Outcome from balloon induced coronary artery dissection after intracoronary beta radiation.

OBJECTIVE: To evaluate the healing of balloon induced coronary artery dissection in individuals who have received beta radiation treatment and to propose a new intravascular ultrasound (IVUS) dissection score to facilitate the comparison of dissection through time. DESIGN: Retrospective study. SETTING: Tertiary referral centre. PATIENTS: 31 patients with stable angina pectoris, enrolled in the beta energy restenosis trial (BERT-1.5), were included. After excluding those who underwent stent implantation, the evaluable population was 22 patients. INTERVENTIONS: Balloon angioplasty and intracoronary radiation followed by quantitative coronary angiography (QCA) and IVUS. Repeat QCA and IVUS were performed at six month follow up. MAIN OUTCOME MEASURES: QCA and IVUS evidence of healing of dissection. Dissection classification for angiography was by the National Heart Lung Blood Institute scale. IVUS proven dissection was defined as partial or complete. The following IVUS defined characteristics of dissection were described in the affected coronary segments: length, depth, arc circumference, presence of flap, and dissection score. Dissection was defined as healed when all features of dissection had resolved. The calculated dose of radiation received by the dissected area in those with healed versus non-healed dissection was also compared. RESULTS: Angiography (type A = 5, B = 7, C = 4) and IVUS proven (partial = 12, complete = 4) dissections were seen in 16 patients following intervention. At six month follow up, six and eight unhealed dissections were seen by angiography (A = 2, B = 4) and IVUS (partial = 7, complete = 1), respectively. The mean IVUS dissection score was 5.2 (range 3-8) following the procedure, and 4.6 (range 3-7) at follow up. No correlation was found between the dose prescribed in the treated area and the presence of unhealed dissection. No change in anginal status was seen despite the presence of unhealed dissection. CONCLUSION: beta radiation appears to alter the normal healing process, resulting in unhealed dissection in certain individuals. In view of the delayed and abnormal healing observed, long term follow up is indicated given the possible late adverse effects of radiation. Although in this cohort no increase in cardiac events following coronary dissections was seen, larger populations are needed to confirm this phenomenon. Stenting of all coronary dissections may be warranted in patients scheduled for brachytherapy after balloon angioplasty.

beta-Particle-emitting radioactive stent implantation. A safety and feasibility study.

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, beta-particle-emitting radioactive stents decrease neointimal hyperplasia by inhibiting smooth muscle cell proliferation. METHODS AND RESULTS: 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. CONCLUSIONS: The use of radioactive stents with an activity of 0.75 to 1.5 microCi is safe and feasible.

Geometric vascular remodeling after balloon angioplasty and beta-radiation therapy: A three-dimensional intravascular ultrasound study.

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 beta-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 beta-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.

Remodeling of atherosclerotic coronary arteries varies in relation to location and composition of plaque.

The aim of this study was to determine the contribution of morphologic characteristics and location of plaque in remodeling of atherosclerotic coronary arteries. Consecutive intravascular ultrasound studies performed in native coronary arteries before an intervention were included in the study. Total vessel, lumen and plaque + media areas were measured at target lesion, and distal and proximal references. Remodeling index was calculated as target total vessel area/proximal reference total vessel area, and categorized into 3 groups based on relative total vessel-area ratio: (1) > 1.1 (group A, adequate remodeling); (2) 0.9 to 1.1 (group B, failure of compensatory enlargement); and (3) <0.9 (group C, coronary shrinkage). Eighty-nine narrowings were assessed in 80 intravascular ultrasound studies. Thirty-eight lesions (43%) were defined as soft and 51 (57%) as hard. Soft plaques were more prevalent in group A than in groups B and C (p = 0.001). Conversely, the arc of calcium was larger in group C lesions (p = 0.005). At distal segments, group A lesions were more prevalent than those in groups B and C, whereas at proximal segments group C lesions were more prevalent (p = 0.007). Multivariate analysis identified the arc of calcium and the location of plaque at distal segments as independent predictors of compensatory enlargement (odds ratio 0.94, 95% confidence interval 0.90 to 0.99; odds ratio 4.6; 95% confidence interval 1.4 to 15.7, respectively), whereas hard plaques were an independent predictor of coronary shrinkage (odds ratio 4.6; 95% confidence interval 1.7 to 12.5). In conclusion, composition and location of plaque appeared to be major determinants of vessel remodeling during the process of atherosclerosis.

