteen healthy adult patients (10 male; 47.8 +/- 17.6) were recruited as a control group. RESULTS: IMT was not significantly higher in patients when compared to the control group (0.59 +/- 0.16 vs 0.56 +/- 0.16 mm, p = 0.4). There was no significant difference between the two groups in relation to the absence (p = 0.7) or presence (p = 0.6) of vascular risk factors. Although the difference did not reach statistical significance (p = 0.1), the irradiated young patients (age < or = 52 years) had IMT measurements higher (0.54 +/- 0.08 mm) than the non-irradiated young patients (0.49 +/- 0.14 mm). The mean carotid IMT increased with increasing doses of radiation to the neck (p = 0.04). CONCLUSION: This study shows that increased IMT of the common carotid artery after RT is radiation-dose-related. Therefore it is important to monitor IMT, which can be used as an imaging biomarker for early diagnosis of cerebrovascular disease in patients who have had radiotherapy for treatment of cancer of the head and neck and who are at increased risk for accelerated atherosclerosis in carotid arteries.

Combining sirolimus-eluting stents and external irradiation in cholesterol-fed rabbits increased incomplete stent apposition and decreased re-endothelialization.

Restenosis after the implantation of a drug-eluting stent or after vascular irradiation therapy shares similar physiopathological mechanisms. No experimental data are currently available on vascular wall behavior after external irradiation on arteries stented with sirolimus-eluting stents (SES). Ten New Zealand white rabbits received a 0.5% cholesterol-enriched chow for 1 month. Bilateral iliac artery stent implantation was then performed with an SES (Cypher; Cordis Corp). The animals were randomized into either an irradiated group (I, 2 Gy external x-ray irradiation, n = 5) or a control group (C, n = 5). The cholesterol-enriched chow was continued for 1 additional month after stent implantation. The stented arteries were harvested for histological analyses. The number and the percentage of incompletely apposed stents struts (IASS) were significantly higher in irradiated versus control group (3.05 +/- 0.46 vs. 1.57 +/- 0.27 IASS, P < 0.01, and 28.44% +/- 3.97% vs. 15.2% +/- 2.46% of IASS, P < 0.01, respectively). The mean neointimal thickness behind the IASS was also higher in the irradiated group (I: 28.3 +/- 2.5 microm vs. C: 18.2 +/- 2.3 microm, P < 0.01). Re-endothelialization was lower in irradiated group (I: 44.6% +/- 17.5% vs. C: 75.2% +/- 5.7%, P < 0.01). The present study revealed that low-dose external irradiation increased incomplete stent apposition and reduced re-endothelialization of SES. These results underscore the potential deleterious cumulative side effects of these 2 procedures to prevent restenosis.

Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries-Part A: dose from radon and thoron.

PURPOSE: There is mounting evidence that a significant fraction of radiation-induced mortality and years-life lost are non-cancerous in nature. This study quantifies the radon dose to the coronary artery walls, especially the intimal layer, vulnerable to the development of atherosclerosis, and associated cardiovascular disease (CVD). Two accompanying papers determine the oxygen levels (Part B) in coronary arteries and the oxygen effect for radon and other exposures (Part C). MATERIALS AND METHODS: The alpha-radiation dose to coronary artery walls was calculated from the proportion of inhaled radon ((222)Rn), thoron ((220)Rn) and their short-lived progeny, which was not deposited in the lung and passed into blood. Age- and gender-dependent morphology and composition for the wall layers of coronary arteries were developed from published data for a normal population and also for individuals with cardiovascular disease. The alpha particle dose to the coronary artery walls was evaluated taking account the diffusion of radon from blood and the solubility of radon-gas in tissues. RESULTS: Diseased arteries exhibited a moderate increase in the solubility of lipophylic radon (190%) in arteries with 88% luminal narrowing, as the high Rn solubility in fat was partially offset by the lower solubility in calcium deposits. The average worldwide dose rate to the diseased intimal layer from (222)Rn and its short-lived progeny was estimated to be as high as 68 muSv y(-1) per 40 Bq m(-3) in air, whereas the corresponding dose rate from (220)Rn per 0.3 Bq m(-3) in air was

Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries-Part B: modeling oxygen diffusion into vessel walls.

