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Background— Restenosis requiring reintervention is the main limitation of coronary angioplasty. Intracoronary irradiation reduces neointimal proliferation. We studied the efficacy of a self-centering liquid rhenium-188–filled balloon catheter for coronary β-brachytherapy. Methods and Results— After successful coronary angioplasty with or without stenting, 225 patients (71% de novo lesions) were randomly assigned to receive 22.5 Gy intravascular β-irradiation in 0.5-mm tissue depth (n=113) or to receive no additional intervention (n=112). Clinical and procedural data did not differ between the groups except a higher rate of stenting in the control group (63%) compared with the rhenium-188 group (45%, P P P P P P =0.006). Conclusions— Intracoronary β-brachytherapy with a rhenium-188 liquid-filled balloon is safe and efficiently reduces restenosis and revascularization rates after coronary angioplasty.

Background— Observations from previous intracoronary radiation therapy trials noted a considerable discrepancy between the prescribed radiation dose and the dose actually delivered. The aims of this study were to investigate the effect of actual delivered dose on vascular changes and to test the appropriateness of the current dose prescription. Methods and Results— Serial volumetric intravascular ultrasound (IVUS) analysis was performed in 30 in-stent restenosis cases treated with a 40-mm 90 Sr/Y source train. The fixed dose was prescribed at 2 mm from the centerline of the source train (18.4 Gy at 2 mm for reference diameter ≤3.35 mm and 23 Gy for diameter ≥3.36 mm). Only stent segments with full radiation coverage and device injury were enrolled and divided into 2-mm-long subsegments (n=202). D S90 EEM (the minimum dose absorbed by 90% of the external elastic membrane surface) was calculated as the delivered dose corresponding to each segment, assuming that the radiation catheter occupied the same position in the vessel as the IVUS catheter. Mean D S90 EEM of 23.5±5.82 Gy (range 12.3 to 41.7 Gy) was delivered to these subsegments. Overall, intimal hyperplasia volume remained constant from postintervention to follow-up (2.23±1.10 to 2.32±1.09 mm 3 /m; P =NS). Regression analysis revealed there was no correlation between delivered dose intensity and changes in intimal hyperplasia volume. No particular dose-dependent complications were appreciated in this delivered dose range. Conclusions— The current dose-prescription protocol of 90 Sr/Y radiation to native in-stent restenosis lesions may provide substantial inhibition of neointimal reproliferation regardless of the actual delivered dose intensity.

Background Long-term biological effects of ionizing radiation on coronary arteries remain poorly defined. We examined late arterial responses 6 months after balloon angioplasty and β-radiation in normal pig coronary arteries. Methods and Results Coronary arteries of 25 adult pigs were randomized to receive 20 Gy (n=8) or 30 Gy (n=9) of 186 Re β-radiation or sham radiation (n=8) immediately after balloon angioplasty. Aspirin was given daily during follow-up. The study vessels were analyzed histopathologically at 6 months. β-Radiation decreased lumen area (20 Gy, 1.55±0.99 mm 2 ; 30 Gy, 1.03±0.82 mm 2 ; and 0 Gy, 2.05±0.80 mm 2 ; P 2 ; 30 Gy, 1.51±0.97 mm 2 ; and 0 Gy, 0.89±0.31 mm 2 ; 0 Gy versus 20 Gy, P 2 ; 20 Gy, 0.98±1.57 mm2; and 0 Gy, 0.00±0.01 mm 2 ; P 2 ; 30 Gy, 2.38±0.98 mm 2 ; and 0 Gy, 1.23±0.29 mm 2 ; 0 Gy versus 20 or 30 Gy, P Conclusions Intracoronary β-radiation did not inhibit neointima formation in balloon-injured normal pig coronary arteries 6 months after the interventional procedure. Unresorbed thrombus contributed to, but was not the sole component of, augmented neointima formation. Irradiated vessels demonstrated more adventitial thickening and fibrosis. These observations may have relevance for long-term clinical outcomes after intracoronary β-radiation.

