Intracoronary irradiation: dose response for the prevention of restenosis in swine.

PURPOSE: Restenosis after percutaneous transluminal coronary angioplasty represents, in part, a proliferative response of vascular smooth muscle at the site of injury. We have previously shown that high-dose radiation (20 Gy), delivered via an intracoronary 192Ir source, causes focal medial fibrosis and markedly impairs the restenosis process after balloon angioplasty in swine. This study sought to delineate the dose-response characteristics of this effect. METHODS AND MATERIALS: Forty juvenile swine underwent coronary angiography; a segment of the left coronary artery was chosen as a target for balloon injury. In 30 swine, a 2 cm ribbon of 192Ir was positioned at the target segment and 20, 15, or 10 Gy were delivered to the vessel wall (10 animals/dose). Subsequently, overdilatation balloon angioplasty was performed at the irradiated segment. In 10 control swine, overdilatation balloon angioplasty was performed without previous irradiation. Thirty-eight animals survived until sacrifice at 30 +/- 3 days. Histopathological analysis was performed by a pathologist in a blinded manner. The area of maximal luminal compromise within the target segment was analyzed via computer-assisted planimetry. RESULTS: Neointimal area was decreased by 71.4% at 20 Gy and by 58.3% at 15 Gy compared with control animals (p < 0.05 for both). A stimulatory effect on smooth muscle cell proliferation was noted at 10 Gy, with a 123% increase in neointimal area compared with controls (p < 0.05). Mean percent area stenosis was also reduced by 63% at 20 Gy and by 74.8% at 15 Gy compared with controls (p < 0.05 for both). CONCLUSIONS: Intracoronary irradiation prior to overstretch balloon angioplasty markedly reduces neointima formation; this effect is dose dependent, with evidence of a significant stimulatory effect at 10 Gy. The effective therapeutic dose range for the prevention of restenosis in this model begins at approximately 15 Gy delivered to the vessel wall.

Anatomic and physiologic heterogeneity in patients with syndrome X: an intravascular ultrasound study.

OBJECTIVES: We used intravascular ultrasound imaging of the epicardial vessels to assess coronary morphology, vasomotor response to exercise and exercise-vasomotion after beta-adrenoceptor blockade in patients with syndrome X. BACKGROUND: Syndrome X is defined as chest pain, abnormal exercise test results and normal coronary angiographic findings. Because of the limitations of coronary angiography, intravascular ultrasound was used to define coronary pathophysiology. METHODS: Thirty patients with syndrome X were studied with intravascular ultrasound imaging (30 MHz, 4.3F catheter) of all three major epicardial vessels. Supine arm exercise was performed during coronary imaging. Lumen area was assessed at rest and during peak exercise. The exercise-imaging protocol was repeated after loading with 0.1 mg/kg body weight of intravenous propranolol. RESULTS: Three morphologic groups were identified using intravascular ultrasound: normal coronary arteries (no plaque, intimal thickness < 0.25 mm, n = 12), atheromatous disease (mean [+/- SD] area stenosis 37.9 +/- 7.2%, n = 10) and marked intimal thickening (0.73 +/- 0.11 mm, n = 8). Patients with normal coronary arteries displayed a vasodilatory response to exercise (+16.9% area increase); patients with abnormal coronary arteries displayed a vasoconstrictive response to exercise (-17.4% in the group with plaque; -17.6% in the group with intimal thickening). Propranolol loading attenuated the vasodilatory response in the group with normal coronary arteries (+6.4% area increase) and attenuated the vasoconstrictive response in the two groups with abnormal coronary arteries (-8.0% in the group with plaque; -8.8% in the group with intimal thickening). CONCLUSIONS: Most patients with syndrome X have abnormal coronary arteries by intravascular ultrasound. Intravascular ultrasound identifies three distinct morphologic groups: normal coronary arteries, atheromatous plaque and intimal thickening. Exercise-vasomotion is normal in patients with syndrome X who have normal coronary arteries by ultrasound; patients with abnormal arteries (plaque or intimal thickening) have an abnormal (constrictive) response to exercise. Propranolol loading attenuates vasoreactivity in all subgroups, suggesting divergent therapeutic utility.

Intracoronary irradiation markedly reduces neointimal proliferation after balloon angioplasty in swine: persistent benefit at 6-month follow-up.