PURPOSE: The aim is to assess the change with age and disease of the oxygen concentration within the coronary artery walls. MATERIALS AND METHODS: In an accompanying paper, Part A, the age-dependent morphology and composition for the wall layers of normal and diseased coronary arteries were developed from published data. In this paper, Part B, the oxygen concentration in the coronary artery walls was evaluated taking account the diffusion of oxygen from blood and the solubility of oxygen in tissues. Part C evaluates the oxygen effect and its biological implications for different radiations. RESULTS: Diseased arteries exhibited a relatively moderate increase in the solubility of oxygen (or=38% stenosis had anoxic areas. CONCLUSION: Based on simulation results from the one-dimensional diffusion model, extensive hypoxic areas were determined for atherosclerotic arteries in this analysis of oxygen levels in coronary arteries modelling for the first time the effects of age and disease and associated changes in oxygen solubility due to the presence of lipids and calcium.

Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries-Part C: oxygen effect and its implications on high- and low-LET dose.

PURPOSE: The aim is to study the implications of the decrease in oxygen concentration in the coronary artery walls with age and atherosclerosis, particularly with regard to an associated reduction in the radiosensitivity to high-and low-linear-energy-transfer (LET) irradiation. MATERIALS AND METHODS: In accompanying papers, the age-dependent morphology and composition for the wall layers of normal and diseased coronary arteries were developed in Part A from published data. In Part B, the oxygen concentration in the coronary artery walls was evaluated taking account the diffusion of oxygen from blood and the solubility of oxygen in tissues. In this part the oxygen effect was evaluated using published experimental data. RESULTS: Based on simulation results from the one-dimensional diffusion model, the oxygen enhancement ratio (OER) is lower in the hypoxic vessel walls of aged and atherosclerotic arteries. Consequently the high-LET radiation damage arising from both the radon ((222)Rn) and thoron ((220)Rn) decay chains to the intimal layer of highly diseased arteries was estimated to be reduced by approximately 37% due to hypoxia. A greater reduction in radiosensitivity (51%) due to hypoxia was determined for low-LET irradiation. CONCLUSION: These results imply that the oxygen effect, and other radiation biological factors, have a significant influence on radiation biological effects and risk of cardiovascular disease (CVD) to Japanese atomic bomb (A-bomb) survivors and patients receiving radiotherapy of the mediastinum.

Radiation effects on the intima-media thickness of the common carotid artery in post-radiotherapy patients with head and neck malignancy.

BACKGROUND: Post-radiation large vessel injury has not received as much attention as microvascular irradiation injury. A few studies have shown that common carotid intima-media thickness (IMT) is increased after radiotherapy to the head and neck. However, in most of these studies, the irradiated subjects also had other major risk factors for atherosclerosis. In this study, irradiated subjects with major risk factors such as hypertension, diabetes, history of previous cerebrovascular accident and connective tissue disorder were excluded. OBJECTIVE: To show in a cross-sectional study if radiotherapy to the carotid area has any effect on the IMT of the common carotid artery. SUBJECTS AND METHODS: 13 patients with head and neck malignancies who had completed radiotherapy to the carotid region at least 1 year previously underwent ultrasound of the carotid artery. IMT measurements were compared with those of 13 healthy controls, matched for age, sex and race, with no history of radiotherapy. RESULTS: The irradiated subjects had significantly larger IMT measurements (mean 0.74 mm) than the non-irradiated subjects (mean 0.46 mm). The difference was significant (p<0.001) with a confidence interval of 95%. CONCLUSIONS: This study shows that there is a measurable, significant (p<0.001) increase in IMT of the common carotid artery after radiotherapy for head and neck malignancy compared with non-irradiated matched controls. This knowledge is important for risk-benefit assessment of prophylactic or therapeutic neck irradiation. Increased awareness of this complication should provide an opportunity to intervene and prevent future cerebrovascular accidents in the majority of such patients.

Intracoronary beta-irradiation for the treatment of de novo lesions: 5-year clinical follow-up of the BetAce randomized trial.

