Christian Dilcher

Repeat Intracoronary Radiation for Recurrent In-Stent Restenosis in Patients Who Failed Intracoronary Radiation

Background—Intracoronary radiation therapy (IRT) is the only proven treatment for in-stent restenosis (ISR). It is, however, associated with a significant failure rate. The present study evaluated the outcomes of patients who underwent repeat intracoronary radiation for recurrent ISR. Methods and Results—Fifty-one consecutive patients who failed a previous radiation treatment, presented with angina and angiographic evidence of ISR, and were treated with percutaneous coronary intervention (PCI) and repeat radiation to the same segment were studied. Twenty-five patients were treated with gamma radiation in a dose of 15 Gy, and 26 were treated with beta radiation doses of 18.3 to 23 Gy. The mean cumulative dose for this cohort was 39.5±11.9 Gy (range, 29 to 75.6 Gy). The outcomes of those patients were compared with outcomes of 299 patients who also failed initial radiation but were treated with repeat conventional PCI to a previously irradiated segment without repeat radiation. At 9 months after treatment, the repeat-IRT group had lower rates of target lesion revascularization (23.5% versus 54.6%; P <0.001) and major adverse cardiac events, including target vessel revascularization (29.4% versus 61.3%; P <0.001). At 9 months, patients with repeat IRT were free of angiographic and clinical events related to the radiation therapy. Conclusions—Repeat gamma or beta radiation to treat failed IRT for ISR after conventional PCI is safe and effective at 9 months and should be considered as a therapeutic option for this difficult patient subset.

Peroxisome proliferator-activated receptor gamma ligand pioglitazone alters neointimal composition in a balloon-denuded and radiated hypercholesterolemic rabbit.

Peroxisome proliferator-activated receptor (PPAR)-γ activation suppresses inflammatory response, monocyte recruitment, and vascular cell proliferation. Because inflammation, deregulated growth, and migration of monocytes and vascular smooth muscle cells (VSMC) play important roles in the development of neointima, we tested the effect of pioglitazone, a high-affinity ligand, for PPAR-γ on neointima formation in the iliac arteries of a balloon-denuded and radiated hypercholesterolemic rabbit. Rabbits were fed a 1.0% cholesterol diet for 7 days followed by denudation of endothelial layer and continued on a 0.15% cholesterol diet. On day 32, animals were divided into 2 groups. One group received a 0.15% cholesterol diet (n = 7) and the other group received a 0.15% cholesterol diet supplemented with 400 mg of pioglitazone per kilogram. On day 35, the balloon-denuded area was radiated. Four weeks after radiation, animals were sacrificed and arterial segments were processed for morphometry and immunohistochemistry. Data analysis showed that the pioglitazone group had smaller neointima (0.85 ± 0.36 vs. 1.41 ± 0.56, P < 0.05), with more cells positive for VSMC (23.07 ± 6.16 vs. 18.33 ± 5.19, P = 0.04), less for monocytes (16.01 ± 5.33 vs. 21.29 ± 4.33, P < 0.05), and fewer cells expressing metalloproteinase (MMP)-1 and MMP-9 (3.69 ± 0.47 vs. 4.82 ± 0.93, P < 0.05 and 3.24 ± 0.71 vs. 4.29 ± 0.74, P < 0.05, respectively). Pioglitazone reduced neointimal area and modified its composition in a balloon-denuded and radiated hypercholesterolemic rabbit model.

Effect of antioxidants on atherosclerotic plaque formation in balloon-denuded and irradiated hypercholesterolemic rabbits.

