Failure of a novel balloon-expandable gamma-emitting ((103)Pd) stent to prevent edge effects.

BACKGROUND: Balloon-expandable beta-particle-emitting ((32)P) stents inhibit within-stent neointimal hyperplasia but induce lumen narrowing beyond the stent margins, ie, the so-called "edge effects." METHODS AND RESULTS: We prospectively investigated the performance of novel stents impregnated with the gamma-emitting isotope (103)Pd, designed to reduce edge effects, in 24 rabbits. The stents had a length of 18 mm and were mounted on 20-mm-long delivery balloons for deployment. Angiograms were obtained immediately and 1 month after direct implantation of control and 1-, 2-, and 4-mCi (103)Pd stents into the iliac arteries without predilatation or postdilatation. Late lumen loss was measured with quantitative angiography. Neointimal hyperplasia and vascular remodeling were evaluated by histomorphometry. Late lumen loss was inhibited within (103)Pd stents (control 0.18 mm, 1 mCi 0.08 mm, 2 mCi 0.05 mm, and 4 mCi -0.03 mm, P<0.05 all activities versus control). Conversely, late lumen loss occurred at the edges of (103)Pd stents, correlating with areas of high balloon/artery ratios and vessel overstretch injury. Edge effects were primarily due to neointimal hyperplasia but were also caused by negative vessel remodeling at high stent activities. CONCLUSIONS: Edge effects after implantation of radioisotope stents can occur independently of the isotope chosen for stent impregnation.

Overestimation of stent delivery balloon diameters by manufacturers' compliance tables: a quantitative coronary analysis of Duet and NIR stent implantation.

Although manufacturers' compliance tables of stent delivery balloons indicate the diameter of the balloon at a given inflation pressure, it is unclear whether these data correlate with in vivo true intracoronary balloon diameters (TBDs). The TBDs of two new-generation balloon-expandable stent delivery systems (Duet and NIR) were measured by quantitative coronary analysis (QCA) in 100 consecutive patients. The manufacturers' stated balloon diameter (BD) of the stent delivery systems overestimated the TBD in 94% +/- 4% of patients receiving both Duet or NIR stent implantations. In only 6% of the patients, the TBD matched the manufacturers' stated balloon diameter. There was no underestimation of TBDs by both manufacturers' compliance tables. The Duet tables overestimated TBDs by 14% +/- 8% (range, 1%-36%), the NIR tables by 18% +/- 8% (range, 1%-41%), P < 0.05, Duet vs. NIR, respectively. When the manufacturers' data were corrected for the differences in reporting data from in vitro tests, i.e., balloon compliance data with or without the stent, the degree of overestimation of diameters was similar for Duet and NIR stent delivery balloons (14% +/- 8% vs. 13% +/- 7%, Duet vs. NIR; P = NS). Manufacturers' compliance tables of both the Duet and NIR stent delivery balloon systems significantly overestimate the true intracoronary balloon diameter. The manufacturers' of stent delivery balloons should clearly state on the box, if balloon compliance data were derived from in vitro bench testing, which phantoms were used for compliance analysis, and that the tables may overestimate the true intracoronary balloon diameter. The findings of the present study have important clinical implications with respect to performing coronary stent implantation with precision.

Ultrasound thrombolysis for the treatment of thrombotic occlusion of degenerated saphenous vein grafts.

Despite improvements in catheter-based revascularization outcomes, coronary interventionalists face difficult challenges in the treatment of the thrombus-laden coronary lesion. In this report, we describe the use of the Acolysis device, which utilizes high-frequency (41.9 kHz) ultrasonic energy to vibrate a small metal tip at the end of a 4.5 Fr catheter to treat two thrombotically occluded saphenous vein grafts in two patients. In both cases, the Acolysis device provided normalization of flow with angiographically evident dissolution of thrombus and excellent acute angiographic and clinical results. We conclude that in these two selected cases the Acolysis device was used safely and effectively for thrombus debulking as an adjunct to stenting in diseased saphenous vein bypass grafts.

The impact of stent design and delivery upon the long-term efficacy of radioisotope stents.

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.

Dose and dose rate effects of beta-particle emitting radioactive stents in a porcine model of restenosis.