BACKGROUND: Vascular brachytherapy (VBT) has been used for the prevention of restenosis. Despite initial positive results, long-term follow-up has shown a progressive loss of benefit in clinical outcome after beta-irradiation. We report the 5-year follow-up of the BetAce trial. METHODS: This prospective, randomized, single-blind trial included 61 patients treated for 64 de novo coronary lesions: 31 patients (33 stenoses) were treated with bare metal stents (control group), and 30 patients (31 stenoses) were treated with intracoronary beta-irradiation at the time of stented angioplasty (VBT group). RESULTS: Baseline and procedural data were similar between treatment arms. At 6 months, VBT reduced the need for target vessel revascularization (13% vs 35.5%, P = .04), but there was no significant difference in the 6- and 12-month event-free survival when clinical events were ranked. Between 1 and 5 years, an increasing number of target vessel failures was observed in both groups, leading to a similar long-term clinical outcome at 5 years (event-free survival 43% and 45% in the VBT and control groups, respectively, log-rank 0.001, P = .9). CONCLUSIONS: Beta-irradiation in de novo coronary lesions significantly reduced in-stent recurrences at 6 months compared with standard procedures. However, this initial benefit was not sustained in the long term. The results of this randomized study confirm the delayed and progressive restenotic process after beta-irradiation and stent implantation in de novo lesions.

Increased expression of nuclear NF-kappaB after coronary artery balloon injury can be inhibited by intracoronary beta-irradiation.

PURPOSE: Molecular mechanisms by which balloon angioplasty injury-induced neointimal hyperplasia can be reduced by intravascular brachytherapy are unclear. We investigated the role of nuclear factor-kappaB (NF-kappaB) in neointimal hyperplasia following intracoronary irradiation. MATERIALS AND METHODS: Fifty-four coronary arteries from 30 pigs were divided into 6 groups: sham control, balloon angioplasty injury alone, beta-irradiation at doses of 14 or 20 Gy, and 14 or 20 Gy beta-irradiation immediately followed by balloon injury. Coronary arteries were injured by overstretch balloon angioplasty and then the arteries were irradiated using a Rhenium-188 ((188)Re) beta-emitting solution-filled balloon. Pigs were scarified one day or one week after coronary interventions for molecular detection and six weeks after the procedures for histological examination. RESULTS: Six weeks after coronary interventions, the histological results show that balloon angioplasty injury had induced intimal hyperplasia in coronary artery but the response was significantly reduced by 28% and 60% when the injury was immediately treated by 14 and 20 Gy (188)Re beta-irradiation, respectively. The expression of arterial NF-kappaB p65, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were detected at one day and one week after the procedures. The treatment of balloon injury could significantly induce the NF-kappaB p65 expression in both gene and protein levels, and such induction could be significantly reduced by (188)Re beta-irradiation at dose of 20 Gy. However, the similar result on the regulation of gene expression affected by the beta-irradiation could not be observed in ICAM-1 and VCAM-1. CONCLUSION: The inhibitory effect of intracoronary brachytherapy on neointimal formation following overstretch balloon angioplasty could involve inhibition of NF-kappaB p65.

Low-energy gamma-emitting stents inhibit intimal hyperplasia with minimal "edge effects" in a pig coronary artery model.

PURPOSE: The objective of this study was to determine the effects of different doses of gamma-emitting radioactive stents on intimal hyperplasia in a porcine coronary stent model at 28 days. METHODS: Sixty-four bare stents and those coated with palladium-103 [activities of 0 (control), 0.5, 1.0, 2.0, and 4.0 mCi] were implanted in the coronary arteries of 32 pigs. Stented segments were evaluated by histomorphometry at 28 days. RESULTS: There was significantly more intima in the 0.5- and 1-mCi stents than in controls (4.27+/-0.52 and 4.71+/-1.13 vs. 1.71+/-0.61 mm(2); P<.0001). Neointimal formation in 2-mCi stents was similar to that in controls, while that in 4-mCi stents was reduced compared to that in controls (2.34+/-1.61 and 0.82+/-0.25 vs. 1.71+/-0.61 mm(2); P=NS and P<.05, respectively). Stent margin neointimal response was representative of that within the stent body, with nonsignficant modest increases in intimal area at adjacent nonstented segments in radioactive stent groups. There was a dose-dependent increase in inflammation scores. Radioactive stents had lower intimal smooth muscle and higher fibrin scores. There was an increase in adventitial fibrosis in 1- and 2-mCi stents versus controls (1.26+/-0.99, and 2.25+/-1.27 vs. 0.21+/-0.31; P<.001). CONCLUSION: Dose-response inhibition of in-stent hyperplasia with minimal "edge effects" occurs with low-energy gamma-emitting stents. An increased inflammatory response at higher doses in palladium-103 stents indicates that later follow-up studies are necessary.

Mechanisms of late lumen loss after antiproliferative percutaneous coronary intervention using beta-irradiation in a porcine model of restenosis.