Compassionate use of intracoronary beta-irradiation for treatment of recurrent in-stent restenosis.

Recurrent in-stent restenosis after balloon angioplasty poses a serious management problem. Previously g-radiation has been shown to be effective in patients with in-stent restenosis. The aim of the study was to determine the feasibility and safety of b-radiation in patients with recurrent in-stent restenosis. From May 1997 to December 1998, 18 patients were treated with balloon angioplasty (n = 8) or laser (n = 10), followed by intracoronary b-radiation at a prescribed dose of 16 Gray at 2 mm from the source, for reference diameters by quantitative coronary angiography < 3.25 mm or 20 Gray for reference diameters > or =3.25 mm. Vessels treated were as follows: left anterior descending: (n = 5); circumflex: (n = 4); right coronary artery: (n = 6); saphenous vein graft: (n = 3). Average recurrence rate was 2.4 +/- 0.7 and the restenotic length was 16 +/- 7 mm. b-radiation was successfully delivered in all patients. Two patients presented complications related to laser debulking: a non-Q wave myocardial infarction in one and a re-angioplasty due to uncovered distal dissection in another. Geographical miss, defined as an area which has been injured but not covered by the radiation source, was demonstrated in 8 patients. Seventeen patients (94%) completed the 6-month angiographic follow-up. Restenosis (> 50% Diameter Stenosis) was observed in 9 patients (53%), leading to target lesion revascularization in 8 patients (47%). Six of the 9 restenoses were located in areas with geographical miss. Intracoronary b-radiation for recurrent in-stent restenosis appears to be a safe and feasible management strategy. However, the mismatch between injured and irradiated area may lead to failure of this therapy.

Effects of thyroid status and thyrostatic drugs on hepatic glucuronidation of lodothyronines and other substrates in rats : Induction of phenol UDP-glucuronyltransferase by methimazole.

Glucuronidation of iodothyronines in rat liver is catalyzed by at least three UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT, and androsterone UGT. Bilirubin and phenol UGT activities are regulated by thyroid hormone, but the effect of thyroid status on hepatic glucuronidation of iodothyronines is unknown. We examined the effects of hypothyroidism induced by treatment of rats with propylthiouracil (PTU) or methimazole (MMI) or by thyroidectomy as well as the effects of T4-induced hyperthyroidism on the hepatic UGT activities for T4, T3, bilirubin,p-nitrophenol (PNP), and androsterone. Bilirubin UGT activity was increased in MMI- or PTU-induced hypothyroid and thyroidectomized rats, and decreased in hyperthyroid animals. T4 and, to a lesser extent, T3 UGT activities were increased in MMI- or PTU-induced hypothyroid rats, and T4 but not T3 glucuronidation also showed a significant increase in thyroidectomized rats. T4 but not T3 UGT activity was slightly decreased in hyperthyroid rats. While PNP UGT activity was decreased in thyroidectomized rats and increased in hyperthyroid animals, it was also markedly increased by MMI and slightly increased by PTU-induced hypothyroidism. In T4-substituted rats, MMI did not affect T4, T3, bilirubin and androsterone UGT activities but again strongly induced PNP UGT activity, indicating that this represented a direct induction of PNP UGT by the drug independent of its thyrostatic action. Androsterone UGT activity was hardly affected by thyroid status. Our results suggest a modest, negative control of the hepatic glucuronidation of thyroid hormone by thyroid status, which may be mediated by changes in bilirubin UGT activity. To our knowledge, this is the first report of the marked induction of a hepatic enzyme by MMI, which is not mediated by its thyroid hormone-lowering effect.

Glucuronidation of thyroid hormone by human bilirubin and phenol UDP-glucuronyltransferase isoenzymes.

The glucuronidation of thyroid hormone by UDP-glucuronyltransferases (UGTs) stably transfected in Chinese hamster V79 lung fibroblasts was investigated. Human bilirubin UGT (HP3) and phenol UGT (HP4) both catalysed the glucuronidation of T4 and rT3, whereas glucuronidation of T3 was not significant, rT3 was the preferred substrate for both isoenzymes, glucuronidation rates being 1.6- and 6.4-times higher than conjugation of T4 by HP3 and HP4 clones, respectively. This is the first identification of thyroid hormone as potential alternative endogenous substrate for bilirubin UGT.