Therapy For Restenosis Research Articles

Age is an important predictor of clinical outcomes following intracoronary radiation therapy for in-stent restenosis

Age is an important predictor of clinical outcomes following intracoronary radiation therapy for in-stent restenosis

Local Delivery of Plasmid DNA Into Rat Carotid Artery Using Ultrasound

Although viral vector systems are efficient to transfect foreign genes into blood vessels, safety issues remain in relation to human gene therapy. In this study, we examined the feasibility of a novel nonviral vector system by using high-frequency, low-intensity ultrasound irradiation for transfection into blood vessels. Luciferase plasmid mixed with or without echo contrast microbubble (Optison) was transfected into cultured human vascular smooth muscle cells (VSMC) and endothelial cells (EC) with the use of ultrasound. Interestingly, luciferase activity was markedly increased in both cell types treated with Optison. We then transfected luciferase plasmid mixed with Optison by means of therapeutic ultrasound into rat artery. Two days after transfection, luciferase activity was significantly higher in carotid artery transfected with luciferase gene with Optison and ultrasound than with plasmid alone. In addition, we transfected an anti-oncogene (p53) plasmid into carotid artery after balloon injury as a model of gene therapy for restenosis. Two weeks after transfection, the intimal-to-medial area ratio in rats transfected with wild-type p53 plasmid complexed with Optison by means of ultrasound was significantly decreased as compared with control, accompanied by a significant increase in p53 protein. No apparent toxicity such as inflammation could be detected in blood vessels transfected with plasmid DNA with ultrasound and Optison. Overall, we demonstrated that an ultrasound transfection method with Optison enhanced transfection efficiency of naked plasmid DNA into blood vessels without any apparent toxicity. Transfection of p53 plasmid with the use of this method should be useful for safe clinical gene therapy without a viral vector system.

Takayasu's arteritis

THE LANCET • Vol 359 • February 16, 2002 • www.thelancet.com 557 11 Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336: 1697–703. 12 Waksman R, White RL, Chan RC, et al. Intracoronary radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000; 101: 2165–71. 13 Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma radiation therapy to inhibit the recurrence of restenosis after stenting N Engl J Med 2001; 344: 250–56. 14 Kleiman NS, Califf RM. Results from late-breaking clinical trials sessions at ACCIS 2000 and ACC 2000. JACC 2000; 36: 310–25. 15 Waksman R, Bhargava B, White L, et al. Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000; 101: 1895–98. 16 Raizner AE, Oesterle S, Waksman R, et al. The PREVENT trial, a feasibility study of intracoronary brachytherapy in the prevention of restenosis: an interim report. Circulation 1998; 98: 3423. 17 Waksman R, Bhargava B, Mintz GS, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000; 36: 65–68. 18 Waksman R, Ajani EA, White L, et al. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary radiation in patients with in-stent restenosis: Washington radiation for in-stent restenosis trial plus 6 months of clopidogrel (WRIST PLUS). Circulation 2001; 103: 2328–31. 19 Kim HS, Waksman R, Cottin Y, et al. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. J Am Coll Cardiol 2000; 37: 1026–30. 20 Verin V, Popowski Y, De Bruyne B, et al. Endoluminal beta radiation therapy for the prevention of coronary restenosis after balloon angioplasty. N Engl J Med 2001; 344: 243–49.

Gene therapy for restenosis: current status.

Atherosclerosis is a major cause of morbidity and mortality in Western world. Vascular occlusion caused by atherosclerosis usually requires invasive treatment, such as surgical bypass or angioplasty. However, bypass graft failure and restenosis limit the usefulness of these procedures, with 20% of patients needing a new revascularisation procedure within 6 months of angioplasty. Numerous pharmacological agents have been investigated for the prevention of restenosis but none has shown undisputed efficacy in clinical medicine. Gene transfer offers a novel approach to the treatment of restenosis because of easy accessibility of vessels and already existing gene delivery methods. It can be used to overexpress therapeutically important proteins locally without high systemic toxicity, and the therapeutic effect can be targeted to a particular pathophysiological event. Promising results have been obtained from many pre-clinical experiments using therapeutic genes or oligonucleotides to prevent restenosis. Early clinical trials have shown that plasmid- and adenovirus-mediated vascular gene transfers can be conducted safely and are well tolerated. Ex vivo gene therapy with E2F-decoy succeeded in reducing graft occlusion rate after surgical bypass in a randomised, double-blind clinical trial. In the future, further development of gene delivery methods and vectors is needed to improve the efficacy and safety of gene therapy. Also, better knowledge of vascular biology at the molecular level is needed to find optimal strategies and gene combinations to treat restenosis. Provided that these difficulties can be solved, gene therapy offers an enormous potential for clinical medicine in the future.