Background —The data on the long-term safety and efficacy of intracoronary β-radiation in animal models are limited. Methods and Results —A total of 30 coronary arteries in 15 swine were subjected to balloon or stent injury followed by β-radiation from a centered 32 P source (2000 cGy to 1 mm beyond lumen surface) or a sham radiation procedure. The animals received aspirin for 6 months and ticlopidine for 30 days. Five of the 10 animals subjected to radiation died (at 5 days, 7 days, 3 months [n=2], and 4 months) as a result of layered, occlusive thrombus at the intervention site (3 stent and 2 balloon injury sites). No deaths occurred in the control group. In the surviving animals, balloon-injured and irradiated vessels showed a trend toward larger lumens than controls (2.15±0.17 versus 1.80±0.08 mm 2 , P =0.06) and larger external elastic lamina areas (3.32±0.21 versus 2.62±0.10 mm 2 , P =0.003). In the stent-injured vessels from surviving animals, lumen, neointimal, and external elastic lamina areas were 3.58±0.33, 3.16±0.35, and 8.12±0.42 mm 2 for irradiated vessel segments; these values were not different from those in controls (3.21±0.15, 2.84±0.27, and 7.76±0.28 mm 2 , respectively). Histologically, healing was complete in most survivors, although intramural fibrin and hemorrhage were occasionally seen. Conclusion —In the long-term (6 month) porcine model of restenosis, the inhibition by intracoronary β-radiotherapy of the neointimal formation that is known to be present at 1 month is not sustained. This lack of effect on neointimal formation after balloon and stent arterial injury is accompanied by subacute and late thrombosis that leads to cardiac death on a background of continuous aspirin but relatively brief ticlopidine treatment.

Background —Restenosis within stents may be prevented by ionizing radiation from an intravascular source. Methods and Results —A liquid β − radiation ( 188 Re) balloon was evaluated in a randomized and blinded porcine coronary model of stent restenosis. Group A pigs (n=17) received 0,16, 22, or 29 Gy at 0.5-mm depth, followed by stenting. Restenosis was quantified by angiography, ultrasound, and histomorphometry at 30 days. Group B (n=7) was stented first and then treated with 0 or 29 Gy with follow-up at 60 days. There was a measurable effect at 16 Gy, which improved with increasing doses. At 29 Gy, the histological stenotic area was reduced by 67% (22% versus 66% in controls, P P P =0.003). Radiated vessels had distinctive histology consisting of neointimal fibrin and reduced smooth muscle cells and matrix ( P Conclusions — 188 Re balloon brachytherapy in porcine coronary arteries results in dose-dependent and injury-independent inhibition of stent restenosis for up to 60 days. Restenosis at the borders of the irradiated zone is a potential limitation and may be related to underdosing. Brachytherapy with the 188 Re balloon appears to be safe and feasible for clinical studies.

Background —A recognized limitation of endovascular β-radiation therapy is the development of new stenosis at the edges of the irradiated area. The combination of injury and low-dose radiation may be the precursor of this phenomenon. We translated the radio-oncological concept of “geographic miss” to define cases in which the radiation source did not fully cover the injured area. The aims of the study were to determine the incidence and causes of geographic miss and evaluate the impact of this inadequate treatment on the outcome of patients treated with intracoronary β-radiation. Methods and Results —We analyzed 50 consecutive patients treated with β-radiation after percutaneous coronary intervention. The prescribed dose ranged between 12 and 20 Gy at 2 mm from the source axis. By means of quantitative coronary angiography, the irradiated segment (IRS) and both edges were studied before and after intervention and at 6-month follow-up. Edges that were injured during the procedure constituted the geographic miss edges. Twenty-two edges were injured during the intervention, mainly because of procedural complications that extended the treatment beyond the margins of the IRS. Late loss was significantly higher in geographic miss edges than in IRSs and uninjured edges (0.84±0.6 versus 0.15±0.4 and 0.09±0.4 mm, respectively; P P Conclusions —These data support the hypothesis that the combination of injury and low-dose β-radiation induces deleterious outcome.

