Norihiro Ishida

Suppression of cell proliferation by tissue plasminogen activator during the early phase after balloon injury minimizes intimal hyperplasia in hypercholesterolemic rabbits.

Thrombus formation is a key component of the pathogenesis of restenosis after arterial balloon injury. The purpose of this study was to determine whether intimal hyperplasia could be attenuated by infusion of recombinant tissue plasminogen activator (tPA). Forty-two Kurosawa and Kusanagi hypercholesterolemic rabbits were divided into tPA (n = 20) and control (n = 22) groups, the former receiving 7 days of continuous tPA infusion (0.6 mg/kg/day) via ear veins. The walls of the common iliac arteries were injured using 2.5-mm balloon catheters and then examined histologically 7, 14, 21, and 28 days later. Cell proliferation was assessed by immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), and transforming growth factor (TGF)-β immunohistochemistry was carried out to estimate cell proliferation and differentiation. It was observed that 28 days after balloon injury, intimal cross-sectional areas in the tPA group were significantly smaller than in controls (0.11 ± 0.03 mm2 vs. 0.57 ± 0.08 mm2, p < 0.01), as were ratios of the cross-sectional areas of the intima and media (0.21 ± 0.07 vs. 1.06 ± 0.18, p < 0.05). In addition, the numbers of PCNA-positive medial cells were significantly lower (0.06 ± 0.01 vs. 0.36 ± 0.08, p < 0.05) and TGF-β-positive vessel wall areas were significantly smaller in tPA-treated animals 7 days after balloon injury (0.47 ± 0.28% vs. 4.55 ± 1.44%, p < 0.05). Thus infusion of tPA after arterial balloon injury appears to decrease medial cell proliferation and suppress intimal hyperplasia.

tPA via infusion catheters followed by continuous IV infusion for 3 days prevents intimal hyperplasia after balloon injury.

A rabbit model was used to examine the effects of tissue plasminogen activator (tPA) on development of intimal hyperplasia following balloon injury. Thirty-two hereditary hypercho lesterolemic (KHC) rabbits underwent percutaneous transluminal coronary artery balloon catheterization and injury to the common iliac artery, after which they were divided into four groups: untreated (control); Dispatch catheterized-30 minutes local saline delivery [D(+)- tPA(-)]; D(+)-30 minutes local tPA delivery (0.6 mg/kg) [D(+)-tPA(30 min)]; and D(+)-30 minutes local tPA + 3 days intravenous infusion (0.6 mg/kg/24 h) [(D(+)-tPA(30 min + 3 d)]. Twenty-eight days later, the intimal cross-sectional areas of all three Dispatch catheterized groups were significantly smaller than those of control groups, as were the intimal/medial area ratios. Moreover, the intima/media ratios of the D(+)-tPA(30 min + 3 d) group were significantly smaller than those of the D(+)-tPA(-) group. Thus, local delivery of tPA via Dispatch catheters followed by continuous intravenous infusion of tPA for 3 days prevented intimal hyperplasia after angioplasty.

Protective effect of PEG-SOD against early coronary reperfusion injury assessed in reperfused and non-reperfused ischaemic areas of the same heart.

Objective — In order to investigate the salvage of ischaemic myocardium by polyethylene glycolconjugated superoxide dismutase (PEG-SOD), we compared reperfused and non-reperfused regions in the same canine heart and measured regional myocardial blood flow (RMBF) and myocardial CPK during coronary occlusion and reperfusion using non-radioactive, coloured microspheres. Methods and results — The chests of 17 mongrel dogs were opened under anaesthesia, and the left circumflex coronary artery was occluded for 90 min and then reperfused for 5 min. During this procedure, polystyrene microspheres of different colours were infused at four different times: prior to occlusion (orange), 10 min (red) and 90 min (blue) after occlusion, and 5 min after reperfusion (yellow). Thereafter, the heart was excised, cut in slices along the left circumflex coronary artery, and flow rates at the various times were assessed as a function of microsphere counts. In the control group (n=9), there are significant differences in the myocardial CPK level between reperfused and non-reperfused areas.The myocardial CPK level in reperfused area was significantly reduced compared to non-reperfused area in the outer layers (54 ± 8 IU/g vs. 74 ± 9 IU/g, P < 0.05), and also reduced in the inner layers (59 ± 9 IU/g vs. 74 ± 13 IU/g), however, it was not significantly different. In the PEG-SOD group (n=8), there was no significant difference in the myocardial CPK level between reperfused and non-reperfused areas in both inner and outer layers (inner layers; 68 ± 11 IU/g vs. 68 ± 6 IU/g, outer layer; 69 ± 17 IU/g vs. 67 ± 18 IU/g), indicating a significant protective effect of PEG-SOD. In the control group, transmural necrosis of the reperfused areas was 22.4 ± 10.0%, which showed no significant difference compared with non-reperfused areas (23.1 ± 9.9%). In the PEG-SOD group, transmural necrosis of the reperfused areas by TTC staining was 8.1 ± 8.1%, which showed no significant difference compared with non-reperfused areas (8.5 ± 7.1%). Conclusions — PEG-SOD prevents infarct extension during early coronary reperfusion.