Basic And Clinical Research On Preventing Restenosis With Intravascular Radiation After Angioplasty

Percutaneous transluminal coronary angioplasty (PTCA) has an established role as a nonsurgical catheter-based treatment for coronary artery disease at present, but restenosis (RS) appreciably limits its long-term effect. Objectives:We design this study to explore the efficacy and possible mechanisms of ionising radiation in preventing RS after PTCA from four aspects: (1) To observe the effect of intravascular radiation(IR) on intimal hyperplasia and vascular remodeling in injuried pig iliac arteries with angiography, intravascular ultrasonography and histopathological examination, and investigate the impact of IR on the proliferation and apoptosis of SMCs in the injured arterial walls in pigs. (2) To observe the dosage response of the rabbit smooth muscle cells (SMCs) in vitro to the gamma radiation, and investigate the cellular and molecular biological mechanisms by which radiation inhibits SMCs proliferation. (3) To observe the efficacy and safety of intracoronary brachytherapy(ICBT) on patients with in-stent restenosis(ISR). Methods:l.(l) Angiographies and IVUS were performed in the pig iliac arteries, followed by balloon overstretch injury and an indium- 192(192Ir) source was positioned at the injured iliac segments with a dose of10Gy. 20Gy and 30.5Gy, respectively. All pigs were killed 28 days later and the injured iliac segments were obtained for histological and morphological study. (2) To dynamically observe the histological and morphological changes of the injuried pig iliac arteries on the 3rd day. 10th day and 28th day after IR treatment. (3) Angiography and IVUS were used in the pig iliac arteries before balloon overstretch injury and after injury or injury plus treating with 20Gy IR at 28th day later. The EEM cross section area, lumen cross section area, maximal lumen diameter and minimal lumen diameter were measured by IVUS to observe effect of IR on vascular remodeling. (4) The injured artery segments were processed to examine SMCs proliferation by proliferation cell nuclear antigen (PCNA) and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), light microscope and transmission electron microscope after treating with different dose of IR on the 3rd day, 10th day and 28th day later.2.(1) We cultured the SMCs of the medial layer of illiac artery from New Zealand rabbits. The cultured SMCs were identified by light microscope, transmission electron microscope, and immunocytochemical staining (biotin-labeled) with a monoclonal antibody against myosin. Quiescent SMCs (passage 5-7) were irradiated with single fraction dose of 2.5Gy, 5Gy, 10Gy, 20Gy and 30Gy of gamma ray separately, and immediately cultured in DMEM medium with 10% PCS for 4h, 24h or 72h, respectively. 3H-TdR, flow cytometry, micronucleus test and electronic microscope were used to measure the effects of gamma ray on DNA synthesis, cell cycle and damage of SMCs. (2) SMCs of quiescent rabbit artery SMCs were irradiated with single fraction dose of 2.5Gy,5Gy,10Gy,20Gy and 30Gy gamma ray, separately, and immediately cultured in DMEM mediumwith 10%FCS for 4h, 24h or 72h. In situ mRNA hybridization assay for the quantification of c-fos and p53 gene expression were used to observe the impact of gamma radiation on SMCs.3. Five patients with single vessel ISR were done PICA again after coronary angiogram (CAG) or CAG plus intravascular ultrasonography, then they were treated with 18.4Gy of 90Sr/Y intracoronary |3 radiation. Blood cell analysis, serum myocardial enzymes and CRP were measured before and after ICBT. The symptoms of angina, cardiac events, CAG and ICBT related complications of all the patients were followed up in the next six months. Results:1. (l)Compared with the control group, IR with 20Gy and 30.5Gy both significantly reduced neointimal area and increased the lumen area and external elastic membrane(EEM) area on the 28th day after balloon injury(p<0.05). IR with 10Gy could reduce the neointimal area and increase the lumen area and EEM area, but there was no s...