Background —Intracoronary γ-radiation therapy reduces recurrent in-stent restenosis (ISR). This study, BETA WRIST (Washington Radiation for In-Stent restenosis Trial) was designed to examine the efficacy and safety of the β-emitter 90-yttrium for the prevention of recurrent ISR. Methods and Results —A total of 50 consecutive patients with ISR in native coronaries underwent percutaneous transluminal coronary angioplasty, laser angioplasty, rotational atherectomy, and/or stent implantation. Afterward, a segmented balloon catheter was positioned and automatically loaded with a 90-yttrium, 0.014-inch source wire that was 29 mm in length to deliver a dose of 20.6 Gy at 1.0 mm from the balloon surface. In 17 patients, manual stepping of the radiation catheter was necessary for lesions >25 mm in length. The radiation was delivered successfully to all patients, with a mean dwell time of 3.0±0.4 minutes. Fractionation of the dose due to ischemia was required in 11 patients. At 6 months, the binary angiographic restenosis rate was 22%, the target lesion revascularization rate was 26%, and the target vessel revascularization rate was 34%; all rates were significantly lower than those of the placebo group of γ-WRIST. Conclusions —β-Radiation with a 90-yttrium source used as adjunct therapy for patients with ISR results in a lower-than-expected rate of angiographic and clinical restenosis.

Background —The main complications of PTCA remain thrombosis and restenosis. Recent studies have demonstrated reduction in the neointimal hyperplasia after intracoronary radiation (IR) with doses of 10 to 25 Gy of ionizing radiation delivered by either β- or γ-emitters to injured vessels. The purpose of this study was to examine the effect of ionizing radiation on the thrombosis rate (TR) of injured porcine coronary arteries. Methods and Results —Thirty-four juvenile swine (63 coronary arteries) were subjected to overstretch balloon injury followed by IR with doses of 0 to 18 Gy of either β- or γ-radiation. Two weeks after treatment, tissue sections were perfusion-fixed, stained with hematoxylin-eosin and Verhoeff–van Gieson’s stain, and analyzed for presence of a thrombus, thrombus morphology, and neointima formation by computer-assisted histomorphometry techniques. Although the overall TR increased dose-dependently from 0 to 18 Gy prescribed dose, luminal thrombi decreased. Thrombus area also decreased with increasing radiation dose, whether assessed at the prescription point or at the luminal surface, which corresponded to decreased intimal area. Furthermore, luminal thrombi present after IR tended to consist mostly of fibrin and thus were less organized than in controls. Conclusions —These results suggest that IR induces thrombosis but does not necessarily compromise the lumen. Strategies for reducing TR may further decrease intimal area as well as increasing the safety of this therapy.

Background —This study represents the Heart Center Rotterdam’s contribution to the Isostents for Restenosis Intervention Study, a nonrandomized multicenter trial evaluating the safety and feasibility of the radioactive Isostent in patients with single coronary artery disease. Restenosis after stent implantation is primarily caused by neointimal hyperplasia. In animal studies, β-particle–emitting radioactive stents decrease neointimal hyperplasia by inhibiting smooth muscle cell proliferation. Methods and Results —The radioisotope 32 P, a β-particle emitter with a half-life of 14.3 days, was directly embedded into the Isostent. The calculated range of radioactivity was 0.75 to 1.5 μCi. Quantitative coronary angiography measurements were performed before and after the procedure and at 6-month follow-up. A total of 31 radioactive stents were used in 26 patients; 30 (97%) were successfully implanted, and 1 was embolized. Treated lesions were in the left anterior descending coronary artery (n=12), the right coronary artery (n=8), or the left circumflex coronary artery (n=6). Five patients received additional, nonradioactive stents. Treated lesion lengths were 13±4 mm, with a reference diameter of 2.93±0.47 mm. Minimum lumen diameter increased from 0.87±0.28 mm preprocedure to 2.84±0.35 mm postprocedure. No in-hospital adverse cardiac events occurred. All patients received aspirin indefinitely and ticlopidine for 4 weeks. Twenty-three patients (88%) returned for 6-month angiographic follow-up; 17% of them had in-stent restenosis, and 13% had repeat revascularization. No restenosis was observed at the stent edges. Minimum lumen diameter at follow-up averaged 1.85±0.69 mm, which resulted in a late loss of 0.99±0.59 mm and a late loss index of 0.53±0.35. No other major cardiac events occurred during the 6-month follow-up. Conclusions —The use of radioactive stents with an activity of 0.75 to 1.5 μCi is safe and feasible.