Abstract

Purpose. Irradiation of the arterial wall with beta particles has been shown to be effective in inhibiting neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA). In this study, we describe the use of 188W/188Re generators to obtain 188Re (half-life 16.9 h, maximal beta energy of 2.12 MeV) as a new candidate radioisotope for endovascular irradiation. We have evaluated two [188Re]-compounds as candidates for use as solution-based radiation sources that would allow conventional liquid-filled balloon inflation for delivery of radiation to the vessel wall. While balloon rupture at nominal inflation pressures is a very rare event, (<1 per 10,000 at high pressure), radioisotope release could potentially result in significant dose to radiation-sensitive organs. We have thus evaluated the biodistribution, dosimetry, and kinetics of excretion in rats of two 188Re-labeled compounds that are proposed for intravascular therapy.Materials and Methods. Rhenium-188 was obtained as [188Re]-sodium perrhenate by saline elution of an alumina-based 188W/188Re generator system (>500 mCi). High specific volume solutions of the [188Re]-sodium perrhenate (>50 mCi/ml) were obtained by postelution concentration of the generator bolus by passage through a tandem silver cation/anion column system. Rhenium-188-labeled benzoylthioacetyltriglycine (MAG3) was prepared by stannous ion reduction of [188Re]-perrhenate in the presence of the benzyl-MAG3 substrate, and was characterized as a single radioactive component. Rhenium-188-perrhenate and [188Re]-MAG3 were administered to separate groups of Fischer rats, which were sacrificed at various times and the tissue distribution of 188Re determined in the major organs. Excretory products were also collected daily from separate groups of rats for each agent over 7 days. The effects of perchlorate and iodide preblocking and postdisplacement of thyroid uptake of [188Re]-perrhenate were also evaluated.Results. Organ uptake values were modest for both agents [<0.25 % injected dose(ID)/gram of tissue at 6 h] for all organs evaluated except for the thyroid, with the intestines and intestinal contents showing the highest uptake values (0.72–1.97 %ID/gram). Whereas thyroid uptake of 188Re after injection of [188Re]-MAG3 was low (0.16 %ID/gram), uptake after injection of [188Re]-perrhenate was higher and could be blocked by pretreatment with perchlorate (intravenous [IV]) or displaced by perchlorate posttreatment. Also, oral or IV iodide pre- or postadministration could also significantly block or displace thyroid uptake of [188Re]-perrhenate. Both [188Re] agents were excreted primarily via the urinary bladder. The excretion half-life of [188Re]-perrhenate was about 7 h; in contrast, the [188Re]-MAG3 complex showed 50% excretion in less than 2 h. The large intestines received the most significant adsorbed dose, with values of 2.0 cGy/mCi for [188Re]-perrhenate and 4.6 × 10−3 cGy/mCi for [188Re]-MAG3.Conclusions. Rhenium-188-MAG3 shows more rapid urinary bladder excretion in rats than perrhenate and both agents show low organ uptake. Thyroid uptake of free [188Re]-perrhenate can be blocked or displaced with oral perchlorate administration. For the projected use of [188Re]-MAG3 for balloon inflation required for irradiation of the arterial wall, calculated organ dose values are within acceptable limits in the unlikely event of low pressure balloon rupture. Rhenium-188-MAG3 in solution is thus a new candidate for balloon dilation providing uniform endovascular irradiation following PTCA for restenosis therapy. Published by Elsevier Science Inc.

Adenovirus-mediated gene transfer of a secreted transforming growth factor-beta type II receptor inhibits luminal loss and constrictive remodeling after coronary angioplasty and enhances adventitial collagen deposition.