BACKGROUND: The short-term results for the prevention of coronary restenosis after intravascular brachytherapy (IVBT) and use of drug-eluting stents (DESs) are excellent. The long-term results either lack or present with late complications (e.g., late thrombosis and late catch-up phenomenon leading to late restenosis even years after the initial procedure). Both IVBT and DESs mediate their potent antirestenotic effects via a cytostatic mechanism, but the cardiovascular pathology at late time points after the use of these antiproliferative therapies is incompletely understood. This study investigated the long-term effects of antiproliferative beta-irradiation in a clinically relevant porcine coronary model to address the pathophysiology of late coronary restenosis after antiproliferative vascular interventions. METHODS: We performed percutaneous transluminal coronary angioplasty (PTCA) in two major coronary arteries in 12 domestic crossbred pigs. One of the two balloon-injured segments was randomly assigned to receive immediate beta-irradiation (PTCA+IVBT group) using a noncentered delivery catheter (20 Gy; Novoste Beta-Cath System, Novoste, Norcross, GA, USA). The animals were sacrificed after 14 days (n=6) or 3 months (n=6). RESULTS: The luminal area in the PTCA+IVBT group decreased significantly 3 months after the intervention as compared with that in the PTCA group (PTCA 3.45+/-0.46 mm2 vs. PTCA+IVBT 1.22+/-0.26 mm2; P=.0017). This lumen loss was primarily due to shrinkage of the external elastic lamina area (negative arterial remodeling; PTCA 5.22+/-0.27 mm2 vs. PTCA+IVBT 3.42+/-0.45 mm2; P=.0064), which was accompanied by an increase in the adventitial area (PTCA 3.07+/-0.2 mm2 vs. PTCA+IVBT 5.41+/-0.5 mm2; P=.0049). CONCLUSIONS: The application of antiproliferative radiation in a porcine coronary model caused an early beneficial effect (reduction of intimal-medial lesion and luminal gain) that was followed by a late lumen loss primarily due to negative arterial remodeling. This mechanism may in part help us understand the pathophysiology of late adverse events occurring after IVBT.

A retrospective analysis of catheter-based sources in intravascular brachytherapy.

PURPOSE: Coronary artery disease involves the deposition of plaque along the walls of a coronary artery leading to narrowed or blocked vessels (stenosis) and is one of the main causes of death in developed countries. Percutaneous transluminal coronary angioplasty (PTCA) is used to reverse stenosis. Restenosis (renarrowing) of the treated vessel is a major complication of PTCA. A metal mesh tube (stent) can be placed inside the vessel to prevent restenosis. Tissue stress incurred during PTCA and stenting can provoke neointimal cell proliferation leading to in-stent restenosis (ISR). Intravascular brachytherapy (IVBT), a form of internal radiotherapy, is used to treat ISR. Renewed interest in IVBT is being expressed as a treatment for patients with ISR in drug-eluting stents. Current treatment planning (TP) of IVBT is extremely limited and assumes human tissue can be approximated by water. The interactions of arterial plaque, guidewires, and the stent have been shown to attenuate radiation significantly but are ignored in TP. Other models have determined the degree of attenuation by each factor in isolation. For the first time, we create a model with several inhomogenities present to determine whether attenuation by multiple inhomogenities combines linearly or if a larger dose reduction than anticipated is realized. We are also able to evaluate a spatial distribution of dose around the source and in arterial walls. METHODS AND MATERIALS: A dosimetric analysis of two commercially available IVBT systems was performed in a Monte Carlo-based particle simulation (Geant4). Absorbed dose was calculated using a model of a human coronary artery with a calcified plaque and stent. Dose delivered in water was also calculated to evaluate the accuracy of a water approximation. RESULTS: Dose as a function of θ shows significant variation around IVBT sources. For the Guidant Galileo, dose is reduced by 20% behind stent struts and as much as 66% in a region occluded by the guidewire, plaque, and stent. For the Novoste Beta Cath device, delivered dose is reduced by 19% and 58%, respectively, in the same regions. CONCLUSIONS: Our findings show that the water approximation used in clinical practice to calculate dose is inaccurate when inhomogeneities are present. Methods proposed for calculating dose perturbations in IVBT may underestimate the magnitude of dose reduction. Increasing source dwell time seems unlikely to resolve dosimetric issues in IVBT. The effectiveness of currently existing ß-emitting devices may be reduced in patients with complex lesions at the treatment site. Investigation of new radioisotopes and off-centering devices should be considered to improve dose outcomes.

Focal induction of ROS-release to trigger local vascular degeneration.