Background —Abnormal endothelium-dependent coronary vasomotion has been reported after balloon angioplasty (BA), as well as after intracoronary radiation. However, the long-term effect on coronary vasomotion is not known. The aim of this study was to evaluate the long-term vasomotion of coronary segments treated with BA and brachytherapy. Methods and Results —Patients with single de novo lesions treated either with BA followed by intracoronary β-irradiation (according to the Beta Energy Restenosis Trial-1.5) or with BA alone were eligible. Of these groups, those patients in stable condition who returned for 6-month angiographic follow-up formed the study population (n=19, irradiated group and n=11, control group). Endothelium-dependent coronary vasomotion was assessed by selective infusion of serial doses of acetylcholine (ACh) proximally to the treated area. Mean luminal diameter was calculated by quantitative coronary angiography both in the treated area and in distal segments. Endothelial dysfunction was defined as a vasoconstriction after the maximal dose of ACh (10 −6 mol/L). Seventeen irradiated segments (89.5%) demonstrated normal endothelial function. In contrast, 10 distal nonirradiated segments (53%) and 5 control segments (45%) demonstrated endothelium-dependent vasoconstriction (−19±17% and −9.0±5%, respectively). Mean percentage of change in mean luminal diameter after ACh was significantly higher in irradiated segments ( P =0.01). Conclusions —Endothelium-dependent vasomotion of coronary segments treated with BA followed by β-radiation is restored in the majority of stable patients at 6-month follow-up. This functional response appeared to be better than those documented both in the distal segments and in segments treated with BA alone.

Background Considerable experimental evidence exists that neointimal hyperplasia after angioplasty is inhibited by γ-irradiation of the treated arteries. A β-particle radiation is absorbed in tissue within a shorter distance away from the source than γ-radiation and may be more suitable for localized vessel irradiation. This study outlines a method to implant a β-particle–emitting radioisotope ( 32 P; half-life, 14.3 days) into metallic stents. The effects of these stents on the inhibition of neointimal hyperplasia was compared with conventional stents in a rabbit model. Methods and Results 32 P was produced by irradiation of red amorphous phophorus ( 31 P) with neutrons and was implanted into Palmaz-Schatz stents (7.5 mm in length) after being kept apart from 31 P in a mass separator. The radioisotope was tightly fixed to the stents, and the ion implantation process did not alter the surface texture. Stent activity levels of 4 and 13 μCi were chosen for the study. Four and 12 weeks after placement of conventional stents and 32 P-implanted stents in rabbit iliac arteries, vascular injury and neointima formation were studied by histomorphometry. Immunostaining for smooth muscle cell (SMC) α-actin was performed to determine SMC cellularity in the neointima. SMCs were quantified by computer-assisted counting of α-actin immunoreactive cells. Endothelialization of the stents was evaluated by immunostaining for endothelial cell von Willebrand factor. No difference in vessel wall injury was found after placement of conventional and 32 P-implanted stents. Neointima formation was potently inhibited by 32 P-implanted stents only at an activity level of 13 μCi after 4 and 12 weeks. Neointimal SMC cellularity was reduced in 32 P-implanted stents compared with conventional stents. Radioactive stents were endothelialized after 4 weeks, but endothelialization was less dense than in conventional stents. Conclusions Neointima formation in rabbits is markedly suppressed by a β-particle–emitting stent incorporating the radioisotope 32 P. In this model, a dose-response relation with this type of radioactive stent was observed, indicating that a threshold radiation dose must be delivered to inhibit neointima formation after stent placement over the long term.

Background Neointima formation contributing to recurrent stenosis remains a major limitation of percutaneous transluminal angioplasty. Endovascular low-dose γ-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 β-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 90 Strontium/ 90 Yttrium sources ( 90 Sr/Y, a pure β-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 192 Ir, a γ-emitting radioisotope. Conclusions Administration of endovascular β-radiation to the site of coronary arterial overstretch balloon injury in pigs with 90 Sr/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 β-irradiation is practical and feasible and may aid in preventing clinical restenosis.

