phosphorus-radioisotopes and Coronary-Disease

Brachytherapy by implantation of a radioactive stent is an alternative approach to catheter-based systems to reduce restenosis. The pilot clinical trials using 32P radioactive b-emitting stents at low-to-intermediate activity (0.5Eth 3.0 mCi) showed that restenosis at 6 months was not different from that of currently available non-radioactive stents. The evaluation of the efficacy in reducing restenosis of radioactive stents with higher activities (3Eth 24 mCi) started in Europe (Milan, Rotterdam and Vienna) between 1998 and 1999. In the Milan and Rotterdam experience, 32P radioactive stents with an activity of 3Eth 12 mCi demonstrated a reduction of intra-stent restenosis to < 4%. However, a high-edge restenosis > 30% was observed in the first 1Eth 3 mm outside the stent margins. This edge effect might be due to a low dose of radiation at the stent margins combined with systematic balloon injury in the reference segments. The hypothesis that a further increase in stent activity (12Eth 21 mCi) associated with a reduced balloon injury outside the stent could solve the problem of edge restenosis was not confirmed by the Milan experience; edge restenosis still occurred in 26% of the lesions treated by a single 32P radioactive stent, even if a nonaggressive stent implantation strategy was used. Two approaches under investigation to solve the problem of edge restenosis are: 1) lengthening the stent with a non-radioactive stent (cold-ends stent) to prevent negative remodeling; and 2) extending the area of irradiation beyond the balloon-injured area by an increased activity at the stent ends (hot-ends stent).

Topics: Blood Vessel Prosthesis Implantation; Brachytherapy; Clinical Trials as Topic; Coated Materials, Biocompatible; Coronary Disease; Coronary Vessels; Dose-Response Relationship, Radiation; Equipment Safety; Europe; Graft Occlusion, Vascular; Humans; Phosphorus Radioisotopes; Stents

Topics: Animals; Clinical Trials as Topic; Combined Modality Therapy; Coronary Disease; Equipment Design; Humans; Phosphorus Radioisotopes; Radiotherapy Dosage; Stents

Intracoronary stenting has improved catheter-based revascularization of obstructive coronary artery disease. Despite the improved outcomes with stenting, restenosis still occurs at an unacceptable rate, particularly in smaller vessels and in longer lesions. In this article, we review the concept of using a stent implanted with low activities of radioisotope as a means to inhibit the proliferative process that is believed to initiate in-stent restenosis. This approach has been shown to be effective in certain animal models of restenosis. The initial clinical results with the phase-1 safety trials are summarized. The early clinical results with more than 200 implants of low activity 32P Palmaz-Schatz and BX radioactive stents have demonstrated excellent procedural and 30-day event-free survival. Further dose-finding safety trials are anticipated in 1998 and 1999. A large scale randomized clinical trial will commence if and when early safety and efficacy data suggest a therapeutic effect from this technology.

Topics: Angioplasty, Balloon, Coronary; Animals; Brachytherapy; Coronary Disease; Coronary Vessels; Disease-Free Survival; Humans; Phosphorus Radioisotopes; Radiotherapy Dosage; Secondary Prevention; Stents

The concept of radioactive stents was initiated to prevent restenosis after angioplasty in patients with coronary artery disease. We review the modes of fabrication, dosimetry and the biological effects of radioactive stents. Radioactive stents deliver ionizing radiation continuously at very low-dose rates according to the half-life of the incorporated radioisotopes. The activity levels of radioactive stents are up to 10,000 times lower than activity levels of sources used for catheter-based vascular brachytherapy. Radioactive stents allow uniform dose distribution and precise dosimetry because of the direct source contact with the circumference of the vessel. Animal studies show that these stents can potently inhibit smooth muscle cell proliferation and neointimal hyperplasia. A persistent inhibition of neointimal hyperplasia appears to be dose dependent. Local or systemic side effects related to the irradiation were not observed. A limitation of radioactive stents could be the dose-dependent delay in stent endothelialization which, however, did not cause thrombotic vessel occlusion in animal experiments. Whether a delay in stent endothelialization is associated with an increased rate of occlusive stent thrombosis in humans requires further studies.

Topics: Animals; Brachytherapy; Cobalt Radioisotopes; Coronary Disease; Coronary Vessels; Dose-Response Relationship, Radiation; Humans; Phosphorus Radioisotopes; Radiotherapy Dosage; Recurrence; Stents

During the past several years, the production of high resolution images of organs in intact animals and human beings using nuclear magnetic resonance (nmr) has generated much interest and raised the possibility that the technique could be usefully applied to clinical problems. Because the images are derived from biochemical as well as structural information, valuable data relating to the metabolic status of the tissues and organs may be obtained. Furthermore, nuclear magnetic resonance imaging involves no potentially hazardous ionizing radiation. The technology of the technique is complex and much work remains to be done defining the biochemical and physiologic basis of such images, but the potential rewards of defining the metabolic state of organs such as heart and brain in the intact animal and human justify continued research.

