Abstract 4334: Coordinated Apoptosis and Tissue-Factor Expression in Human Coronary Atheroma After Percutaneous Coronary Intervention: Evidence for Role of Apoptosis in Determining Arterial Wall Thrombogenicity
Background: Apoptosis is a tightly regulated process that involves repackaging of cellular content into small apoptotic bodies or microparticles. The execution of the programmed cell death process is dependent on the activation of effector caspases such as Caspase-3 and has been associated with Tissue-Factor (TF) expression. Evidence is increasing that arterial wall thrombogenicity is associated with increased numbers of apoptotic cells resulting in dispersal of apoptotic bodies containing Tissue-Factor. Therefore, we evaluated the expression pattern of Active-Caspase-3 (ACS3) and Tissue-Factor in human coronary atherectomy specimens from patients post percutaneous intervention (PCI) in comparison with primary stable coronary atheroma.
Methods and Results: The expression of ACS3 and TF in human coronary atherectomy samples (n=30) was evaluated by immunohistochemistry (data presented as mean percentage of intimal cells positive for ACS3 or TF, ±SEM). In atherectomy samples from patients post PCI (n=15) TF expression was observed in extra-cellular as well as intra-cellular location and was selectively increased in smooth muscle cells compared to primary lesions (28±4 % vs. 5±2 %, P<0.05). The expression of TF was associated with foci of increased ACS3 expression and high microparticle content (P<0.05). Immunofluorescence double labeling confirmed a close co-localization between ACS3 and TF in areas with strong presence of apoptotic bodies. In contrast, the number of TF positive microparticles was significantly lower in primary lesions. In addition, we performed transmission electron microscopy to confirm the presence of apoptotic smooth muscle cells and of apoptotic bodies in coronary lesions post PCI comprising up to 12±9 % of intimal cells and 16±4 apoptoctic bodies per cell. In primary lesions these foci of apoptosis were nearly completely absent.
Conclusions: We are reporting for the first time in human coronary atheroma post PCI a strong spatio-temporal coordination of apoptosis and Tissue-Factor expression. This focal increase of smooth muscle cell apoptosis and associated generation of pro-coagulant microparticles favors continued thrombogenicity of the arterial wall post PCI possibly contributing to restenosis.