BACKGROUND Restenosis after catheter-based revascularization has been demonstrated to be primarily caused by medial and/or intimal smooth muscle cell (SMC) proliferation. The objective of this study was investigate the ability of local emission of beta-particles from a 32P-impregnated titanium "stent" wire source to inhibit vascular SMC and endothelial cell proliferation in cell culture and to determine the dose-response characteristics of this inhibition. METHODS AND RESULTS A series of experiments were performed using 0.20-mm-diameter titanium wires that were impregnated with varying low concentrations of 32P (activity range, 0.002 to 0.06 microCi/cm wire, n = 47) or 31P (nonradioactive control, n = 28) in cultures of rat and human aortic SMCs and in cultured bovine aortic endothelial cells. The zone of complete cell growth inhibition (in millimeters from stent wire) was measured using light microscopy in the cultures exposed to the radioactive (32P) or control (31P) wires at 6 and 12 days after plating. In both rat and human SMC cultures there was a distinct 5.5- to 10.6-mm zone of complete SMC inhibition at wire activity levels > or = 0.006 microCi/cm. In contrast, there was no zone of inhibition surrounding the control (31P impregnated) wires (P < .001 versus 32P wires at all wire activities > or = 0.006 microCi/cm for human and rat SMCs). Proliferating bovine endothelial cells were more radioresistant than SMCs, with no zone of inhibition observed at wire activity levels up to 0.019 microCi/cm (P < .001 versus SMCs at 0.006 microCi/cm and 0.019 microCi/cm). CONCLUSIONS We conclude that very low doses of beta-particle emission from a 32P-impregnated stent wire (activity levels as low as 0.006 microCi/cm of wire) completely inhibit the growth and migration of both rat and human SMCs within a range of 5.5 to 10.6 mm from the wire. Endothelial cells appear to be much more radioresistant than SMCs. These data suggest that an intra-arterial stent impregnated with a low concentration of 32P may have a salutary effect on the restenosis process. Whether this approach can be used successfully and safely to inhibit restenosis in vivo and in the clinical setting is under investigation.

Background— Creating linear lesions is important for the treatment of arrhythmias such as atrial flutter and fibrillation. Making these lesions with standard radiofrequency catheters can be difficult and may result in charring and thrombosis. The purpose of this study was to evaluate β-radiation as a novel energy source for creating linear myocardial lesions. Methods and Results— Eight dogs with intact conduction across the cavotricuspid isthmus were studied. The isthmus was irradiated (25 to 50 Gy) with strontium/yttrium-90 delivered via a deflectable 7F catheter (Novoste Corporation). There were no immediate effects, but bidirectional conduction block developed during follow-up studies in 7 of 8 dogs. The dog without conduction block received 25 Gy. After the animals were euthanized, histology revealed transmural, linear areas of fibrosis without any thrombus. Conclusions— β-Radiation can safely and effectively create linear lesions that are contiguous and nonthrombogenic. This energy source may become an interesting adjunct to radiofrequency for the treatment of atrial flutter and fibrillation.

Background— After conventional treatment of in-stent restenosis, the incidence of recurrent clinical restenosis may approach 40%. We report the first multicenter, blinded, and randomized trial of intracoronary radiation with the use of a 90 Sr/ 90 Y β-source for the treatment of in-stent restenosis. Methods and Results— After successful catheter-based treatment of in-stent restenosis, 476 patients were randomly assigned to receive an intracoronary catheter containing either 90 Sr/ 90 Y (n=244) or placebo (n=232) sources. The prescribed dose 2 mm from the center of the source was 18.4 Gy for vessels between 2.70 and 3.35 mm in diameter and 23.0 Gy for vessels between 3.36 and 4.0 mm. The primary end point, ie, clinically driven target-vessel revascularization by 8 months, was observed in 56 (26.8%) of the patients assigned to placebo and 39 (17.0%) of the patients assigned to radiation ( P =0.015). The incidence of the composite including death, myocardial infarction, and target-vessel revascularization was observed in 60 (28.7%) of the patients assigned to placebo and 44 (19.1%) of the patients assigned to radiation ( P =0.024). Binary 8-month angiographic restenosis (≥50% diameter stenosis) within the entire segment treated with radiation was reduced from 45.2% in the placebo-treated patients to 28.8% in the 90 Sr/ 90 Y-treated patients ( P =0.001). Stent thromboses occurred in 1 patient assigned to placebo 90 Sr/ 90 Y at day 244. Conclusions— The results of this study demonstrated that β-radiation using 90 Sr/ 90 Y is both safe and effective for preventing recurrence in patients with in-stent restenosis.