Reactive oxygen species (ROS) play an important role in the process of cardiovascular degeneration. We evaluated the potential of a controlled, local induction of ROS-release by application of rose bengal (RB) and photo energy to induce atherosclerosis-like focal vascular degeneration in vivo. After injection of RB, rats fed with a pro-degenerative diet underwent focal irradiation of the abdominal aorta by a green laser (ROS group), while the controls received irradiation without RB. Aortic tissue was analyzed by histology and immunohistochemistry at 0, 2, 4, 8, 28 and 56 days (n = 5). The intimal surface topography was analyzed by scanning electron microscopy. In the ROS group, an initial thrombus formation had disappeared by day 8. Similarly, ROS-derived products displayed the highest concentrations at day 0. Relative matrix metalloproteinase (MMP) activity achieved a maximum after 8 days (ROS group vs. CONTROL GROUP: 1.60 ± 0.11 vs. 0.98 ± 0.01; p < 0.001). After 28 days, no significant differences in any aspect were found between the ROS group and the controls. However, after 56 days, the aortic tissue of ROS animals exhibited relative media-pronounced thickening (ROS vs. CONTROL: 2.15 ± 0.19 vs. 0.87 ± 0.10; p < 0.001) with focal calcification and reduced expression of alpha smooth muscle actin (aSMA). The ROS-releasing application of RB and photo energy allowed for the induction of vascular degeneration in a rodent model. This protocol may be used for the focal induction of vascular disease without systemic side effects and can thereby elucidate the role of ROS in the multifactorial processes of vessel degeneration and atherogenesis.

Safety and effectiveness of radioactive coil embolization of aneurysms: effects of radiation on recanalization, clot organization, neointima formation, and surrounding nerves in experimental models.

BACKGROUND AND PURPOSE: Recanalization after coil embolization can be prevented by radiation emitted from 32P coils. We wanted to determine the upper limits of 32P activities that could be implanted onto coils with respect to the potential injury to nearby nerves, delay in organization of the clot, and effects on neointima formation and recanalization. METHODS: We studied the effects of various 32P activities on recanalization and organization of thrombus after coil occlusion of canine arteries and on neointima formation at the neck of canine carotid bifurcation aneurysms. We also tested potential injury to nerves in the vicinity of radioactive or nonradioactive coils in 3 models: the brachial plexus (near proximal vertebral arteries) and the lingual nerve in a lingual artery bifurcation aneurysm model, both models being treated by radioactive or standard coil occlusion. Finally, we wrapped lingual nerves with nonradioactive or high-activity coils and studied their effects on lingual nerves and tongues. Results were assessed with a pathological scoring system and compared with Mann-Whitney and Kruskal-Wallis tests. RESULTS: No deleterious effect of radiation on nerves could be detected. Neointima formation was not hampered, scores of aneurysms treated with 32P-coils being significantly better when compared with treatments with standard coils (P=0.002). Arteries treated with high-activity coils (>3.39 microCi) showed absent recanalization but delayed organization of the clot at 3 months compared with low-activity or nonradioactive coils (P<0.05). CONCLUSIONS: beta-Radiation can prevent recanalization after coil occlusion. We could not demonstrate any deleterious effects of radioactivity on nervous structure or on neointima formation. Delayed organization of thrombus provides a rational basis to establish an upper limit for 32P activities to be implanted onto coils.

Poly(ADP-ribose) polymerase inhibition combined with irradiation: a dual treatment concept to prevent neointimal hyperplasia after endarterectomy.

PURPOSE: In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. METHODS AND MATERIALS: Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or with combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. RESULTS: Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. CONCLUSIONS: We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.

Is radiation a risk factor for atherosclerosis? An echo-color Doppler study on Hodgkin and non-Hodgkin patients.

AIMS AND BACKGROUND: The aim of the present paper was to study the role of irradiation in the atherosclerotic process in patients affected by Hodgkin and non-Hodgkin lymphoma. METHODS: We studied 84 subjects, 42 with Hodgkin or non-Hodgkin disease and 42 controls. All 42 cases had been irradiated and were comparable in terms of risk factors for atherosclerosis. All 84 subjects underwent echo-color Doppler of the arterial axis (carotids, abdominal aorta, and femoral arteries), and the intima-media thickness was measured. RESULTS: The irradiated cases had a greater intima-media thickness in the carotid district, even after dividing them according to age and sex; males were affected more than females. The irradiated patients were at greater risk of developing cardiovascular events than the controls. CONCLUSIONS: An echo-color Doppler of the carotid district is advisable in all patients who have been submitted to radiotherapy, and the patients with a significantly greater than normal intima-media thickness need a strict follow-up, and antioxidant or antiaggregant therapy should be considered.