Extracellular matrix (ECM) remodeling is central to the development of restenosis after coronary angioplasty (PTCA). As a regulator of ECM deposition by vascular cells, substantial evidence implicates transforming growth factor-beta1 (TGF-beta1) in the pathogenesis of restenosis. We investigated the effects of intracoronary expression of a transgenic antagonist of TGF-beta1 on luminal loss after PTCA. Porcine coronary arteries were randomized to receive a recombinant adenovirus expressing a secreted form of TGF-beta type II receptor (Ad5-RIIs), an adenovirus expressing beta-galactosidase (Ad5-lacZ), or vehicle only by intramural injection at the site of PTCA. Computerized morphometry 28 days after angioplasty revealed a greater minimum luminal area in Ad5-RIIs-injected arteries (1.71+/-0.12 mm(2)) than in the Ad5-lacZ (1.33+/-0.13 mm(2)) or vehicle-only (1.08+/-0.17 mm(2); P=0.010 by ANOVA) groups. This was accompanied by greater areas within the internal (P=0.013) and external (P=0.031) elastic laminae in Ad5-RIIs-treated vessels. Adventitial collagen content at the site of injury was increased in the Ad5-RIIs group, in contrast to decreases in the Ad5-lacZ and vehicle-only groups (P=0.004). Adenovirus-mediated antagonism of TGF-beta1 at the site of PTCA reduces luminal loss after PTCA by inhibiting constrictive remodeling. Antagonism of TGF-beta1 stimulates the formation of a dense collagenous adventitia, which prevents constrictive remodeling by acting as an external scaffold. These findings demonstrate the potential of gene therapy-mediated antagonism of TGF-beta1 as prophylactic therapy for restenosis.

Comparison of 3-dimensional conformal external beam radiotherapy vs. endovascular brachytherapy for stented coronary arteries

Purpose: Endovascular brachytherapy is a potent new therapy for restenosis, but suffers from several biological, physical and logistic disadvantages that - in theory - could be addressed by external beam radiotherapy (EBR). However, the results with EBR using relatively large radiation fields have been inconsistent. Three-dimensional (3D) conformal EBR would offer the possibility to use small radiation fields, e.g. targeted at the volume encompassing all 3D positions of a coronary stent during the cardiac cycle. The design of such fields would require knowledge of the 3D position of the stent throughout the cardiac cycle. The purpose of this study was to define the target volume for 3D conformal EBR to treat restenotic stented coronary arteries.

Three-year follow-up after intracoronary gamma radiation therapy for in-stent restenosis: Original WRIST

Background: The Washington Radiation for In-Stent Restenosis Trial (WRIST) is a double-blinded randomized study evaluating the effects of intracoronary radiation therapy (IRT) in patients with in-stent restenosis (ISR). Methods: One hundred and thirty patients with ISR (100 native coronary and 30 vein grafts) underwent PTCA, laser ablation, rotational atherectomy, and/or additional stenting (36% of lesions). Patients were randomized to either Iridium-192 IRT or placebo, with a prescribed dose of 15 Gy to a 2-mm radial distance from the center of the source. Results: Angiographic restenosis (27% vs. 56%, P=.002) and target vessel revascularization (TVR; 26% vs. 66%, P<.001) were dramatically reduced at 6 months in IRT patients. Between 6 and 36 months, IRT compared to placebo patients had more target lesion revascularization (TLR; IRT=17% vs. placebo=2%, P=.002) and TVR (IRT=17% vs. placebo=3%, P=.009). At 3 years, the major adverse cardiac event (MACE) rate was significantly reduced with IRT (39% vs. 65%, P=.003). Conclusions: In WRIST, patients with ISR treated with IRT using 192Ir had a marked reduction in the need for repeat target lesion and vessel revascularization at 6 months, with the clinical benefit maintained at 3 years.

Gene transfer therapy in vascular diseases.