Background — Intravascular brachytherapy is being applied more and more in patients with coronary artery disease for the prevention of restenosis subsequent to balloon angioplasty, in particular after stent implantation. Several radiation sources (β- and γ-emitters) are available in clinical routine. It was the purpose of this study to compare the radiation doses at the level of the adventitia in diseased and stented human coronary arteries for 192 Ir and 90 Sr/Y emitters in routine use. In contrast to previously published work, we performed dosimetry instead of calculating depth-dose distribution by use of the Monte Carlo system. Methods and Results — Postmortem calcified human coronary artery segments were stented and placed in an organ bath. Commercially available γ-emitters ( 192 Ir; Cordis Checkmate) and β-emitters ( 90 Sr/Y; Novoste Beta-Cath) were used. Relative dose distributions along the adventitia were measured by a specially designed scintillation detector system. Whereas dose perturbations caused by stents and calcified plaque were negligible for the 192 Ir source, radiation from the beta source was significantly impaired (as much as 40%) at the level of the adventitia (3.0-mm vessel diameter). Dose perturbation was clearly dependent on the extent and severity of calcification, less affected by stent material. Conclusions — Dose perturbation caused by calcified plaque and metallic stents is significant for β-sources. This dosimetric difference between β- and γ-emitters in diseased coronary arteries should be considered when calculating doses in intravascular brachytherapy.

Background —Intracoronary γ- and β-radiation have reduced restenosis in animal models. In the clinical setting, the effectiveness of β-emitters has not been studied in a broad spectrum of patients, particularly those receiving stents. Methods and Results —A prospective, randomized, sham-controlled study of intracoronary radiotherapy with the β-emitting 32 P source wire, using a centering catheter and automated source delivery unit, was conducted. A total of 105 patients with de novo (70%) or restenotic (30%) lesions who were treated by stenting (61%) or balloon angioplasty (39%) received 0 (control), 16, 20, or 24 Gy to a depth of 1 mm in the artery wall. Angiography at 6 months showed a target site late loss index of 11±36% in radiotherapy patients versus 55±30% in controls ( P P =0.012) and at target site plus adjacent segments (22% versus 50%; P =0.018). Target lesion revascularization was needed in 5 radiotherapy patients (6%) and 6 controls (24%; P Conclusions —β-radiotherapy with a centered 32 P source is safe and highly effective in inhibiting restenosis at the target site after stent or balloon angioplasty. However, minimizing edge narrowing and late thrombotic events must be accomplished to maximize the clinical benefit of this modality.

Background —Inhomogeneity of dose distribution and anatomic aspects of the atherosclerotic plaque may influence the outcome of irradiated lesions after balloon angioplasty (BA). We evaluated the influence of delivered dose and morphological characteristics of coronary stenoses treated with β-radiation after BA. Methods and Results —Eighteen consecutive patients treated according to the Beta Energy Restenosis Trial 1.5 were included in the study. The site of angioplasty was irradiated with the use of a β-emitting 90 Sr/ 90 Y source. With the side branches used as anatomic landmarks, the irradiated area was identified and volumetric assessment was performed by 3D intracoronary ultrasound imaging after treatment and at 6 months. The type of tissue, the presence of dissection, and the vessel volumes were assessed every 2 mm within the irradiated area. The minimal dose absorbed by 90% of the adventitial volume (D v90 Adv) was calculated in each 2-mm segment. Diffuse calcified subsegments and those containing side branches were excluded. Two hundred six coronary subsegments were studied. Of those, 55 were defined as soft, 129 as hard, and 22 as normal/intimal thickening. Plaque volume showed less increase in hard segments as compared with soft and normal/intimal thickening segments ( P v90 Adv was associated with plaque volume at follow-up after a polynomial equation with linear and nonlinear components ( r =0.71; P =0.0001). The multivariate regression analysis identified the independent predictors of the plaque volume at follow-up: plaque volume after treatment, D v90 Adv, and type of plaque. Conclusions —Residual plaque burden, delivered dose, and tissue composition play a fundamental role in the volumetric outcome at 6-month follow-up after β-radiation therapy and BA.