The oxidative modification of low-density lipoprotein (LDL) hypothesis implies that antioxidants should be effective in suppressing atherosclerosis. This study is designed to test the potential of antioxidants to inhibit atherosclerotic plaque progression in balloon-denuded and irradiated hypercholesterolemic rabbits. Rabbits were fed with a 1% cholesterol diet supplemented with or without a mixture of antioxidants (vitamin E, vitamin C, selenium, zinc, copper, manganese, N-acetylcysteine, glutamine). At 7 days both iliac arteries were balloon denuded, and 4 weeks later, 1 iliac artery underwent endovascular irradiation (n = 12), while the contralateral was sham treated (n = 12). Four weeks after irradiation, animals were euthanized, and arteries were fixed and processed for histo- or immunohistochemistry for determining the plaque area, macrophage count, and oxidized LDL-positive areas. Plasma antioxidant levels were significantly higher in the animals fed with antioxidant diet. Plasma (thiobarbituric acid-reactive substances) and arterial tissue oxidized LDL (immunoreactive to specific oxidized LDL antibody) levels were significantly higher in the irradiated as compared with nonirradiated animals (0.69 ± 0.09 and 31.05 ± 4.21 versus 0.24 ± 0.04 and 18.42 ± 4.62, P < 0.001 and 0.05), and antioxidants partially lowered the oxidized LDL levels (0.35 ± 0.14 and 25.41 ± 4.82, P < 0.001 and 0.01). Plaque area in the irradiated animals was 175% greater than in nonirradiated animals (P < 0.05). Antioxidant supplementation resulted in a 50% decrease in plaque area of both control and irradiated animals. Antioxidants reduced both the cholesterol-induced and radiation-enhanced circulating and tissue oxidized LDL levels, resulting in reduced plaque.

Dose volume histogram assessment of late stent malapposition after intravascular brachytherapy.

PURPOSE Positive remodeling and decreased neointima proliferation are among the causes for Late Stent Malapposition (LSM). It was our interest to investigate a possible relationship between dose and incidence of LSM. METHODS Index and follow up IVUS examinations of 238 patients (152 treated with Intravascular Brachytherapy (IVBT), 86 control) enrolled in IVBT trials were reviewed to identify patients with LSM. 7.2% of patients treated with IVBT and 2.3% of patients in the control group were found to have LSM on their 6-month follow-up IVUS. Using the index IVUS study. Dose Volume Histograms (DVH) were constructed for a segment of the adventitia comprising an arc deep to the area where LSM is present at follow up. For control, two areas: an arc deep to complete apposition (Control 1) and a segment within the stent but 5 mm apart from the LSM (Control 2). Volumes were defined by IVUS images that were 1 mm apart and the media-adventitial contour was taken to be 0.5 mm thick from the border. RESULTS DVH of 90% and 50% adventitial volume of LSM area received a significantly (p < .05) higher dose compared to both controls. Calculated are 12 LSM sites in 9 patients and 9 control sites. At all 12 sites Mean Cross Sectional Area of External Elastic Membrane (EEM CSA) was significantly larger in the LSM group at follow up compared to index (p-.001). CONCLUSIONS DVH analysis showed a positive correlation between radiation dose to the adventitia and incidence of LSM. The myofibroblasts in the adventitia are known to be the target for irradiation. Proliferation of myofibroblasts leads to neointima formation. LSM may be due to the higher dosages delivered to 50% and 90% of the adventitia volume (LSM area) which may have led to profound neointima suppression. In turn the neointima could not compensate positive remodeling reflected by an increase in EEM CSA.

Antioxidants attenuate atherosclerotic plaque development in a balloon-denuded and -radiated hypercholesterolemic rabbit

BACKGROUND Oxidation of lipoproteins is considered to be a key contributor to atherogenesis. Antioxidants are potential antiatherogenic agents because they can inhibit lipoprotein oxidation. Radiation has been shown to increase oxidative stress leading to increased atherogenesis. This study is designed to test the potential of antioxidants to inhibit atherosclerotic plaque progression in balloon-denuded and -radiated rabbits. METHODS AND RESULTS Two groups of New Zealand white rabbits (n=36) were fed with 1% cholesterol diet (control diet) or with 1% cholesterol diet containing a mixture of various antioxidants for 1 week. Iliac arteries in all the animals were balloon denuded and continued to fed with 0.15% cholesterol diet or 0.15% cholesterol diet containing antioxidants (antioxidant diet). Four weeks after balloon denudation one iliac artery in 12 animals from each group was radiated and all the animals were continued to be fed with the same diet. Four weeks after radiation animals were sacrificed and morphometric analysis of iliac arteries (n=12) in nonradiated and radiated animals were performed. Plaque area (PA) in the rabbits that were fed with cholesterol diet is 0.2+/-0.12 mm2, and it is increased by 2.75-fold (P<.05) in the radiated arteries of animals fed with cholesterol diet. Plaque area in the animals fed with antioxidant diet is 50% less then the one in the animals fed with cholesterol diet. Similarly, plaque area in radiated arteries of the animals fed with antioxidant diet is 50% less then the animals fed with cholesterol diet. CONCLUSION Antioxidants significantly attenuate atherosclerotic plaque progression in balloon-injured and -radiated hypercholesterolemic rabbits.