Topics: Animals; Coronary Disease; Heart; Humans; Magnetic Resonance Spectroscopy; Myocardial Infarction; Phosphorus Radioisotopes; Rabbits; Radionuclide Imaging; Spectrum Analysis

Topics: Angioplasty, Balloon, Coronary; Beta Particles; Brachytherapy; Coronary Angiography; Coronary Disease; Coronary Restenosis; Coronary Vessels; Humans; Logistic Models; Phosphorus Radioisotopes; Stents; Treatment Outcome

Restenosis after conventional stenting is almost exclusively caused by neointimal hyperplasia. Beta-particle-emitting radioactive stents decrease in-stent neointimal hyperplasia at 6-month follow-up. The purpose of this study was to evaluate the 1-year outcome of (32)P radioactive stents with an initial activity of 6 to 12 microCi using serial quantitative coronary angiography and volumetric ECG-gated 3D intravascular ultrasound (IVUS).. Of 40 patients undergoing initial stent implantation, 26 were event-free after the 6-month follow-up period and 22 underwent repeat catheterization and IVUS at 1 year; they comprised half of the study population. Significant luminal deterioration was observed within the stents between 6 months and 1 year, as evidenced by a decrease in the angiographic minimum lumen diameter (-0.43+/-0.56 mm; P:=0.028) and in the mean lumen diameter in the stent (-0.55+/-0. 63 mm; P:=0.001); a significant increase in in-stent neointimal hyperplasia by IVUS (18.16+/-12.59 mm(3) at 6 months to 27.75+/-11. 99 mm(3) at 1 year; P:=0.001) was also observed. Target vessel revascularization was performed in 5 patients (23%). No patient experienced late occlusion, myocardial infarction, or death. By 1 year, 21 of the initial 40 patients (65%) remained event-free.. Neointimal proliferation is delayed rather than prevented by radioactive stent implantation. Clinical outcome 1 year after the implantation of stents with an initial activity of 6 to 12 microCi is not favorable when compared with conventional stenting.

Topics: Adult; Aged; Brachytherapy; Coronary Angiography; Coronary Disease; Endosonography; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Phosphorus Radioisotopes; Radiation Dosage; Stents; Treatment Failure; Treatment Outcome

A high restenosis rate has been reported at the edges ("edge restenosis") of (32)P radioactive stents with an initial activity level of 3 to 12 microCi. This edge effect might be due to balloon injury and to a low dose of radiation at the stent margins. The aim of this study was to evaluate whether the implantation of (32)P radioactive stents with a higher activity level (12 to 21 microCi) combined with a nonaggressive stent implantation strategy could solve the problem of edge restenosis.. We compared the results of lesions treated with single radioactive BX stents with an activity of 12 to 21 microCi (group 2, n = 54 lesions) with the results of lesions treated by single radioactive BX stents with an initial activity level of 3 to 12 microCi (group 1, n = 42 lesions). There were no procedural events. At the 6-month follow-up, no myocardial infarctions, deaths, or stent thromboses had occurred. Intrastent binary restenosis was 0% in group 1 versus 4% in group 2 (n = 2, both at the ostium of the right coronary artery, P = NS). Intrastent neointimal hyperplasia was significantly lower in group 2 than in group 1. The intralesion (intrastent plus peri-stent) restenosis rate was 38% in group 1 versus 30% in group 2 (P = NS). Conclusions-Single (32)P radioactive stents with an initial activity level of 12 to 21 microCi reduced intrastent neointimal hyperplasia compared with stents of 3 to 12 microCi, but they did not solve the problem of edge restenosis, even if a nonaggressive stent implantation strategy was used.

Topics: Angioplasty, Balloon, Coronary; Brachytherapy; Coronary Angiography; Coronary Disease; Female; Humans; Male; Middle Aged; Phosphorus Radioisotopes; Radiotherapy Dosage; Recurrence; Stents

Intracoronary gamma- and beta-radiation have reduced restenosis in animal models. In the clinical setting, the effectiveness of beta-emitters has not been studied in a broad spectrum of patients, particularly those receiving stents.. A prospective, randomized, sham-controlled study of intracoronary radiotherapy with the beta-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:<0.0001). A low late loss index was seen in stented and balloon-treated patients and was similar across the 16, 20, and 24 Gy radiotherapy groups. Restenosis (>/=50%) rates were significantly lower in radiotherapy patients at the target site (8% versus 39%; 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:<0.05). Stenosis adjacent to the target site and late thrombotic events reduced the overall clinical benefit of radiotherapy.. beta-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.

Topics: Angioplasty, Balloon, Coronary; Aspirin; Automation; Beta Particles; Combined Modality Therapy; Coronary Angiography; Coronary Disease; Coronary Vessels; Dose-Response Relationship, Radiation; Drug Delivery Systems; Humans; Phosphorus Radioisotopes; Platelet Aggregation Inhibitors; Radiopharmaceuticals; Stents; Ticlopidine; Time Factors; Treatment Outcome

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, beta-particle-emitting radioactive stents decrease neointimal hyperplasia by inhibiting smooth muscle cell proliferation.. The radioisotope (32)P, a beta-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 microCi. 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.. The use of radioactive stents with an activity of 0.75 to 1.5 microCi is safe and feasible.

