Long-term effects of intracoronary beta-radiation in balloon- and stent-injured porcine coronary arteries.

BACKGROUND: The data on the long-term safety and efficacy of intracoronary beta-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 beta-radiation from a centered 32P 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 mm2, P=0.06) and larger external elastic lamina areas (3.32 +/- 0.21 versus 2.62 +/- 0.10 mm2, 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 mm2 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 mm2, 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 beta-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.

Prevention of restenosis with intravascular beta-radiotherapy.

Beta radiation has been clearly shown, in a specific dose range, to be highly effective in the inhibition of the restenotic process after balloon or stent injury in animal experiments, as well as in randomized, placebo-controlled human trials. The major advantage of beta radiation, in comparison with gamma radiation, is a significantly lower radiation exposure to the personnel and patient, and easier adaptability to existing cardiac catheterization laboratories. Rapidly accumulating evidence indicates that the two major problems, late thrombosis and edge stenosis, may be minimized with prolonged antiplatelet therapy (6 months or more) and broader radiation coverage of the intervention site. Although there may be better, safer, and easier options to reduce restenosis in the years to come, intravascular radiotherapy is the first breakthrough modality that has been shown to significantly reduce restenosis after percutaneous vascular interventions.

Dose-response study of intracoronary beta-radiation with 32P in balloon- and stent-injured coronary arteries in swine.

PURPOSE: A dose-response study was performed in swine to investigate the vascular effects of 32P over a broad range of doses in order to define the therapeutic window of intracoronary radiotherapy (ICR) with 32P. METHODS AND MATERIALS: A total of 131 porcine arteries were subjected to balloon injury or stenting followed by 0-36 Gy of ICR from a centered 32P source wire to 1 mm beyond lumen surface or a sham ICR procedure. Animals were euthanized at 4 weeks, and vessels were harvested for histomorphometry. RESULTS: In the balloon-injured arteries, doses of 7 and 9 Gy did not impact restenosis. At doses of 14-36 Gy, neointima was markedly reduced, with mild dilatation at the highest dose, 36 Gy. In the stent-injured arteries, the lowest dose of 9 Gy failed to reduce neointimal growth, while 14-26 Gy showed the most favorable response. CONCLUSIONS: ICR with 32P features a broad therapeutic window. Doses of 14-26 Gy to 1 mm beyond lumen surface provided an optimal combination of efficacy and safety. Doses of 7 and 9 Gy were generally ineffective, suggesting a minimum threshold for ICR with 32P to effectively inhibit restenosis.

Inhibition of restenosis with beta-emitting radiotherapy: Report of the Proliferation Reduction with Vascular Energy Trial (PREVENT).

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Catastrophic outcomes of noncardiac surgery soon after coronary stenting.

OBJECTIVES: To assess the clinical course of patients who have undergone coronary stent placement less than six weeks before noncardiac surgery. BACKGROUND: Surgical and percutaneous transluminal coronary angioplasty revascularization performed before high-risk noncardiac surgery is expected to reduce perioperative cardiac morbidity and mortality. Perioperative and postoperative complications in patients who have undergone coronary stenting before a noncardiac surgery have not been studied. METHODS: Forty patients who underwent coronary stent placement less than six weeks before noncardiac surgery requiring a general anesthesia were included in the study (1-39 days, average: 13 days). The records were screened for the occurrence of adverse clinical events, including myocardial infarction, stent thrombosis, peri- and postoperative bleeding and death. RESULTS: In 40 consecutive patients meeting the study criteria, there were seven myocardial infarctions (MIs), 11 major bleeding episodes and eight deaths. All deaths and MIs, as well as 8/11 bleeding episodes, occurred in patients subjected to surgery fewer than 14 days from stenting. Four patients expired after undergoing surgery one day after stenting. Based on electrocardiogram, enzymatic and angiographic evidence, stent thrombosis accounted for most of the fatal events. The time between stenting and surgery appeared to be the main determinant of outcome. CONCLUSIONS: Postponing elective noncardiac surgery for two to four weeks after coronary stenting should permit completion of the mandatory antiplatelet regimen, thereby reducing the risk of stent thrombosis and bleeding complications.

Intracoronary radiotherapy for prevention of restenosis after percutaneous coronary interventions.

More than 50 different pharmacological and mechanical interventions have been tested to date for prevention of vascular restenosis without success. Intracoronary radiotherapy is the first one showing promise of significantly attenuating neointimal proliferation, causing positive vascular remodelling and thus inhibiting restenosis. This promising modality has moved from animal experiments via safety and feasibility testing into the phase of clinical trials of efficacy in large numbers of patients. While ongoing research continues to search for new sources and delivery techniques, currently available technology is being optimized. The randomized clinical trials conducted to date have shown consistently a reduction of target site restenosis rates by 55-79%. Lower incidence of major adverse cardiac events after radiotherapy has also been demonstrated, primarily as a result of reduction in target site and target vessel revascularization rates. However, experimental and clinical research has identified two major complications of this approach: stenosis at the ends of the radiation zone ('edge effect' or 'candywrapper') as well as late thrombosis (beyond 30 days after intervention) of the angioplasty or stent site. If these two adverse effects can be minimized, intracoronary radiotherapy may prove to be a major breakthrough in percutaneous coronary interventions.

Clinical experience with a spiral balloon centering catheter for the delivery of intracoronary radiation therapy.

PURPOSE: To develop and evaluate an intravascular radiation delivery catheter that incorporates a centering mechanism and that allows side branch and distal artery perfusion. METHODS AND MATERIALS: The Galileo Centering Catheter (Guidant Vascular Interventions, Houston, TX) incorporates a rapid exchange tip design. A unique spiral balloon allows centering and facilitates perfusion to the distal artery and side branches. The catheter contains a dedicated dead-end lumen for source wire delivery to the lesion site. The treatment area is precisely defined by radiopaque markers. RESULTS: In three clinical trials to date, radiation (or placebo) was delivered successfully to 300 of 312 patients (96%). With balloon inflation, TIMI grade 2 or 3 flow was achieved in side branches in 82% and in the distal artery in 77% of patients. Despite treatment (dwell) times ranging from 87 to 948 s (mean = 250 s), only 8% of patients required fractionation of treatment. CONCLUSION: The Galileo Centering Catheter is a safe and highly effective method for delivering intracoronary radiation therapy. Its unique design provides centering of the source while allowing side branch and distal coronary perfusion during treatment. This catheter would facilitate intracoronary radiation therapy and allow uniform and reproducible dose delivery to the target in the artery wall.

The cardiac endothelium: functional morphology, development, and physiology.

Cardiac endothelial cells, regardless of whether they are from endocardial or from coronary (micro)vascular origin, directly modulate performance of the subjacent cardiomyocytes, resulting in control of the onset of ventricular relaxation and rapid filling of the heart. This review summarizes major features of the morphology, embryology, and comparative physiology of cardiac endothelial cells as well as the experimental observations on how cardiac endothelial cells affect the mechanical performance of the heart. As for the underlying mechanisms of the interaction between cardiac endothelial cells and cardiomyocytes, two working hypotheses have been postulated over the past years; (1) interaction mediated through a trans-endothelial physicochemical gradient for various ions (active blood-heart barrier), and (2) interaction mediated through the release by the cardiac endothelial cells of various cardioactive substances, eg, nitric oxide, endothelin, and prostacyclin. These two mechanisms may act in concert or in parallel.