Effect of Paclitaxel Local Delivery on Neointimal Formation after Endothelial Denudation of the Rat Carotid Artery

BACKGROUND AND OBJECTIVES: Mechanisms of restenosis following successful coronary angioplasty (PTCA) are knownasvascularsmoothmuscle cells(VSMCs)proliferationandmigration, elastic recoil or vascular wall remodeling. Paclitaxel whose effect on the stabilization of microtubles leads to cell death is highly lipophilic, permitting easy pass through cell membrane, and has a long-term antiproliferative effect. This study was performed to evaluate effect of paclitaxel on VSMCs proliferation and whether locally delivered paclitaxel can prevent stenosis and neointimal formation in rat carotid artery injury model. MATERIALS AND METHODS: Cultured VSMCs were exposed to sequential concentrations of paclitaxel in vitro, and proliferation inhibition was analyzed with 3H-thymidine incorporation. Paclitaxel of a suitable concentration was applied to the endothelium-denuded carotid artery of Fisher 344 inbred rats for 20 minutes. Angiogram and morphometric analysis of carotid artery was performed after 2 weeks. RESULTS: 3H-thymidine incorporation in cultured VSMCs was decreased dose-dependently from the concentration of 0.1 micromol/L (2,454+/-149cpm/ microgram protein) to 100 micromol/L (1,323+/-69cpm/ microgram protein) of paclitaxel by single and 20-minute exposure in the presence of platelet-derived growth factor (p<0.005). In the absence of platelet-derived growth factor, the decrement of 3H-thymidine incorporation was evident above the concentration of 5 micromol/L of paclitaxel. To evaluate in vivo effect, paclitaxel (0.1 or 1 micromol/L) was administered into the endothelium-denuded carotid artery by balloon injury and incubated for 20 minutes. Percent stenoses (32.2+/-9.8%) of paclitaxel-treated group was less than those (46.3+/-7.5%) of control group on histologic analysis (p<0.01). Paclitaxel-treated group also had wider lumen on carotid angiogram and less neointimal thickening than control on histologic examination (p<0.005). CONCLUSION: Proliferation of VSMCs was effectively inhibited and neointimal formation and luminal stenosis was prevented in rat carotid artery injury model by single, brief and local delivery of low-dose paclitaxel. This strategy could be applied to clinical settings for the prevention of restenosis after PTCA.

Association of Coronary Artery Disease with B-Mode Ultrasonographic Intima-Media Thickness of the Carotid Artery

BACKGROUND: Many autopsy studies have shown that the extent of extracranial carotid and coronary artherosclerosis is correlated and B-mode ultrasonographic intima-media thickness(IMT) and histologic IMT have been good correlation. In recent years. as it has been reported that IMT of carotid artery had something to do with risk factors of atherosclerosis and occurrence of coronary artery disease, in this study, we tried to investigate if the grade of atherosclerosis in B-mode ultrasonography of carotid artery could predict coronary artery disease and have something to do with the severity of coronary artery disease. METHODS: We classified the patients who were examined coronary angiography into control group without significant(>50%) stenosis(11 patients) and coronary artery disease(CAD) group(45 patients) according to the existence of significant stenosis, and we subdivided CAD group into single vessel disease(SVD) group(25 patients) and multivessel disease(MVD) group(20 patients). Practicing B-mode ultrasonography of common carotid artery(CCA), carotid artery bifurcation(BIF) and internal carotid artery(ICA), we measured IMT and IMT/L(lumen diameter) of each segment. Adding all values of each segment, we got mean aggregated IMT and mean aggregated IMT/L. RESULTS: 1) As IMT of left BIF in both six segments, control group was 0.55+/-0.16mm, SVD group was 0.71+/-0.36mm and MVD group was 1.02+/-0.61mm. So compared with control group and SVD, MVD group were significantly thick. As IMT/L, control group was 0.07+/-0.02, SVD group 0.08+/-0.05 and MVD group was 0.13+/-0.08. So compared with control group and SVD, MVD group was ignificantly high. 2)IMT of BIF in three segments, control group was 0.59+/-0.16mm, CAD group was 0.82+/-0.47mm and MVD group was 0.90+/-0.54mm. So compared with control group and CAD, MVD group were significantly thick. Also as IMT/L of BIF, compared with control group(0.07+/-0.02) and CAD(0.10+/-0.06), MVD(0.11+/-0.07) group was high.= 3) As mean aggregated IMT, control group was 0.57+/-0.34mm, CAD group was 0.69+/-0.45mm, SVD group was 0.63+/-0.12mm and MVD group was 0.74+/-0.21mm. So CAD group was thicker than control group and MVD group was thicker than SVD group. As mean aggregated IMT/L, control group was 0.07+/-0.03, CAD group was 0.10+/-0.05, SVD group was 0.09+/-0.01 and MVD group was 0.11+/-0.03. So CAD group was higher than control group and MVD group was higher than SVD group. CONCLUSION: These data support use of the mean aggregated B-mode ultrasonographic IMT and IMT/L in carotid bifurcation for correlation with the status of coronary atherosclerosis.