Incidence and mechanism of late stent malapposition after phosphorus-32 radioactive stent implantation

Late stent malapposition is a potential complication of intracoronary brachytherapy. The aim of our study was to determine the incidence and mechanism of late stent malapposition after implantation of phosphorus-32 radioactive stents. We analyzed 159 patients for de novo lesions after the implantation of phosphorus-32 radioactive stents. There were 15 late stent malappositions. The incidence of malapposition was higher in patients who received Hot-Ends Isostents. External elastic membrane expansion greater than plaque increase in malapposed segments was observed. Late stent malapposition is caused by a localized increase in external elastic membrane that is greater than the increase in plaque area; this is believed to be a dose-dependent phenomenon because it was more common with Hot-Ends Isostents.

Effects of gamma radiation on the noninjured and unprotected left main.

The aim of this study was to evaluate the effect of gamma radiation on the noninjured, unprotected left main coronary artery. Noninjured vessel segments are often radiated during treatment of in‐stent restenosis with PCI and gamma radiation. Angiographic analysis using QCA methods was performed on 55 left main arteries of patients (32 with radiation of the left main compared to 23 controls) who participated in the Washington Radiation for In‐Stent Restenosis Trials (WRIST). Baseline demographics and follow‐up were comparable between the two groups, concluding that gamma radiation with long radiation safety margins is feasible and safe. Gamma radiation of noninjured irradiated left main vessels when used to facilitate wide radiation margins for proximal irradiated injured LAD and LCx is safe and does not compromise the vessel integrity and its lumen. Catheter Cardiovasc Interv 2004;61:477–481.

The initial course of in-stent restenosis influences the response to vascular brachytherapy

BACKGROUND Vascular brachytherapy (VBT) reduces the rate of recurrence of in-stent restenosis (ISR) by inhibiting intimal proliferation. However, the rate of cell proliferation, reflected by the speed of ISR development, is variable in ISR lesions and might influence the responsiveness of ISR to radiation. The aim of this study was to determine the influence of the initial ISR course on the clinical outcome of patients undergoing VBT. METHODS In 1165 patients treated for ISR with VBT in the WRIST studies, we determined the time for ISR (time between initial stent implantation and restenosis), the time for VBT treatment (time between stent implantation and VBT), and previous ISR treatment with conventional strategies. Target lesion revascularization (TLR) at 6 months was available in all patients. RESULTS Previous ISR treatment did not influence the result of VBT (TLR was 17% vs. 16% without previous angioplasty). Time to ISR influences the outcome of patients undergoing VBT; TLR decreased when ISR occurred later. TLR was 18.2%, 16.7%, and 11.1% when time to ISR was <90, 90-2700, and >270 days, respectively, P=.03. Early ISR (time for ISR <90 days) is a factor for radiation failure (OR=2.1, P<.05). In patients with early ISR, TLR is lower when VBT is delayed; TLR was 11% if performed 90 days after stent implantation as compared to 22% if VBT is performed early (<90 days), P<.05. CONCLUSION The course of ISR development affects the long-term efficacy of VBT. Early restenosis remains a factor of treatment failure in the VBT era. Delaying VBT beyond 90 days after stent implantation reduces the rate of subsequent revascularization in these patients.

Radiation-induced plaque formation decreased by concomitant antioxidant diet in a hypercholesterolemic rabbit model

Purpose/Objective: Apoptotic cell death has been suggested to play an important role in the acute normal tissue injury induced by radiation. Accordingly, the ability to image radiation-induced apoptosis would aid in the detection and investigation of normal tissue injury resulting from radiotherapy as well as from environmental exposure. Near infrared optical fluorochromes can be utilized for imaging cellular events both in vivo and ex vivo. GSAO is an agent that is selectively bound in apoptotic cells. We now report on the use of 4-(N-(S-glutathionylacetyl)amino)pherylarsenoxide (GSAO) linked to the fluorochrome Cy5.5 for imaging apoptosis in the mouse spleen following total body irradiation (TBI).