Differential histopathology of primary atherosclerotic and restenotic lesions in coronary arteries and saphenous vein bypass grafts: analysis of tissue obtained from 73 patients by directional atherectomy. Vascular tissue obtained using a directional percutaneous atherectomy device was examined microscopically. Tissue was obtained from coronary arteries without prior instrumentation (primary lesions, n = 31), aortocoronary saphenous vein bypass grafts with primary lesions (n = 8), coronary arteries with lesions developing after prior balloon angioplasty or mechanical atherectomy (restenotic lesions, n = 30) and vein bypass grafts with restenotic lesions (n = 4). Primary lesions were characterized by dense intimal fibrosis with necrotic debris (83% of intimal tissue) and foam cells typical of atherosclerosis. These lesions frequently contained cholesterol crystals (45% of coronary arteries, 50% of vein grafts) and calcium deposits (65% of coronary arteries, 38% of vein grafts). Restenotic lesions were characterized by an increased proportion of loose fibroproliferative tissue (45% of coronary artery intima, 35% of vein graft intima). Immunohistochemical stains confirmed this proliferative tissue to be primarily smooth muscle cells. Thrombus was rarely observed. Comparison of resected tissues indicated that dense fibrosis and necrosis are significantly more common in primary than in restenotic lesions (83% versus 56% of intimal tissue, p = 0.0005), whereas smooth muscle cell hyperplasia is more common in restenotic than in primary lesions (44% versus 17% of intimal tissue, p less than 0.0005). Partial-thickness resection of medial tissue or full-thickness resection of media with associated adventitial tissue occurred in 27 (56%) of 39 primary atheromatous lesions and 16 (47%) of 34 restenotic lesions; subintimal tissue obtained from primary lesions appeared identical to that obtained from restenotic lesions. These data indicate that the histopathologic characteristics of the neointimal layer of restenotic lesions differ from those of the intimal layer of primary atherosclerotic lesions. 