Somatic gene therapy of vascular diseases is a promising new field in modern medicine. Recent advancements in gene transfer technology have greatly evolved our understanding of the pathophysiologic role of candidate disease genes. With this knowledge, the expression of selective gene products provides the means to test the therapeutic use of gene therapy in a multitude of medical conditions. In addition, with the completion of genome sequencing programs, gene transfer can be used also to study the biologic function of novel genes in vivo. Novel genes are delivered to targeted tissue via several different vehicles. These vectors include adenoviruses, retroviruses, plasmids, plasmid/liposomes, and oligonucleotides. However, each one of these vectors has inherent limitations. Further investigations into developing delivery systems that not only allow for efficient, targeted gene transfer, but also are stable and nonimmunogenic, will optimize the clinical application of gene therapy in vascular diseases. This review further discusses the available mode of gene delivery and examines six major areas in vascular gene therapy, namely prevention of restenosis, thrombosis, hypertension, atherosclerosis, peripheral vascular disease in congestive heart failure, and ischemia. Although we highlight some of the recent advances in the use of gene therapy in treating vascular disease discovered primarily during the past two years, many excellent studies published during that period are not included in this review due to space limitations. The following is a selective review of practical uses of gene transfer therapy in vascular diseases. This review primarily covers work performed in the last 2 years. For earlier work, the reader may refer to several excellent review articles. For instance, Belalcazer et al. (6) reviewed general aspects of somatic gene therapy and the different vehicles used for the delivery of therapeutic genes. Gene therapy in restenosis and stimulation of angiogenesis in the cardiac muscle are discussed in reviews by several investigators (13,26,57,74,83). In another review, Meyerson et al. (43) discuss advances in gene therapy for vascular proliferative disorders and chronic peripheral and cardiac ischemia.

Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis

Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis

Fas ligand/Fas-mediated apoptosis in human coronary artery smooth muscle cells: therapeutic implications of fratricidal mode of action

This study aimed to determine the mode of action of Fas ligand (FasL)/Fas at mediating apoptosis so as to evaluate the potential of FasL in gene therapy for restenosis. Passaged human coronary artery smooth muscle (HCASM) cells were infected with recombinant adenoviral vectors expressing murine FasL. Various parameters of FasL expression and apoptosis were measured using FACS, immunofluorescence, calorimetric, and cytotoxicity assays. Most HCASM cells under normal growth conditions expressed Fas and were shown to be susceptible to membrane bound but not soluble FasL. However, some FasL expressing cells survived for up to 7 days. These surviving cells were observed to be spatially distributed and were not in direct physical contact with each other. Upon examination, it was determined that although the majority of the surviving cells expressed FasL, only 30% expressed both Fas and FasL. These cells were capable of inducing apoptosis of target cells and some were also susceptible to FasL expressing cells, provided that the effector and target cells were in close physical contact. FasL/Fas-mediated apoptosis was inhibited by p35, a baculovirus gene that inhibits caspases. Additionally, in contrast to HCASM cells, neither membrane-bound nor soluble FasL induced apoptosis in coronary artery endothelial cells. FasL expressing HCASM cells do not undergo FasL/Fas mediated "suicide" but kill neighboring cells bearing Fas in a "fratricidal" manner. A small population of HCASM cells expresses no surface Fas. These results imply that HCASM cells transduced in vivo with FasL may serve as "scavengers" and exert a bystander effect on surrounding cells that may be enhanced by co-expression of p35. As FasL-mediated apoptosis occurs in coronary arterial smooth muscle but not endothelial cells, FasL may also offer an advantage over other genes for use in restenosis since the latter may indiscriminately delay re-endothelialization at the sites of gene.

Endovascular treatment of renal artery stenosis.

Significant changes have occurred in the treatment of renal artery disease over the past few years. Although excellent clinical results can be obtained with surgery, percutaneous transluminal renal angioplasty has proved similarly efficacious and is now the treatment of choice for nonostial atherosclerotic stenoses and fibromuscular dysplasia. The introduction of stents has become a valuable adjunctive therapy for postangioplasty restenosis and dissection.

Recombinant Sendai virus-mediated gene transfer to vasculature: a new class of efficient gene transfer vector to the vascular system.

SPECIFIC AIMSFrustrations associated with currently available vectors in gene therapy for clinical restenosis involve either lower gene transfer efficiency (for lipid and adeno-associated virus) or...

Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis

OBJECTIVESWe sought to determine the relationship between geographical miss (GM) and edge restenosis (ERS) following intracoronary radiation therapy.BACKGROUNDEdge restenosis may be a limitation of intracoronary irradiation to prevent in-stent restenosis (ISR). Inadequate radiation source coverage of the injured segment (GM) has been proposed as a cause of ERS. We studied the relationship between GM and ERS following 192Ir treatment of ISR.METHODSThere were 100 patients with native vessel ISR in WRIST (Washington Radiation for In-Stent Restenosis Trial), in which patients with ISR were first treated with conventional techniques and then randomized to gamma irradiation (192Ir) or placebo. Geographical miss was defined as segments proximal or distal to the treated lesion that were subjected to injury during primary intervention but were not covered by the radiation source.RESULTSGeographical miss was documented in 56 of 164 edges (34%). Edge restenosis was noted at eight of 80 radiated edges and in four of 84 placebo edges. In the irradiated group, ERS was observed in 21% of edges with GM and in 4% of edges without GM (p = 0.035). In contrast, in the placebo group, ERS was observed in only 7% of edges with GM and in 4% of edges without GM (p = NS). The late edge lumen loss was higher in the irradiated group with GM as compared to placebo with GM (0.74 ± 0.57 vs. 0.41 ± 0.50 mm, p = 0.016).CONCLUSIONSEdge restenosis following gamma irradiation treatment of ISR is related to GM: a mismatch between the segment of artery injured during the primary catheter-based intervention and the length of the radiation source.

Characterization of a soft x-ray source for intravascular radiation therapy

Purpose: A soft X-ray device for intravascular radiation therapy of restenosis is characterized in terms of dose delivery for several artery configurations, including arteries with implanted stents, calcified plaque, and noncentered sources. Methods and Materials: The Monte Carlo code MCNP4B was used to determine the X-ray fluence and energy spectra for 15, 20, and 30-kV X-ray source generating voltages. Dose as a function of distance was calculated under a variety of artery conditions. Results: Calculated depth–dose profiles for the X-ray sources are within presumed artery dose tolerance limits for the range of generating voltages considered. Treatment times to deliver 8 Gy to the adventitia range from 2.7 minutes to 6.7 minutes for the 20-kV generating voltage and a 3-cm-long lesion, depending on the diameter of the artery. The does perturbation due to stent wires or calcified plaque is found to be more severe for the X-ray sources than for the radioactive sources. The effects of noncentering are found to be similar for radioactive sources and X-ray sources with generating voltages of 20 kV or higher. Conclusion: The results of this study indicate that soft X-ray sources are suitable candidates for intravascular radiation therapy over a wide range of artery sizes, tissue compositions, and stent configurations.

Effects of probucol on rat carotid artery responses to balloon catheter injury

Balloon catheter injury to the rat common carotid artery has been widely used for testing potential therapies for post-angioplasty restenosis. However, the model has become somewhat discredited because a number of drugs that inhibit intimal thickening, measured 14 days after balloon catheter injury, have been found to be ineffective in clinical trials. Probucol has recently been shown to reduce the incidence of post-angioplasty restenosis in a number of small clinical trials, making it possible to reassess the validity of the rat balloon injury model. The effects of probucol on the underlying causes of intimal thickening in balloon-injured rat carotid arteries were quantified. Probucol inhibited medial smooth muscle cell proliferation by 23% on day 4 after injury ( P=0.009), and by 65% on day 10 after injury ( P=0.026). Smooth muscle cell migration was reduced by 64% ( P=0.008) in probucol-treated animals. In marked contrast, intimal smooth muscle cell proliferation was significantly increased by 41% ( P=0.024) by probucol. There was no significant effect on intimal thickening or smooth muscle cell death. These data suggest that drugs that inhibit both medial smooth muscle cell proliferation and migration in the rat balloon injury model may prove useful in the treatment of post-angioplasty restenosis.

The effect of intracoronary gamma-radiation therapy for in-stent restenosis: an intravascular ultrasound study

The effect of intracoronary gamma-radiation therapy for in-stent restenosis: an intravascular ultrasound study

Treatment of restenosis by controlled‐release delivery systems of tyrphostins

Percutaneous transluminal coronary angioplasty (PTCA) procedures include balloon dilation, excisional atherectomy, endoluminal stenting, and laser ablation. However, despite significant advances in reducing the acute complications of percutaneous revascularization procedures with premedications and better techniques, chronic restenosis of dilated lesions remains a serious and frequent problem. The neointimal formation is dependent on smooth muscle cells and most probably fibroblast proliferation and migration mediated by various cytokines and growth factors. The unsuccessful attempts to control restenosis by systemic pharmacological interventions have prompted many researchers to look for more promising therapeutic approaches such as local drug delivery. In this review we discuss the rationale for local drug delivery based on restenosis pathophysiology, local drug delivery approaches, the rationale for antiproliferative therapy, and review the in vitro and in vivo studies of local drug delivery systems of tyrphostins (protein tyrosine kinase inhibitors) in restenosis therapy.