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 β-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 β-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 μCi 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 β-particle–emitting stents ( P P Conclusions —Neointima formation in pigs is markedly increased by β-particle–emitting stents with 198 Au as the radioisotope. This study provides evidence that dosages of 3 to 18 Gy of low-dose-rate β-particle irradiation via endovascular stents cause pronounced luminal narrowing in the animal model at 3 months.

Background —Radioactive 32 P β-emitting stents have been shown to reduce intrastent neointimal hyperplasia in a substantial dose-related manner in the animal model. The aim of this dose-response study was to evaluate, in the clinical setting, the safety and efficacy at 6-month follow-up of this approach to reducing restenosis. Methods and Results —A total of 122 32 P radioactive β-emitting stents (initially the Palmaz-Schatz and later the BX Isostent) with an activity level of 0.75 to 3.0 μCi (group 1), 3.0 to 6.0 μCi (group 2), and 6.0 to 12.0 μCi (group 3) were implanted in 91 lesions in 82 patients. There were no procedural events. At 6-month follow-up, no deaths had occurred, and only 1 patient had stent thrombosis. Pure intrastent binary restenosis was 16% in group 1, 3% in group 2, and 0% in group 3. However, intralesion restenosis was 52% in group 1, 41% in group 2, and 50% in group 3. Conclusions —The use of 32 P radioactive β-emitting stents in patients with CAD is feasible. At 6-month follow-up, intrastent neointimal hyperplasia was reduced in a dose-related manner. However, in the 3 groups, intralesion restenosis was high because of a high late lumen loss in the reference segments at the stent edges, possibly as a result of a low activity level of radiation at the edges of the stent combined with an aggressive approach to stenting. We called this “edge effect” the “candy wrapper.”

Background —Endovascular radiation appears to inhibit intimal thickening after overstretching balloon injury in animal models. The effect of brachytherapy on vascular remodeling is unknown. The aim of the study was to determine the evolution of coronary vessel dimensions after intracoronary irradiation after successful balloon angioplasty in humans. Methods and Results —Twenty-one consecutive patients treated with balloon angioplasty and β-radiation according to the Beta Energy Restenosis Trial-1.5 were included in the study. Volumetric assessment of the irradiated segment and both edges was performed after brachytherapy and at 6-month follow-up. Intravascular ultrasound images were acquired by means of ECG-triggered pullback, and 3-D reconstruction was performed by automated edge detection, allowing the calculation of lumen, plaque, and external elastic membrane (EEM) volumes. In the irradiated segments, mean EEM and plaque volumes increased significantly (451±128 to 490.9±159 mm 3 and 201.2±59 to 241.7±74 mm 3 ; P =0.01 and P =0.001, respectively), whereas luminal volume remained unchanged (250.8±91 to 249.2±102 mm 3 ; P =NS). The edges demonstrated an increase in mean plaque volume (26.8±12 to 32.6±10 mm 3 , P =0.0001) and no net change in mean EEM volume (71.4±24 to 70.9±24 mm 3 , P =NS), resulting in a decrease in mean luminal volume (44.6±16 to 38.3±16 mm 3 , P =0.01). Conclusions —A different pattern of remodeling is observed in coronary segments treated with β-radiation after successful balloon angioplasty. In the irradiated segments, the adaptive increase of EEM volume appears to be the major contributor to the luminal volume at follow-up. Conversely, both edges showed an increase in plaque volume without a net change in EEM volume.

