Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death

Although apoptosis is a well-recognized phenomenon in chronic atherosclerot ic disease, its role in sudden coronary death, in particular, acute plaque rupture is unknown, Culprit lesions from 40 cases of sudden coronary death were evaluated. Cases were divided into two mechanisms of death: ruptured p laques with acute thrombosis (n = 25) and stable plaques with and without h ealed myocardial infarction (n = 15). Apoptotic cells were identified by st aining of fragmented DNA and confirmed in select cases by gold conjugate la beling combined with ultrastructural analysis. Additional studies were perf ormed to examine the expression and activation of two inducers of apoptosis , caspases-1 and -3. Ruptured plaques showed extensive macrophage infiltrat ion of the fibrous cap, in particular at rupture sites contrary to stable l esions, which contained fewer inflammatory cells, Among the culprit lesions , the overall incidence of apoptosis in fibrous caps was significantly grea ter in, ruptured plaques (P < 0.001) and was predominantly localized to the CD68-positive macrophages, Furthermore, aa optosis at plaque rupture sites was more frequent than in areas of intact fibrous cap (P = 0.028), Plaque rupture sites demonstrated a strong immunoreactivity to caspase-1 within th e apoptotic macrophages; staining for caspase-3 was weak. Immunoblot analys is of ruptured plaques demonstrated caspase-1 upregulation and the presence of its active p20 subunit whereas stable lesions showed only the precursor ; nonatherosclerotic control segments were negative for both precursor and active enzyme, These findings demonstrate extensive apoptosis of macrophage s limited to the site of plaque rupture. The proteolytic cleavage of caspas e-1 In ruptured plaques suggests activation of this apoptotic precursor. wh ether macrophage apoptosis is essential to acute plaque rupture or is a res ponse to the rupture itself remains to be determined.