Gene therapy for restenosis.

Atherosclerosis is one of the leading causes of major morbidity and mortality in the United States. Arterial insufficiency resulting from flow-limiting lesions can lead to myocardial, renal, mesenteric, and extremity dysfunction. Treatments for these atherosclerotic arterial lesions include arterial bypass and angioplasty. These therapies are limited by the development of intimal hyperplasia (IH), thus reducing hemodynamic improvement significantly. A number of pharmacological agents with antiplatelet and anticoagulant properties have failed to reduce the incidence and rate of restenosis. Because of the magnitude of the patient population affected by IH, there has been a tremendous need to develop a therapy that will successfully reduce its incidence. Over the last decade, the field of vascular gene therapy has emerged as a viable therapeutic approach, permitting the targeting of genes to produce local and transient effects on the development of IH. This review will discuss the rationale and preliminary data for the different genes that have been evaluated to date. One of the first reports of successful gene transfer to vascular cells was by Nabel et al in 1989.1 These investigators transfected porcine endothelial cells ex vivo with a retrovirus encoding the β-galactosidase gene and reintroduced the cells onto the denuded iliofemoral artery of a syngeneic animal. The arterial segments isolated 2 to 4 weeks later demonstrated endothelial cells that expressed the β-galactosidase gene, thus indicating successful incorporation of the transgene into the transduced cells. Landmark follow-up experiments in which herpes simplex virus thymidine kinase (HSV-tk) was delivered to injured porcine iliac2 or rat carotid3 arteries using an adenoviral vector were published 5 years later (see Table online; http://www.circresaha.org). This approach, which is based on the conversion of coadministered ganciclovir to a toxic metabolite by HSV-tk, decreased the neointima by 86% in the porcine model2 and 46% in the …

Meeting highlights: the 11th Annual Symposium on Transcatheter Cardiovascular Therapeutics.

The following studies were presented at the 11th Annual Symposium on Transcatheter Cardiovascular Therapeutics, September 22–26, 1999, in Washington, DC. ### GAMMA 1 The Presenter: Martin Leon, Cardiology Research Foundation, Washington Heart Center, Washington, DC. The Study: A multicenter, randomized, prospective, placebo-controlled study of radiation therapy for in-stent restenosis. A total of 252 patients with in-stent restenosis in native coronary arteries were randomized to receive adjunctive radiation therapy with an Ir192 gamma source (n=131) or sham placebo treatment (n=121) after percutaneous therapy (at the discretion of the operator). Dosimetry was guided by intraprocedural intravascular ultrasound (IVUS) measurements. All patients received aspirin and ticlopidine for 8 weeks. Follow-up angiography was performed at 6 months, with measurement of both in-lesion and in-stent minimum lumen diameter (MLD). The primary end point of the study was the cumulative incidence of adverse clinical events (death, myocardial infarction [MI], or target lesion revascularization) at 9 months. Results: More than 80% of the patients received additional adjunctive stents as part of their therapy. In-hospital outcomes were similar between groups. The primary end point was significantly reduced in the radiation therapy group (28.2% versus 43.8% in the sham treatment group); this was largely driven by a dramatic reduction in the need for target vessel revascularization. However, the composite incidence of death or MI tended to be somewhat higher in the radiation therapy group (16% versus 8% in the sham treatment group), and there was a significant increase in the incidence of late stent closure in the radiation therapy group (6.1% versus 0% in the sham treatment group). On qualitative coronary angiography at 6 months, in-stent MLDs were significantly higher in the radiation therapy group; in-lesion MLDs also tended to be higher with radiation. This effect was somewhat more prominent in shorter lesions, and it was very prominent in diabetic patients. There …