Pathogenetic mechanism of senile calcific aortic stenosis: The role of apoptosis

Objective To investigate the pathogenetic mechanisms leading to the development of calcific degeneration of the aortic valve in the elderly patients with particular reference to the relationship between apoptosis and calcification in the aortic valve tissue. Methods High resolution scanning and transmission electron microscopic observations of the calcified aortic valves obtained during aortic valve replacement were carried out in 10 patients with senile calcific aortic stenosis. Results Various degrees of endothelial alterations from focal disruption of individual endothelial cells to extensive denudation of entire endothelium were observed particularly on the aortic side of the valve tissues. The apoptotic changes occurring in the nuclei of endothelial cells and fibroblasts were common findings in the calcified valve tissues. It was noteworthy that the severity of endothelial damage was closely related to apoptotic changes of the fibroblasts. Calcific deposits were frequently observed in association with the cellular fragments mainly derived from the apoptotic fibroblasts. Conclusions Our results strongly indicate that apoptosis may play an important role in the alterations of endothelial integrity leading to the increased filtration of calcium into the deeper layer of the valve tissues. Then, the cellular degradation products and organelles extruded from the dead cells, mainly resulted from apoptosis provided the substrates for calcium binding with progressive development of calcification in the valve tissue. Although the role of apoptosis in contribution to the pathogenesis of senile calcific aortic stenosis is evident, further studies using modem molecular biotechnology are mandatory in order to clarify the mechanism for the initiation of apoptotic process in the endothelial cells and fibroblasts.