OBJECTIVES: This study examined the long-term efficacy of intracoronary irradiation for limiting neointimal proliferation after overstretch balloon angioplasty in a porcine model of restenosis. In addition, this study sought to identify any adverse late sequelae of this novel therapy for restenosis. BACKGROUND: Restenosis after coronary angioplasty represents in part a proliferative response of vascular smooth muscle at the site of injury. We have shown previously that high dose intracoronary radiation induces focal medial fibrosis and markedly reduces neointimal proliferation early after balloon angioplasty in swine. METHODS: Twenty-two juvenile swine underwent intervention at a target segment of the left coronary artery. In 11 swine, a 2-cm ribbon of iridium-192 was positioned at the target segment and 2,000 cGy was delivered to the vessel wall. Subsequently, overdilation balloon angioplasty was performed at the irradiated segment. In 11 control swine, overdilation balloon angioplasty was performed without previous irradiation. Twenty animals survived and underwent histopathologic analysis at 180 +/- 8 days. RESULTS: Mean (+/- SD) neointimal area was 1.59 +/- 0.78 and 0.46 +/- 0.35 mm2 (p < 0.001) in control and irradiated animals, respectively. Mean percent area stenosis was 37.9 +/- 12.4% and 14.2 +/- 9.0% (p < 0.001) in the control and irradiated animals, respectively. Thus, by 6-month follow-up, intracoronary irradiation before balloon angioplasty had reduced the bulk of the neointimal lesion by 71.1% and reduced percent area stenosis by 62.5% compared with that in control animals. There was no evidence of radiation vasculopathy or myocardial damage at 6 months. CONCLUSIONS: Intracoronary irradiation (2,000 cGy) produces persistent impairment of neointimal proliferation 6 months after balloon injury, with no evidence of late radiation sequelae.

Effects of high-dose intracoronary irradiation on vasomotor function and smooth muscle histopathology.

A significant component of restenosis after coronary angioplasty is due to medial proliferation. Targeted ablation of the proliferating cells by ionizing radiation may prevent restenosis. We delivered high-dose intracoronary gamma-irradiation in porcine coronary arteries and assessed vasomotor function acutely and at 32 days, with pathological analysis at 32 days. Changes in luminal area were assessed by intravascular ultrasound. Irradiated segments acutely displayed vasoconstriction to acetylcholine, with loss of smooth muscle response to nitroglycerin. Restudy revealed restoration of normal vasodilatory response to acetylcholine but persistent loss of response to nitroglycerin. Histopathology at 32 days revealed minor neointima formation without luminal compromise and diffuse fibrosis of the smooth muscle layer. The surrounding myocardium was normal. Focal medial fibrosis without significant endothelial or myocardial damage can be achieved via this technique; intracoronary irradiation, therefore, may be an effective way of impairing the restenosis process.

Intracoronary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model.

OBJECTIVES: This study examined the effects of intracoronary irradiation on neointimal proliferation after overstretch balloon angioplasty in a normolipemic swine model of restenosis. BACKGROUND: Restenosis after percutaneous transluminal coronary angioplasty represents, in part, a proliferative response of vascular smooth muscle at the site of injury. We have previously shown that ionizing radiation, delivered by means of an intracoronary source, causes focal medial fibrosis. We therefore hypothesized that intracoronary irradiation delivered at the time of balloon angioplasty might impair the restenosis process. METHODS: Nineteen juvenile swine underwent coronary angiography; a segment of the coronary artery was chosen as a target for balloon injury. In 10 swine, a ribbon of iridium-192 was positioned at the target segment, and 2,000 cGy was delivered at the vessel wall. Subsequently, overdilation balloon angioplasty was performed at the irradiated segment. In nine control swine, overdilation balloon angioplasty was performed without previous irradiation. Eighteen animals survived and were killed at 30 days. Histopathologic analysis was performed by a pathologist in blinded manner. The area of maximal lumen compromise within the target segment was analyzed by computer-assisted planimetry. RESULTS: In the control group, mean (+/- SD) neointimal area was 0.84 +/- 0.60 mm2 compared with that in the irradiated group, 0.24 +/- 0.13 mm2 (p = 0.01). In the control group, mean percent area stenosis was 47.6 +/- 20.7%, whereas that in the irradiated group was 17.6 +/- 10.5% (p = 0.001). This represents a 71.4% reduction in neointimal area and a 63.0% reduction in percent area stenosis in the irradiated group. Adjacent coronary segments and surrounding myocardium were unaffected. CONCLUSIONS: Intracoronary irradiation (2,000 cGy) delivered to a target porcine coronary segment before balloon overdilation markedly reduces neointima formation at 30 days and thus significantly impairs the restenosis process.