Acute lumen overdilation improves outcome after brachytherapy of in-stent restenosis.

BACKGROUND: The aim of our study was to test the impact of acute lumen overdilation on neointimal hyperplasia and late lumen size after vascular brachytherapy for in-stent restenosis (ISR). METHODS: Forty-seven ISR lesions located in 47 coronary arteries in 44 consecutive patients underwent beta brachytherapy with serial intravascular ultrasound studies. Vessel, lumen, and stent cross-sectional area were measured at 1-mm steps. Based on an interpolated reference cross-sectional area, each cross section was assessed as overdilated (lumen cross-sectional area>interpolated reference cross-sectional area) or not overdilated (lumen cross-sectional area

Endovascular irradiation from beta-particle-emitting gold stents results in increased neointima formation in a porcine restenosis model.

BACKGROUND: Recent studies have shown that ionizing radiation reduces neointima formation after balloon angioplasty and stent implantation in experimental models of restenosis and first clinical trials. The objective of this study was to determine the dose distribution of a new beta-particle-emitting radioactive gold stent and to evaluate the dose-dependent vascular response in the coronary overstretch pig model. METHODS AND RESULTS: Sixteen Göttinger minipigs underwent placement of 11 nonradioactive and 36 beta-particle-emitting stents with activity levels of 10.4+/-0.6, 14.9+/-2.4, 22.8+/-1.3, 35.8+/-2. 8, and 55.4+/-5.3 microCi of (198)Au. Three months after implantation, the percent area stenosis, neointimal thickness, neointimal area, and vessel injury were analyzed by quantitative histomorphometry. The lifetime radiation doses at a depth of 1 mm were 3.3+/-0.2, 4.7+/-0.5, 7.2+/-0.4, 11.4+/-0.9, and 17.6+/-1.7 Gy for the different activity groups. No dose-response relationship was observed in the radioactive stents with respect to percent area stenosis (P=0.297), mean neointimal thickness (P=0.82), or mean neointimal area (P=0.65). Significantly lower neointima formation and less luminal narrowing was seen in the control group than in the beta-particle-emitting stents (P<0.001). Multilinear regression analysis revealed that only radioactivity made a significant independent contribution to the degree of percent area stenosis (P<0. 001). CONCLUSIONS: Neointima formation in pigs is markedly increased by beta-particle-emitting stents with (198)Au as the radioisotope. This study provides evidence that dosages of 3 to 18 Gy of low-dose-rate beta-particle irradiation via endovascular stents cause pronounced luminal narrowing in the animal model at 3 months.

Pathological effects of extensive radiofrequency energy applications in the pulmonary veins in dogs.

INTRODUCTION: The long-term complications of catheter ablation within the pulmonary veins are unknown. The development of pulmonary vein stenosis has recently been described after catheter ablation to treat either chronic or paroxysmal atrial fibrillation. The purpose of this study was to examine the pathological and hemodynamic effects of radiofrequency (RF) energy application within the pulmonary veins. METHODS AND RESULTS: Right heart and transseptal catheterization were performed in 9 anesthetized mongrel dogs. The pulmonary vein ostia were cannulated and pulmonary venous pressure was measured before RF energy application in up to 4 separate pulmonary veins. Animals were euthanized at intervals of 2 to 4 weeks (n=3), 6 to 8 weeks (n=3), or 10 to 14 weeks (n=3) after ablation. Repeat catheterization before euthanasia demonstrated statistically significant differences in pulmonary capillary wedge pressure, cardiac output, pulmonary vascular resistance, and systemic vascular resistance (P<0.05) compared with the baseline. Luminal narrowing was observed in 22 of 33 pulmonary veins to which RF energy was applied. Of these, 7 were totally occluded, 7 had severe stenosis, and 8 were only minimally narrowed. Histological examination revealed intimal proliferation with organizing thrombus, necrotic myocardium in various stages of collagen replacement, endovascular contraction, and a proliferation of elastic lamina. CONCLUSIONS: Applications of RF current within the pulmonary veins may result in pulmonary vein narrowing or complete occlusion. These observations should be considered in treatment of arrhythmias originating within the pulmonary veins.