Topics: Adult; Aged; Aspirin; Beta Particles; Brachytherapy; Coronary Angiography; Coronary Disease; Feasibility Studies; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Patient Selection; Phosphorus Radioisotopes; Platelet Aggregation Inhibitors; Stents; Ticlopidine

The Proliferation REduction with Vascular ENergy Trial (PREVENT) is a prospective randomized study of the safety and efficacy of intracoronary brachytherapy to reduce restenosis. A beta-emitter, 32P, is embedded on a wire tip and delivered to the target site through a centering catheter immediately following a coronary intervention. The radiation doses are 16, 20, and 24 Gy measured at 1 mm within the vessel wall. Follow-up includes an angiogram and IVUS at 6 months. Phase I of this trial has been completed with results expected in early 1999.

Topics: Angioplasty, Balloon, Coronary; Brachytherapy; Coronary Angiography; Coronary Disease; Equipment Design; Female; Humans; Male; Phosphorus Radioisotopes; Prospective Studies; Radiotherapy Dosage; Recurrence; Retreatment; Stents

Intravascular brachytherapy has been adopted for the indication of in-stent restenosis on the basis of results of clinical trials using mainly stainless steel stents. Recently, a new stent made of cobalt-chromium L-605 alloy (CoCr, p=9.22 g/cm3) (MULTI-LINK VISION) was introduced as an alternative to the 316L stainless steel stent design (SS, p=7.87 g/cm3) (MULTI-LINK PENTA). In this work, we used the Monte Carlo code MCNPX to compare the dose distribution for the 32P GALILEO source in CoCr and SS 8 mm stent models. The dose perturbation factor (DPF), defined as the ratio of the dose in water with the presence of a stent to the dose without a stent, was used to compare results. Both stent designs were virtually expanded to diameters of 2.0, 3.0, and 4.0 mm using finite element models. The complicated strut shapes of both the CoCr and SS stents were simplified using circular rings with an effective width to yield a metal-to-tissue ratio identical to that of the actual stents. The mean DPF at a 1 mm tissue depth, over the entire stented length of 8 mm, was 0.935 for the CoCr stent and 0.911 for the SS stent. The mean DPF at the intima (0.05 mm radial distance from the strut outer surface), over the entire stented length of 8 mm, was 0.950 for CoCr, and 0.926 for SS. The maximum DPFs directly behind the CoCr and SS struts were 0.689 and 0.644, respectively. All DPF estimates have a standard deviation of +/-0.6%(k=2), approximating the 95% confidence interval. Although the CoCr stent has a higher effective atomic number and greater density than the SS stent, the DPFs for the two stents are similar, probably because the metal-to-tissue ratio and strut thickness of the CoCr stent are lower than those of the SS stent.

Topics: Brachytherapy; Chromium; Cobalt; Coronary Disease; Coronary Restenosis; Humans; Monte Carlo Method; Phosphorus Radioisotopes; Radiometry; Software; Time Factors

Pure beta emitters are the sources of choice for intracoronary irradiations in restenosis prevention. In this work we reconsidered preparation of low activity 32P sources by ion-implantation of stable 31P into highly biocompatible pure titanium stents, followed by neutron activation. Gamma-spectrometrical analysis has shown that during activations with high thermal neutrons flux production of gamma-active long-lived contaminants is much beyond the dosimetrically acceptable limit, mainly due to the competing (n,p) reactions induced by the fast neutrons on isotopes of the bulk stent material, and to a lesser extent due to (n,gamma) reactions on chemical impurities. A potential applicability of this method for obtaining alternative beta radioactive stents is discussed.

Topics: Brachytherapy; Chromium Radioisotopes; Coronary Disease; Gamma Rays; Ions; Neutrons; Phosphorus Radioisotopes; Spectrophotometry; Stents; Titanium

Intravascular brachytherapy may cause "exaggerated" vessel remodeling with late incomplete apposition in segments that have little disease, which are exposed to higher radiation doses. The long-term clinical impact of this finding is unclear.

Topics: Aged; Brachytherapy; Coronary Angiography; Coronary Disease; Coronary Restenosis; Coronary Vessels; Equipment Design; Equipment Failure; Female; Follow-Up Studies; Humans; Incidence; Linear Models; Male; Middle Aged; Phosphorus Radioisotopes; Risk Factors; Single-Blind Method; Stents; Time Factors; Treatment Outcome; Ultrasonography, Interventional

Topics: Brachytherapy; Coronary Disease; Humans; Medical Staff, Hospital; Occupational Exposure; Phosphorus Radioisotopes; Radiation Dosage; Radiation Protection; Radiometry

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.

Topics: Brachytherapy; Coronary Disease; Coronary Vessels; Dose-Response Relationship, Radiation; Equipment Design; Female; Humans; Male; Middle Aged; Phosphorus Radioisotopes; Stents; Ultrasonography, Interventional

A very quantitative, destructive-analysis procedure was devised for assaying the 32P activity content of "hot-wall" angioplasty-balloon catheters. These sources, developed and under investigation by Radiance Medical Systems, Inc. (Irvine, CA), are intended for use in the prophylactic inhibition of restenosis following balloon angioplasty in heart-disease patients. The assay was based on performing a physicochemical digestion of the balloon catheter to extract the 32P activity followed by liquid-scintillation (LS) spectrometry of the resultant solutions. Measurement-based corrections were applied for the residual activity remaining in the digested balloon debris and in all of the digestion apparatus. The LS spectrometry, with 3H-standard efficiency tracing, utilized a previously-developed method for resolving the always-present 33P impurity. Initial ionization current measurements on the sources prior to the destructive assays led to the establishment of calibration factors that can be used for subsequent non-destructive radionuclidic measurements on similar balloon-catheter sources.