BACKGROUND: Radioactive stents have been proposed as a means to prevent in-stent restenosis by inhibiting intimal proliferation with continuous low-dose irradiation. OBJECTIVES: The purpose of this study is to determine the effects of cumulative dose and dose-rate delivery on neointimal formation using 32P and 90Y beta-particle emitting radioactive stents in a porcine coronary model of restenosis. METHODS AND MATERIALS: We compared the late histologic results of 0.25 to 32.0 microCi 90Y (half-life 64 hours) (n = 64 stents) and 0.1 to 57.6 microCi 32P (half-life 14.3 days) (n = 55 stents) Beta-particle emitting radioactive stents with non-radioactive (n = 40) stents in a porcine coronary model of restenosis. A computer-based dosimetry modeling program was used to determine the 28 day cumulative dose and dose-rate delivery for the beta-particle emitting radioactive stents at a distance of 0.1 mm from the stent surface. RESULTS: Continuous low dose-rate (1 to 5 cGy/hr) radiation delivery for > 2 weeks via a 0.1 to 0.5 microCi 32P radioactive stent effectively reduced in-stent neointimal hyperplasia at 90 days. Cumulative doses of > 55 Gy induced severe adventitial fibrosis, microvascular damage and promoted the formation of a matrix-rich neointima. Delayed vascular repair was evident at focal regions within the body of radioactive stents that delivered cumulative doses of > or = 140 Gy at 28 days and cumulative doses of 1,100 Gy at 90 days. CONCLUSIONS: These data may be useful in predicting safe and effective dose and dose rate delivery for beta-particle emitting radioactive stents.

Stent design favorably influences the vascular response in normal porcine coronary arteries.

OBJECTIVES: The purpose of this study was to compare the arterial response following implantation of a stainless-steel, balloon-expandable, tubular slotted stent with that of a novel computer-designed, multi-cellular stent in normal porcine coronary arteries. BACKGROUND: Intracoronary stent placement has evolved into the primary strategy for percutaneous revascularization of symptomatic coronary arterial lesions. Presently there is intense interest in developing new stent designs to improve stent delivery and biocompatability. METHODS: Computer-assisted design was utilized to develop a balloon-expandable stent with symmetric expansion properties, uniform arterial wall coverage, longitudinal flexibility and radial strength. Quantitative coronary angiography and histological assessment of the stented arteries was used to evaluate the acute and chronic vascular responses to a stainless-steel, balloon-expandable, tubular slotted stent as compared to the computer-designed BX stent in the normolipemic swine. RESULTS: Forty stents (24 BX, 16 tubular slotted) were implanted in 19 miniature swine at a mean inflation pressure of 9 atm using identical delivery systems. Eight of the BX and none of the tubular slotted stents were post-dilated with a non-compliant balloon at 12-14 atm. The mean stent-to-artery ratio was similar for the BX (1.03 +/- 0.06) and tubular slotted (1.04 +/- 0.11; p = 0.59) designs. Protrusion or asymmetric radial flaring of a strut at the stent margin was present in 1 of 23 BX stents (4.3%) and 10 of 15 tubular slotted stents (66.7%; p < 0.0001). The mean arterial injury score was significantly less for the BX stent (0.2 +/- 0.2) as compared with the tubular slotted stents (0.4 +/- 0.4; p = 0.025). At 3 days, thrombus area was similar for the BX and tubular slotted designs (0.42 +/- 0.16 mm2 versus 0.44 +/- 0.18 mm2, respectively; p = 0.88). The mean neointimal area was significantly less for the BX at 2 months (1.09 +/- 0.25 mm2 versus 2.93 +/- 2.26 mm2 in the tubular slotted stent) and at 6 months (1.10 +/- 0.26 mm2 versus 2.07 +/- 0.65 mm2 in the tubular slotted stent; p = 0.01), resulting in approximately 50% less in-stent stenosis. CONCLUSIONS: The arterial response to a balloon-expandable stent can be favorably influenced by computer-assisted modification of design in an experimental model. Further study is warranted to determine the impact of stent design upon clinical in-stent restenosis.

Reversal of "no reflow" during vein graft stenting using high velocity boluses of intracoronary adenosine.

