DECREASED APOPTOSIS AS PATHOGENIC FACTOR OF INTIMAL HYPERPLASIA IN HUMAN ARTERIOSCLEROTIC LESIONS - RESTENOTIC VERSUS PRIMARY CORONARY AND PERIPHERAL LESIONS AFTER PERCUTANEOUS ATHERECTOMY

Restenosis remains a persistent problem following intravascular recons truction. Smooth muscle cell proliferation, extracellular matrix produ ction and remodeling are accepted mechanisms of restenotic lesion form ation. Decreased programmed cell death (apoptosis) may also contribute to restenosis by prolonging the life span of intimal cells, with thei r subsequent accumulation and development of hyperplastic lesions. The objectives of the present study were as follows: i) to identify cell death, ii) to distinguish and quantify apoptosis from necrosis, and ii i) to compare restenotic with primary lesions. To this end, human athe rectomy specimens from 25 primary and 14 restenotic coronary and perip heral lesions were studied by TUNEL test (TdT-mediated dUTP Nick End L abeling; detection of cell death by the presence of fragmented DNA), t ransmission electron microscopy and morphometric analysis. Intimal hyp erplasia was more consistent with restenosis than with primary lesion origin, and was mainly attributed to increased smooth muscle cell dens ity (649 vs. 219 cells/mm(2); p < 0.001). The main finding of the pres ent study is that hypercellular-restenotic tissue contains fewer TUNEL + cells than hypocellular plaques (14% vs. 27%; p < 0.05), Most import antly, ultrastructural evaluation revealed a markedly reduced portion of intimal plaque cells. especially smooth muscle cells exhibiting dis tinct morphologic signs of apoptosis (3% vs. 13%; p < 0.001). In contr ast, incidence of necroses did not differ between both lesion types (0 .13 vs. 0.12 necroses/ cell; p = 0.49). Thus, our data indicate apopto sis and not necrosis to be the crucial cell death form to account for the apparent discrepancy found in both lesion types with reduced apopt osis in cell-rich restenoses, The findings of the present study sugges t that decreased apoptosis is an important regulatory mechanism ultima tely leading to intimal hyperplasia as commonly found in human resteno sis post angioplasty.