Topics: Angioplasty, Balloon, Coronary; Brachytherapy; Calibration; Cardiac Catheterization; Coronary Disease; Humans; Phosphorus Radioisotopes; Photons; Recurrence; Reproducibility of Results; Scintillation Counting

Topics: Angioplasty, Balloon, Coronary; Brachytherapy; Coronary Disease; Humans; Phosphorus Radioisotopes; Recurrence; Stents

Intracoronary radiation has shown the potential to reduce formation of neointima in porcine models of restenosis.. To investigate the feasibility, safety, and efficacy of a new 'deployable-balloon' device with radioisotope 32P integrated into the balloon material.. Ten swine were subjected to balloon-overstretching injury in 20 coronary arteries and were randomly allocated to receive a radiation dose of 0, 15, or 20Gy prescribed to 1 mm from the surface of the radioactive balloon material. The animals were killed 4 weeks after the procedure. Their coronaries were perfusion fixed and stained. Vessel parameters (area of intima and length of fracture) and area of thrombus area were analyzed by computer-aided histomorphometry.. Radiation treatment with the new 32P balloon device was performed without complications. The lengts of fracture for the three groups were similar (NS). Formation of neointima after balloon injury was less in members of the radiated groups than it was in controls (area of intima/length of fracture was 0.70 +/-0.12 mm for controls, 0.08+/-0.13mm with 15 Gy, and 0.07+/-0.17 mm with 20 Gy; P < 0.001). Vessels treated with 20 Gy had a greater total area of thrombus (0.00+/-0.00 versus 0.51+/-0.98 mm2, P< 0.01).. Intracoronary radiation therapy using a new 32P deployable-balloon system is feasible and safe. A radiation dose of 15 Gy was sufficient to inhibit neointimal response in the porcine coronary-balloon-injury model.

Topics: Angioplasty, Balloon, Coronary; Animals; Brachytherapy; Coronary Disease; Coronary Vessels; Feasibility Studies; Graft Occlusion, Vascular; Phosphorus Radioisotopes; Random Allocation; Secondary Prevention; Swine; Tunica Intima

Topics: Angioplasty, Balloon, Coronary; Beta Particles; Brachytherapy; Cell Division; Coronary Disease; Coronary Vessels; Humans; Hyperplasia; Phosphorus Radioisotopes; Secondary Prevention; Stents; Tunica Intima

Edge restenosis is a major problem after radioactive stenting. The cold-end stent has a radioactive mid-segment (15.9 mm) and non-radioactive proximal and distal 5.7 mm segments. Conceptually this may negate the impact of negative vascular remodelling at the edge of the radiation.. ECG-gated intravascular ultrasound with three-dimensional reconstruction was performed post-stent implantation and at the 6-month follow-up to assess restenosis within the margins of the stent and at the stent edges in 16 patients. Angiographic restenosis was witnessed in four patients, all in the proximal in-stent position. By intravascular ultrasound in-stent neointimal hyperplasia, with a >50% stented cross-sectional area, was seen in eight patients. This was witnessed proximally (n=2), distally (n=2) and in both segments (n=4). Echolucent tissue, dubbed the 'black hole' was seen as a significant component of neointimal hyperplasia in six out of the eight cases of restenosis. Neointimal hyperplasia was inhibited in the area of radiation: Delta neointimal hyperplasia=3.72 mm3 (8.6%); in-stent at the edges of radiation proximally and distally Delta neointimal hyperplasia was 7.9 mm3 (19.0%) and 11.4 mm3 (25.6%), respectively (P=0.017). At the stent edges there was no significant change in lumen volume.. Cold-end stenting results in increased neointimal hyperplasia in in-stent non-radioactive segments.

Topics: Brachytherapy; Cell Division; Coronary Disease; Coronary Vessels; Humans; Hyperplasia; Phosphorus Radioisotopes; Secondary Prevention; Stents; Tunica Intima; Ultrasonography, Interventional