Slow or no reflow is a serious problem complicating catheter-based revascularization of degenerated saphenous vein bypass grafts. We examined the efficacy of rapidly delivered, high-velocity injections of intracoronary adenosine to reverse 11 slow-flow events complicating stenting of diseased bypass grafts. Ten of 11 events were rapidly improved to TIMI 3 flow by this technique within 3.8+/-1.6 min of the initial adenosine injection. In an ex vivo model, 3-ml syringes created higher peak pressures and velocities than 10- and 20-ml syringes. We conclude that rapid and repeated high-velocity intragraft administration of adenosine is a promising new approach to promptly reverse no-reflow events complicating PTCA and stenting of diseased saphenous vein grafts. Ex vivo studies demonstrate a potentially important mechanical advantage with the use of small syringes for injection. Further randomized studies will be required to better define the mechanism(s) and efficacy of this approach for treating no reflow, including its use in native vessels.

The radioisotope stent for the prevention of restenosis.

The use of intracoronary stenting has revolutionized catheter-based revascularization of obstructive coronary artery disease. These devices provide excellent scaffolding, predictable immediate success with the creation of a large, dissection-free luminal cross-section and improved long-term outcomes, when compared to "plain old balloon angioplasty". Despite these improvements restenosis still occurs at 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. The potential advantages, as well as the limitations of this means of intravascular brachytherapy are reviewed. This approach has been shown to be effective in certain animal models of restenosis. The initial clinical results with the Phase I safety trials will be summarized. Future directions for this technology, including the evaluation of new stent designs and new radioisotopes will be discussed. The early clinical results with more than 170 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. Implementation of a large scale randomized clinical trial will commence if and when early safety and efficacy data suggest a therapeutic effect from this technology. Thus, future studies will focus on optimal stent design and will evaluate alternative isotopes and dosing strategies.

A system for postoperative visualization and analysis of left ventricular pressure-volume loops.

A patient monitoring system for continuous real-time monitoring of left ventricular (LV) function in the postoperative setting was developed. Common hemodynamic parameters and LV functional indices are all calculated from left ventricular pressure-volume loops (PV-loops). Visualization of the PV-loops, along with the hemodynamic parameter derived from them, provides valuable insight into ventricular function and patient recovery. The pressure component is obtained via a pressure sensing catheter placed during surgery. Volume is measured via non-imaging radionuclide techniques using a modified Capintec-VEST. Following surgery and transfer to the recovery unit, the patient's blood is labeled with Tc-99m. A portable gamma camera is used to measure baseline ejection fraction (EF) and to aid in placing the VEST. The specific radioactivity of the blood is calibrated using the baseline EF and thermodilution cardiac output. To confirm the volume measurement accuracy of this technique six patients undergoing bilateral heart catheterization were studied. Single-plane cineventriculographic LV volumes were compared to those calculated from the VEST's time activity curve.

Current status of radioactive stents for the prevention of in-stent restenosis.

PURPOSE: The objective of this paper was to provide an update on the clinical and experimental evaluation of radioactive stents for the prevention of restenosis. MATERIALS AND METHODS: Direct ion implantation of 32P onto the surface of a 15-mm length balloon expandable stainless-steel Palmaz-Schatz stent was employed to render this commercially available vascular stent radioactive. 32Phosphorous, a pure beta-particle-emitting radioisotope, was selected because of its short half-life (14.3 days) and limited range of tissue penetration (3-4 mm). The vascular response to radioactive 7-mm length Palmaz-Schatz stents with activities 0.14 to 23 microCi of 32P were evaluated in animal models of arterial injury and restenosis. The Phase-1 isostent for restenosis intervention study (IRIS trial) was a nonrandomized safety trial designed to evaluate the use of a low activity 32P (0.5 to 1.5 microCi) 15-mm length Palmaz-Schatz stent for the treatment of de novo or restenosis native coronary arterial lesions. RESULTS: In the porcine coronary restenosis model, at < or =0.5 microCi and > or =3.0 microCi stent activities, there was a 30% reduction in the neointimal and percent area stenosis as compared to nonradioactive stents. The 1.0 microCi stents, however, had nearly 2-fold greater neointimal formation and more luminal narrowing than the control stents. In the Phase 1 IRIS trial, 57 patients with symptomatic de novo or restenosis native coronary lesions have been treated with low activity (0.5 to 1.5 microCi) 32P Palmaz-Schatz coronary stents. Fifty-seven stents were successfully implanted without a major procedural complication (death, urgent coronary bypass, Q-wave myocardial infarction). There were no cases of stent thrombosis, target vessel revascularization, or other adverse events in the first 30 days after implant. CONCLUSION: The early clinical results with a low-activity 32P Palmaz-Schatz radioactive stent demonstrate sufficient procedural and 30-day event-free survival to warrant consideration of additional clinical studies to determine the safety and efficacy of this therapy for the prevention of restenosis. Future studies will focus on optimal stent design for delivery of radiation, and will further evaluate safe and effective dosing strategies.

