FREQUENCY AND LOCALIZATION OF APOPTOTIC B ODIES IN HUMAN ARTERIOSCLEROSIS - RESTENOTIC VERSUS PRIMARY CORONARY AND PERIPHERAL LESIONS AFTERPERCUTANEOUS ATHERECTOMY

Increased density of smooth muscle cells is an accepted feature of hum an restenosis after angioplasty. In addition to migration and prolifer ation, deregulated forms of programmed cell death may represent pathog enic mechanisms which lead to increased intimal cellularity. The goal of the present study was (i) to demonstrate programmed cell death in h uman plaque tissue by the detection of apoptotic bodies and to disting uish it from cellular necrosis, (ii) to evaluate the frequency and the localization of apoptotic bodies, and (iii) to compare restenotic and primary lesions for different expression patterns. To this end, coron ary and peripheral atherectomy specimens from 14 restenotic and 25 pri mary lesions were examined by electron microscopy and morphometric ana lysis. Apoptotic bodies were distinguished from cellular necroses due to distinct morphological features, and were observed extracellularly, isolated or cell membrane-bound, as well as intracellularly in smooth muscle cells and macrophages. The main finding of this study is that hypercellular restenotic tissue from both coronary and peripheral lesi ons contains fewer apoptotic bodies than hypocellular plaques from pri mary lesions (p < 0.01 and p < 0.05, respectively). Most importantly, a highly significant, inverse correlation was seen between the density of apoptotic bodies and intimal cellularity (r = -0.67; p < 0.0001). Especially in the extracellular matrix regions, restenotic lesions sho wed fewer apoptotic bodies (p < 0.001). Again, these plaques exhibited a smaller number of apoptotic bodies with intracellular or membrane-b ound localization; however, this observation was without statistical s ignificance compared to primary lesions. For both plaque types, apopto tic bodies were found more frequently (by the factor 4-10) in the pres ence of smooth muscle cells than with macrophages. With respect to the cellular composition of the plaques, apoptotic bodies were evenly det ected in 15-28 % of all smooth muscle cells and macrophages. Our resul ts document a considerable intimal density of apoptotic bodies in high -grade human arteriosclerotic lesions and, in addition, reveal nearby smooth muscle cells and macrophages exhibiting intensive phagocytotic capacity. Differences in the density of apoptotic bodies and in cellul arity, coincident with an inverse correlation between these determinan ts, were observed for restenotic and primary tissue. These findings st rongly point to deregulated forms of programmed cell death as importan t pathogenic mechanisms involved in human restenosis.