A recognized limitation of radioactive stents is the development of restenosis at the stent edges, known as the "candy-wrapper" effect. The mechanisms of this effect remain incompletely understood and controversial. The aim of this study is to assess the effect of endovascular irradiation on neointima formation and vascular remodeling. (32)P Palmaz-Schatz stents (1.5-4 microCi) were implanted in 11 patients with restenosis after previous percutaneous transluminal coronary angioplasty (PTCA). Intravascular ultrasound (IVUS) images of target sites and adjunct vessel segments were acquired both during intervention and after 6 months. The angiographic restenosis rate was 54%, and the MLD decreased from 2.21 +/- 0.6 mm to 1.38 +/- 0.4 mm at follow-up (P < 0.01). IVUS analysis demonstrated that late lumen loss was the result of neointimal tissue proliferation, which was nonuniformly distributed and exaggerated at both the central articulation and the distal stent edges. Negative remodeling did not contribute to restenosis. In contrast, we found a linear relationship between increase of area stenosis and a positive remodeling index (r = 0.84, P < 0.0001). Restenosis after implantation of (32)P Palmaz-Schatz stents was mainly the result of neointimal tissue proliferation which tended to be nonuniformly distributed in the stent articulation and edges. Negative remodeling or stent recoil was not observed. Cathet Cardiovasc Intervent 2001;54:41-48.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Disease; Endothelium, Vascular; Female; Graft Occlusion, Vascular; Humans; Hyperplasia; Male; Middle Aged; Phosphorus Radioisotopes; Stents; Ultrasonography, Interventional

Topics: Brachytherapy; Coronary Disease; Graft Occlusion, Vascular; Humans; Phosphorus Radioisotopes; Stents

With the increase in popularity of endovascular brachytherapy for prevention of restenosis following coronary angioplasty, it remains to be determined which isotope and isotope form is the most ideal. An issue concerning the use of wire sources is the influence of the centering of the wire on dose uniformity across the artery wall and the potential problems this can lead to in terms of underdosage of the target tissues. In this investigation, the dosimetric characteristics of three currently used sources (gamma-emitting 192Ir wire; beta-emitting 32P wire; and beta-emitting 188Re solution) were determined with EGS4 Monte Carlo. The dose results were then used to determine the dose-area relationships for the three sources in arteries with concentric and non-concentric lumens/walls, including situations in which the wire sources are moved away from the centre of the artery. It is found that, in order to ensure dose uniformity, centering is substantially more important for beta-emitting wire sources. This is highlighted most significantly in the case of an example large irregular artery. Although the suitability of a source depends on many criteria (e.g., cost, availability, radiation protection, possible radiation-induced late effects), the problem of centering a wire source in possibly large and/or irregular arteries is greatly eased by the use of a gamma-emitting source.

Topics: Angioplasty, Balloon, Coronary; Brachytherapy; Coronary Disease; Humans; Iridium Radioisotopes; Models, Cardiovascular; Monte Carlo Method; Phosphorus Radioisotopes; Radioisotopes; Radiometry; Radiotherapy Dosage; Rhenium

Both gamma and beta irradiation delivered via a radioactive catheter-based line source have been shown to have efficacy in reducing restenosis. However, these catheter-based treatments have some limitations, including the safety of handling sources ranging from 30 mCi to 500 mCi. Alternatively, one could use a stent as the platform for local radiation delivery as a means to prevent restenosis. Experimental studies have demonstrated that stents ion implanted with the b-particle emitter 32P can reduce neointima formation. Clinical evaluation of the radioisotope stent began in the fall of 1996. Dose escalation studies have now been completed in approximately 250 patients with 32P, b-particle emitting stents ranging from 0.5 microCi to 24 microCi. Overall, these feasibility trials have demonstrated a clear, dose-dependent reduction of neointimal hyperplasia within the stent structure, but with an unanticipated finding of a relatively high incidence of restenosis at the stent margins. The purpose of this paper is to review the current status of radioactive stents, with an emphasis on the key elements of stent design and stent delivery that could impact the long-term efficacy of this device.

Topics: Brachytherapy; Coronary Angiography; Coronary Disease; Dose-Response Relationship, Radiation; Equipment Design; Feasibility Studies; Humans; Phosphorus Radioisotopes; Radiotherapy Dosage; Recurrence; Stents

A very quantitative, destructive assay procedure was devised for accurately measuring the 32P activity content of TiNi-encapsulated intravascular brachytherapy sources and was applied to four different sources (termed 'seeds') which were developed and provided by Guidant Intravascular Intervention (formerly NeoCardia). These seeds are intended for use in the prophylactic treatment of restenosis following balloon angioplasty in heart-disease patients. The assays involved the dissolution of the TiNi jacket, extraction of the activity from the internal 32P-containing source material, quantitative solution transfers, and a gravimetrically based dilution; followed by liquid scintillation (LS) spectrometry of the resulting master solution with 3H-standard efficiency tracing using composition-matched LS cocktails. The LS spectrometry utilized a previously-developed method for resolving the always-present 33P impurity. The protocol included provisions for accounting for all possible losses of 32P in the digestion procedure (based on radiochemical tracing experiments), for any unrecovered activity in the remaining source material, and for any residual activity in the solution-transfer and containing vessels. Sections of the TiNi jackets adjacent to the cut-off active seed portions were also assayed for any contained activity. Such destructive assays were required for relating measurements of the absorbed dose spatial distribution for the seeds to theoretic dose modelling and for establishing calibration factors for subsequent non-destructive radionuclidic measurements on the seeds.

Topics: Alloys; Angioplasty, Balloon; Brachytherapy; Calibration; Coronary Disease; Humans; Nickel; Phosphorus Radioisotopes; Radionuclide Imaging; Titanium

A calibration factor ('dial setting') for the nondestructive assay of Guidant TiNi-encapsulated 32P intravascular brachytherapy wire sources has been determined for measurements with the Capintec CRC-12 (sic. 'dose calibrator') ionization chamber. The calibration factor was derived from ionization current measurements with the CRC-12 followed by very quantitative, destructive assays of the 32P content in two sources.

