We examined the rabbit aortic injury induced by passage of a balloon catheter (4F) and neointimal thickening. Balloon catheterization was performed at three different inflation pressures (400, 600, or 800mmHg). For comparative studies, rabbit aortas were subjected to intimal injury by insertion of a polyethylene tubing (PESO) for 24hrs. Aortic injury by passage of the balloon catheter at 600 or 800mmHg caused both endothelial denudation and varying degrees of medial damage such as interruption of the elastic lamina and necrosis of medial smooth muscle cells, furthermore, significant loss of DNA content was detected in these injured aortas. While balloon catheterization at 400mmHg and insertion of the polyethylene tubing induced only endothelial denudation. The neointimal thickening developed following each aortic injury. However, the neointimal thickening and the frequency of intimal smooth muscle cell proliferation following balloon catheterization at 800mmHg was rather mild. Norepinephrine-induced vascular constriction was significantly reduced in the aortic rings injured by balloon catheter at 600 and 800mmHg compared with those of uninjured and injured ones at 400mmHg.
These results demonstrate that a denuding injury by passage of a balloon catheter causes varying degrees of medial damage dependent on the inflation pressure in contrast with that by insertion of a polyethylene tubing.

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The morphological regeneration and functional recovery in the ilio-femoral artery of male New Zealand White rabbits under normal diets were compared between two different techniques at immediately after and at 2, 6 and 12 weeks, on endothelial denudation. After denudation with a new device of a filament catheter which removed the endothelium without further damaging the media, a complete endothelial regrowth was achieved by 6 weeks. With a classical method of balloon-catheter, vascular sizes were enlarged, and sluggish endothelial regrowth with severe intimal thickening was observed. To study the function of artery in regenerative process, cine-angiography was performed. Endothelium-dependent relaxation to methacholine disappeared immediately after filament catheterization, and began to appear at 2 weeks. Following balloon catheterization, it was not observed until 6 weeks. Although in either catheterization methods, contractive responses to norepinephrine were tended to be increased, at 2 weeks, in the balloon injured arteries hypercontraction was observed more frequently (p<0.01).
These results suggest the intimal regeneration and endothelial dysfunction are influenced significantly by the severity of the medial damage as a complication of the intimal injury.

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Rat common carotid arteries were injured by insertion of balloon catheters (2Fr) or loops of surgical nylon thread (4-0) into their lumens. Necrosis of medial smooth muscle cells (SMCs) and endothelial denudation, results of the injury, evoked proliferation of SMCs in the media, proven by increased labeling indicies of BrdU and PCNA. Augmentation of the BrdU labeling index was observed twice on 2nd and 5th days after injuries. When SMCs in the inner media were positive in PCNA, PDGFs A and B, collagenase and elastase were positive in their cytoplasms in immunohistochemical stainings. Migration of medial SMCs into the intima was induced 24hrs after the balloon injury and 48hrs after the loop injury. The majority of migrating SMCs across the internal elastic lamina, were PCNA positive. Under an electron microscope on the 3rd day after the loop injury. SMCs in the inner media showed a synthetic type and a loose attachment to the basement membrane and elastic fibers while SMCs in the outer media showed a contractile type and a close attachment to the intimal thickness appeared to be dependent to the grade of medial injury basement membrane and elastic fibers.
In conclusion, medial injury seems to play an important role in the formation of intimal thickening.

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Injury of the vessel wall was induced by the balloon catheters in 159 male wistar rats. Rats were subjected to five different trials comprising single, twice, three times, four times, and five times injuries to their carotid arteries. Morphologic changes were observed from postoperative 6 hours to 14 days. Histological examination disclosed that the degree of intimal thickening was proportionally intensified to the severity of medial damage. Electron microscopically, degenerated or dead cells were seen in the tunica media of singly injured carotid artery at the postoperative 6 hours. Mitotic cells were seen in five times injured artery at 3rd day, and in three and five times injured artery at 7th day. Frequency of dead or degenerated cells was parallel to the frequency of the vessel wall injury. DNA content of five times injured carotid artery was highest at 14th day and it was 2.5 times as that of non-injured artery by illuminescent DNA analysis. These results suggest that balloon catheter induces injury to the tunica media as well as endothelium, and that the severity of the medial injury correspond to the degree of intimal thickening.

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We present the recent data confirming the angiographic and pathological efficacy of LDLapheresis for coronary atherosclerosis in a patient of familial hypercholesterolemia (FH) using collected data of a large number of cases and especially of one autopsy case. Change in coronary artery stenosis have been assessed angiographically in 37 FH patients in the LDL-Apheresis Regression Study (LARS) group of 13 institutions in Japan. Visual and Computer analysis confirmed definite regression in 21 segments. Fouteen of 37 patients (37.8%) who had received LDL-apheresis in combination with cholesterollowering drugs had at least one regressed segment without progressed segments. We pathologically examined at autopsy the coronary arteries in one FH patient who had received long-term LDL-apheresis therapy before death. The results showed the process of scarring of atheromatous plaque, suggesting pathological regression correlated with the angiographic regression shown in serial angiograms taken during LDL-apheresis. This suggested that the formation of an eccentric thickened wall lesion rich in collagen fiber prevented atheromatous plaque from tearing off. Such tearing off might cause to an acute coronary event. Aggressive cholesterol-lowering therapy based on LDL-apheresis can induce both angiographic and pathological regression in coronary atherosclerosis of FH patients.

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Coronary restenosis remains one of major obstacles for angioplasty. Histopathologic studies in both animals and humans suggest that migration and proliferation of smooth muscle cells and synthesis of extracellular matrix are central to the healing process of an injured artery and contribute substantially to restenosis. To date, efforts to prevent or reduce restenosis by targeting these process have been largely unsuccessful. We hypothesized that restenosis was not merely a problem of intimal formation in response to balloon injury, but a problem of vessel remodeling in response to balloon injury and intimal formation.
To test this hypothesis, morphometric analysis of histologic cross-sectional areas of vessels from animals sacrificed four weeks after angioplasty were perfomed. The lumen area, the area circumscribed by the external elastic lamina (EEL area) and the intima plus media area (I+M area) were measured at 57 lesions. Angiographical gain by angioplasty was associated with angiographical loss at follow-up (r=0.55, p<0.0001). With restenosis defined more than 50% diameter stenosis at follow-up, 25 lesions (43.9%) showed restenosis. The lumen areas were significantly different between restenotic and nonrestenotic subgroups (0.11±0.13mm² for restenotic subgroup, 0.60±0.24mm² for non-restenotic subgroup, p<0.001), whereas no significant difference in I+M areas was observed (3.35±0.97mm² for restenotic subgroup, 3.20±0.93mm² for non-restenotic subgroup, p=ns). EEL area was tend to be smaller in restenotic subgroup. Univariate analysis revealed that none of % diameter stenosis, minimal lumen diameter and angiographical loss at follow-up showed significant correlation with I+M area (r=0.18, r=0.11, r=0.15, respectively).
These findings suggest that intimal formation does not account for all restenosis after angioplasty and arterial remodeling may be more important in determining the late outcome after angioplasty. Future studies targeting arterial remodeling my be required to reduce restenosis.

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