Radioactive 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.

Coronary artery vasomotion after percutaneous transluminal coronary angioplasty.

Substantial evidence of postangioplasty vasoconstriction is available, both at the dilated site and distal to balloon injury, demonstrating its frequent occurrence. It is likely that even mild or moderate vasoconstriction at the site of balloon injury may create flow turbulence, promoting platelet aggregation and contributing to thrombotic vessel closure. The regulation of arterial smooth muscle tone is a complex process and should be distinguished from elastic recoil, which occurs at the site of balloon injury due to passive elastic properties of the artery, generally immediately after balloon deflation. The contribution of a variety of messengers generated by humoral, neurogenic, myogenic, and endothelium-derived factors in this regulatory process has been implicated. The possible mechanisms of post-percutaneous transluminal coronary angioplasty vasoconstriction at the dilated site (local) and in segments of coronary artery beyond the dilated site (distal) are reviewed in this article.

Histopathology of restenosis after stenting of narrowed coronary arteries after cardiac transplantation during the teenage years.

This study describes the detailed histopathologic appearance of human coronary arteries at 3 weeks, and 3 and 7 months after stent implantation in a cardiac transplant recipient. There was modest arterial injury associated with stent implantation, and immunocytochemistry staining provided evidence that a proliferative response from the adventitia contributes to neointimal hyperplasia.

Radiation dose from a phosphorous-32 impregnated wire mesh vascular stent.

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.

Effects of endovascular radiation from a beta-particle-emitting stent in a porcine coronary restenosis model. A dose-response study.

BACKGROUND: Neointimal formation causes restenosis after intracoronary stent placement. Endovascular radiation delivered via a stent has been shown to reduce neointimal formation after placement in porcine and rabbit iliac arteries. The objective of this study was to evaluate the dose-related effects of a beta-particle-emitting radioactive stent in a porcine coronary restenosis model. METHODS AND RESULTS: Thirty-seven swine underwent placement of 35 nonradioactive and 39 beta-particle-emitting stents with activity levels of 23.0, 14.0, 6.0, 3.0, 1.0, 0.5, and 0.15 microCi of 32P. Treatment effect was assessed by histological analysis 28 days after stent placement. Neointimal and medial smooth muscle cell density were inversely related to increasing stent activity. The neointima of the high-activity (3.0- to 23.0-microCi) stents consisted of fibrin, erythrocytes, occasional inflammatory cells, and smooth muscle cells with partial endothelialization of the luminal surface. In the 1.0-microCi stents, the neointima was expanded and consisted of smooth muscle cells and a proteoglycan-rich matrix. The neointima of the low-activity (0.15- and 0.5-microCi) stents was composed of smooth muscle cells and matrix with complete endothelialization of the luminal surface. At low and high stent activities, there was a reduction in neointimal area (low, 1.63 +/- 0.67 mm2 and high, 1.73 +/- 0.97 mm2 versus control, 2.40 +/- 0.87 mm2) and percent area stenosis (low, 26 +/- 7% and high, 26 +/- 12%) compared with control stents (37 +/- 12%, P < or = .01). The 1.0-microCi stents, however, had greater neointimal formation (4.67 +/- 1.50 mm2) and more luminal narrowing (64 +/- 16%) than the control stents (P < .0001). CONCLUSIONS: The differential response to the doses of continuous beta-particle irradiation used in this experimental model suggests a complex biological interaction of endovascular radiation and vascular repair after stent placement. Further study is required to determine the clinical potential for this therapy to prevent stent restenosis.