Topics: Brachytherapy; Calibration; Coronary Disease; Humans; Nickel; Phosphorus Radioisotopes; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Titanium

Restenosis, caused by proliferation of smooth-muscle cells, limits the efficacy of catheter-based revascularization of coronary arteries. Irradiation has been shown to inhibit growth of smooth-muscle cells in vitro and to prevent restenosis in animal models following stent placement. An intraarterial source of 32P, a pure beta emitter with a half-life of 14.28 days and a 90% range in water of 3.6 mm, is almost ideal for irradiating just arterial wall without exposing any other part of the patient's heart or any other organs, while posing minimal hazards to medical personnel. Two types of previously developed coronary stent impregnated with 32P were investigated. This study aimed to calculate and measure the dose outside of two types of 32P-impregnated beta-emitting coronary stents under conditions closely simulating clinical use.. The dose distributions in water surrounding these stents were calculated using a convolution method and measured by exposing radiochromic film in a solid-water phantom.. Experimental results were in excellent agreement with theoretical calculations.. Radiochromic dosimetry can be used to measure the dose distribution around a beta-emitting intraarterial stent at distances as small as 0.1 mm from the stent surface. A simple cylindrical shell model is adequate for calculating the dose at points farther than 0.5 mm from the stent surface.

Topics: Angioplasty, Balloon, Coronary; Cell Division; Coronary Disease; Coronary Vessels; Humans; Muscle, Smooth, Vascular; Phosphorus Radioisotopes; Radiometry; Radiotherapy Dosage; Recurrence; Stents; X-Ray Film

The near field dose distribution of a realistic vascular stent impregnated with radioactive 32P is calculated employing the dose-point-kernel (DPK) method in a homogeneous and uniform medium. The cylindrical wire mesh geometry for the Palmaz-Schatz [Palmaz-Schatz is a tradename of Cordis (a Johnson & Johnson company)] stent is incorporated in the model calculation, and the dose distribution generated by the beta particles emitted from the decayed radioactive 32P is computed at distances ranging from 0.1 to 2 mm exterior to the stent surface. Dose measurements were obtained using radiochromic film dosimetry media on an actual Palmaz-Schatz half-stent impregnated with 32P using ion implantation, and compared to the DPK model predictions. The close agreement between the model calculation and the film dosimetry data confirms the validity of the model which can be adapted to a variety of different stent designs.

Topics: Angioplasty, Balloon, Coronary; Biophysical Phenomena; Biophysics; Brachytherapy; Coronary Disease; Film Dosimetry; Humans; Models, Theoretical; Phosphorus Radioisotopes; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Recurrence; Stents; Technology, Radiologic

The dose distribution from a 32P source has been measured and calculated in order to evaluate its application in endovascular irradiation. The source dimension was 27 mm in length and 0.3 mm in diameter and was embedded in the end of a Ni-Ti wire. Dose measurements were performed using radiochromic film in several specially designed tissue equivalent phantoms. Loevinger's point dose kernel was used for the calculation. The approximate dose rate at a radial distance of 1.5 mm from the center of the source was found to be 6.75 cGy/s per GBq (0.25 cGy/s per mCi), which allows the delivery of a therapeutic dose in a short time interval with a satisfactory homogeneity without stepping the source. However, the dose rate falls off almost exponentially along the radial distance. Therefore it may not be suitable for treating large diameter vessel from a centrally located source. The effect of a curved 32P wire source on the radial dose distribution was also investigated. The results showed that for a maximum bend of 180 degrees the dose rate was increased by as much as 20% along the inner radial distance but decreased by as much as 20% along the outer radial distance compared to the dose along a straight wire. However, for curvatures normally encountered in a clinical situation, the dose rate was changed less than 5%.

Topics: Angioplasty, Balloon, Coronary; Biophysical Phenomena; Biophysics; Brachytherapy; Catheterization; Combined Modality Therapy; Coronary Disease; Humans; Phantoms, Imaging; Phosphorus Radioisotopes; Radiotherapy Dosage

Recent data indicate that intraluminal irradiation of coronary arteries following balloon angioplasty reduces proliferation of smooth muscle cells, neointima formation, and restenosis. We present calculations for various isotopes and geometries in an attempt to identify suitable source designs for such treatments.. Analytical calculations of dose distributions and dose rates are presented for 192Ir, 125I, 103Pd, 32P, and 90Sr for use in intracoronary irradiation. The effects of source geometry and positioning accuracy are studied.. Accurate source centering, high dose rate, well-defined treatment volume, and radiation safety are all of concern; 15-20 Gy are required to a length of 2-3 cm of vessel wall (2-4 mm diameter). Dose must be confined to the region of the angioplasty, with reduced doses to normal tissues. Beta emitters have radiation safety advantages, but may not have suitable ranges for treating large diameter vessels. Gamma emitters deliver larger doses to normal tissues and to staff. Low energy x-ray emitters such as 125I and 103Pd reduce these risks but are not available at high enough activities. The feasibility of injecting a radioactive liquid directly into the angioplasty balloon is also explored.. Accurate source centering is found to be of great importance. If this can be accomplished, then high energy beta emitters such as 90Sr would be ideal sources. Otherwise, gamma emitters such as 192Ir may be optimal. A liquid beta source would have optimal geometry and dose distribution, but available sources, such as 32P are unsafe for use with available balloon catheters.