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 90 Sr/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 mm 2 after treatment to 6.04±2.63 mm 2 at follow-up), with no significant change in external elastic membrane area (13.71±4.54 to 14.22±4.71 mm 2 ) over the 6-month follow-up. Wall area was 8.01±3.85 mm 2 after radiation therapy and 8.19±3.44 mm 2 at follow-up ( P =NS). No significant differences were noted between the different dose groups. Conclusions —β-Radiation therapy resulted in a low restenosis rate with negligible late loss by angiography. By IVUS, β-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 β irradiation remain to be elucidated. Methods and Results —We investigated in vitro the ability of 32 P-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. β radiation significantly reduced proliferation of VSMCs (ED 50 1.10 Gy) and ECs (ED 50 2.15 Gy) in a dose-dependent manner. Exposure to β emission interfered with cell cycle progression, with induction of G 0 /G 1 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 α-actin immunostaining in β-irradiated cells compared with control cells. Conclusions — 32 P-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. β irradiation–induced G 1 arrest was not associated with cytotoxicity and apoptosis, thus demonstrating a potent cytostatic effect of β-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.

Background —In the porcine overstretch injury model of restenosis, endovascular β-radiation reduces neointima formation. To determine whether this therapy could be applied to patients with coronary artery disease, a special device was developed to allow delivery of 12 encapsulated 90 Sr/Y sources, measuring a total of 30 mm, to various sites within the coronary arterial tree. This study was designed to evaluate the feasibility of the delivery of 12, 14, or 16 Gy at 2 mm after balloon angioplasty of stenoses of native coronary vessels. Methods and Results —Delivery of β-radiation was attempted in 23 patients after successful balloon angioplasty. Source delivery was successful in 21 of the 23 patients (91%). There was no in-hospital or 30-day morbidity or mortality. Follow-up quantitative coronary arteriography in 20 patients demonstrated a late loss of 0.05 mm, a late loss index of 4%, and a restenosis rate of 15%. The use of the β-emitter 90 Sr/Y significantly reduced treatment time and operator exposure compared with previous trials with the γ-emitter 192 Ir. Conclusions —In this study, the administration of endovascular β-radiation after angioplasty was safe and feasible and substantially altered the postangioplasty late lumen loss, resulting in a lower-than-expected rate of restenosis. On the basis of these encouraging results, a multicenter, randomized trial with operators and patients blinded to treatment assignment is planned.

Background With the aim of decreasing the incidence of restenosis after coronary balloon angioplasty, we developed a technique of intracoronary β-irradiation using an endoluminally centered pure metallic 90 Y source. The purpose of the present study was to evaluate the clinical feasibility and safety profile of this approach with a dose of 18 Gy delivered to the inner arterial surface. Methods and Results Between June 21 and November 15, 1995, fifteen patients (6 women and 9 men; mean age, 71±5 years) underwent intracoronary β-irradiation immediately after a conventional percutaneous transluminal coronary angioplasty (PTCA) procedure. The PTCA/irradiation procedure was technically feasible in all attempted cases, and the delivery of the 18 Gy dose was accomplished without complications. In 4 patients, the intervention was completed through intra-arterial stent implantation because of dissection induced by the initial PTCA. During the follow-up period of 178±17 days (range, 150 to 225 days), no complication occurred that could be attributed to radiation therapy. No aneurysm or angiographically detectable thrombus was observed in any of the irradiated arterial segments. The clinical event rate (4 of 15 patients underwent further target lesion revascularization) and the angiographic follow-up (6 of 15 patients had a >50%-diameter stenosis at the previously treated site) did not suggest a marked impact on the expected restenosis rate. Conclusions This early experience demonstrates that our approach is feasible, and no side effects attributable to radiation were noted during a 6-month period of follow-up. Whether higher doses of β-irradiation will favorably affect post-PTCA restenosis in patients must await further evaluation.

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 β-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 β-particle–emitting radioisotope stents ( 32 P, activity level 0.14 μCi) and seven control stents ( 31 P, 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 mm 2 versus 2.81±1.22 mm 2 , P =.05) and percent area stenosis (24.6±2.9% versus 36.0±10.7%, P =.02) within the β-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 β-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 β-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.