Topics: Brachytherapy; Coronary Disease; Humans; Iodine Radioisotopes; Iridium Radioisotopes; Models, Cardiovascular; Palladium; Phosphorus Radioisotopes; Radioisotopes; Radiotherapy Dosage; Recurrence; Strontium Radioisotopes

Thrombolytic therapy has increased the need for a technique to assess the viability of recently reperfused myocardium. This study examined the ability of in vivo phosphorus-31 (P-31) nuclear magnetic resonance (NMR) spectroscopy to distinguish reperfused-viable (stunned) from reperfused-infarcted myocardium at 6, 30, and 54 hours following coronary artery occlusion in a canine model. A 15-minute occlusion produced reperfused-viable myocardium in five animals and a 360-minute occlusion produced reperfused-infarcted myocardium in six animals. Postreperfusion risk zone myocardial phosphocreatine (PCr) concentration measured by P-31 NMR spectroscopy was significantly depressed throughout the 3-day study period in infarcted but not in viable myocardium (p less than 0.01 between groups, all time points). The postreperfusion ratio of inorganic phosphate (Pi) to PCr concentration, as determined by NMR spectroscopy, was elevated throughout the study period in infarcted but not in viable reperfused myocardium (p less than 0.01 between groups, all time points). Postreperfusion Pi concentration was elevated at 6 hours but not subsequently in reperfused-infarcted myocardium, and was not elevated in reperfused-viable myocardium. Logistic regression models selected PCr concentration and the Pi/PCr ratio as providing the best discrimination between reperfused-viable and reperfused-infarcted myocardium. The accuracy of P-31 NMR variables selected by logistic regression analysis for determining myocardial viability ranged from 97% to 100%.

Topics: Animals; Coronary Circulation; Coronary Disease; Diagnosis, Differential; Disease Models, Animal; Dogs; Magnetic Resonance Spectroscopy; Myocardial Infarction; Myocardial Reperfusion; Phosphorus Radioisotopes; Regression Analysis; Time Factors

The use of NMR spectroscopy in the non-invasive assessment of myocardial metabolism has greatly increased over the last decade. The initial experiments were performed on isolated perfused heart preparations, but these have since been extended to whole animal and clinical studies. The use of the phosphorus-31 nucleus allows assessment of energetic metabolism and intramyocardial pH. Carbon-13 spectroscopy based on the use of substrates selectively enriched with the C-13 isotope enables the study of a specific chosen metabolic pathway and provides qualitative and quantitative information about the metabolic changes. Research is now preceding in two directions: firstly, the study of fundamental problems such as the mechanisms of ischaemia, the consequences of intracellular acidosis and the precise role of ATP and phosphocreatine: secondly, very active clinical and pharmacological research in using NMR in animal models of cardiac pathology. Finally, recent technological progress suggests that NMR spectroscopy will soon be used for direct studies of the human heart.

Topics: Carbon Radioisotopes; Cardioplegic Solutions; Citric Acid Cycle; Coronary Disease; Energy Metabolism; Glycogen; Heart Arrest, Induced; Humans; Magnetic Resonance Spectroscopy; Myocardium; Phosphorus Radioisotopes

To assess whether the prophylactic administration of anipamil, a new calcium antagonist, protects the heart against the effects of ischemia and reperfusion, rats were injected intraperitoneally twice daily for 5 days with 5 mg/kg body weight of this drug. The heart was then isolated and perfused by the Langendorff technique. Phosphorus-31 nuclear magnetic resonance spectroscopy was used to monitor myocardial energy metabolism and intracellular pH during control perfusion and 30 min of total ischemia (37 degrees C), followed by 30 min of reperfusion. Pretreatment with anipamil altered neither left ventricular developed pressure under normoxic conditions nor the rate and extent of depletion of adenosine triphosphate (ATP) and creatine phosphate during ischemia. Intracellular acidification, however, was attenuated. On reperfusion, hearts from anipamil-pretreated animals recovered significantly better than untreated hearts with respect to replenishment of ATP and creatine phosphate stores, restitution of low levels of intracellular inorganic phosphate and recovery of left ventricular function and coronary flow. Intracellular pH recovered rapidly to preischemic levels, whereas in untreated hearts a complex intracellular inorganic phosphate peak indicated the existence of areas of different pH within the myocardium. It is concluded that anipamil pretreatment protects the heart against some of the deleterious effects of ischemia and reperfusion. Because this protection occurred in the absence of a negative inotropic effect during normoxia, it cannot be attributed to an energy-sparing effect during ischemia. Therefore, alternative mechanisms of action are to be considered.

Topics: Animals; Calcium Channel Blockers; Coronary Circulation; Coronary Disease; Hydrogen-Ion Concentration; Injections, Intraperitoneal; Intracellular Fluid; Magnetic Resonance Spectroscopy; Male; Myocardial Contraction; Myocardium; Phosphorus Radioisotopes; Premedication; Propylamines; Rats; Rats, Inbred Strains

The mechanism of Ca2+ overload production in ischaemia-reperfusion of the heart is unclear. The present study was designed to examine whether loss of second messenger (Ca2+ and cyclic AMP) control of sarcolemmal Ca2+ transport systems occurs during ischaemia. Ischaemic (1, 2 and 3 h duration) and non-ischaemic tissue samples were taken from the coronary-ligated porcine heart and a membrane fraction, enriched in sarcolemmal vesicles, was isolated. The membranes were phosphorylated using [gamma-32P] ATP in the presence of either cyclic AMP or Ca2+-calmodulin. The in vitro 32P incorporation into the electrophoretically separated phospholamban-like protein, became markedly reduced depending on the duration of ischaemia. The reduction could neither be attributed to factors as ischaemia-induced changes in membrane-bound kinase or phosphatase nor in situ phosphorylation of phospholamban. It is postulated that during ischaemia and reperfusion, a deficient control of the sarcolemmal Ca2+ pump by phospholamban-like protein may serve as a source of intracellular Ca2+ overload.

Topics: Adenosine Triphosphate; Animals; Calcium; Calcium-Binding Proteins; Coronary Disease; Cyclic AMP; Disease Models, Animal; Phosphoprotein Phosphatases; Phosphoproteins; Phosphorus Radioisotopes; Phosphorylation; Proteins; Swine

Topics: Animals; Calcium-Binding Proteins; Coronary Disease; Cyclic AMP; Dogs; Heart; Hypoxia; Microsomes; Myocardium; Phosphorus Radioisotopes; Phosphorylation; Protein Kinases; Trypsin

Perfused rat hearts prelabelled with 32P were made ischaemic by reducing the medium flow from 12 ml/min to 0.5 ml/min. There was a rapid decrease in the contractile performance, but no significant changes in the phosphorylation state of troponin I, myosin P-light chain, an 11 K protein or in the proportion of phosphorylase in the a form occurring up to 5 min of ischaemia. Control hearts stimulated with a bolus of isoproterenol showed a large increase in the contractile force and in the phosphorylation of troponin I, 11 K protein, and phosphorylase, respectively. These responses were progressively reduced by increasing periods of ischaemia. The reduction and loss of increased phosphorylation of these proteins on exposure to isoproterenol was parallelled with an inhibition of cyclic AMP accumulation in the ischaemic heart. Phosphorylation of the myosin P-light chain remained unchanged under all the conditions studied.

Topics: Animals; Calcium-Binding Proteins; Coronary Disease; Heart; Isoproterenol; Kinetics; Myocardial Contraction; Myocardium; Phosphorus Radioisotopes; Phosphorylases; Phosphorylation; Proteins; Rats; Rats, Inbred Strains; Troponin; Troponin I

Previous studies from this laboratory utilized mass spectrometry to measure myocardial oxygen (PO2) and carbon dioxide (PCO2) tensions in isolated feline hearts subjected to periods of global ischemia and reperfusion. Myocardial carbon dioxide tension was found to increase during ischemia, and its rate of increase was found to correlate inversely with subsequent recovery of myocardial function following reflow. The present study utilized phosphorus-31 nuclear magnetic resonance (NMR) to assess whether the severity of intracellular acidosis or the depletion of high energy phosphate stores would show a similar correlation with recovery of function. Hyperkalemic cardioplegia employed as a myocardial preservation technqiue in combination with hypothermia was compared with hypothermia alone as the control intervention. The experimental results demonstrated that intracellular pH fell to 6.09 +/- 0.13 with hypothermia alone and to 6.31 +/- 0.09 with cardioplegia plus hypothermia. Furthermore, myocardial ATP content fell to 22% +/- 2% of control with hypothermia alone, while falling to 36% +/- 4% of control with the combined therapy. Recovery of myocardial performance was found to correlate inversely with the severity of intracellular acidosis and depletion of ATP during ischemia. In contrast, no relationship was observed between preservation of phosphoryl-creatinine levels either during ischemia or after reflow and recovery of ventricular function. These results suggest that, similar to mass spectrometry, which allows monitoring of myocardial PCO2, 31P NMR permits the on-line monitoring of intracellular pH as well as high energy phosphate compounds, and thereby provides useful metabolic indices of the severity of ischemia. Since tight coupling was found between changes in these parameters and subsequent recovery of contractile performance, further development of 31P NMR for evaluation of techniques designed to minimize the severity of ischemic damage would seem indicated.

Topics: Acidosis; Animals; Carbon Dioxide; Coronary Disease; Heart Arrest, Induced; Hypothermia, Induced; Magnetic Resonance Spectroscopy; Mass Spectrometry; Myocardium; Organophosphorus Compounds; Phosphorus Radioisotopes; Rabbits

Topics: Adult; Arteriosclerosis; Cardiac Glycosides; Coronary Disease; Female; Humans; Male; Middle Aged; Phosphorus Radioisotopes; Potassium; Rheumatic Heart Disease; Scintillation Counting