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Ann Thorac Surg 2003;75:457-465
© 2003 The Society of Thoracic Surgeons
a Cardiology Research Laboratory, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
b Department of Medicine, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA
Accepted for publication August 19, 2002.
* Address reprint requests to Dr Levy, Children’s Hospital of Philadelphia, Abramson Research Building, 3416 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA.
e-mail: levyr{at}email.chop.edu
BACKGROUND: Aortic valve stenosis characteristically progresses due to cuspal calcification, often necessitating valve replacement surgery. The present study investigated the hypothesis that TGF-ß1, a cytokine that causes calcification of vascular smooth muscle cells in culture, initiates apoptosis of valvular interstitial cells as a mechanistic event in cuspal calcification.
METHODS: Noncalcified and calcified human aortic valve cusps were obtained at autopsy or at the time of cardiac surgery. The distributions within cusps of TGF-ß1, latent-TGF-ß1-associated peptide, and TGF-ß receptors were studied using immunohistochemistry. The effects of TGF-ß1 on mechanistic events contributing to aortic valve calcification were also investigated using sheep aortic valve interstitial cell (SAVIC) cultures.
RESULTS: Immunohistochemistry studies revealed that calcific aortic stenosis cusps characteristically contained within the extracellular matrix qualitatively higher levels of TGF-ß1 than noncalcified cusps. Noncalcified normal valves demonstrated only focal intracellular TGF-ß1. Addition of TGF-ß1 to SAVIC cultures led to a cascade of events, including: cellular migration, aggregation, formation of apoptotic-alkaline phosphatase enriched nodules, and calcification of these nodules. The time course of these events in the SAVIC culture system was rapid with nodule formation with apoptosis by 72 hours, and calcification after 7 days. Furthermore, ZVAD-FMK, an antiapoptosis agent (caspase inhibitor), significantly inhibited calcification and apoptosis induced by TGF-ß1, but had no effect on nodule formation. However, cytochalasin D, an actin-depolymerizing agent, inhibited nodule formation, but not calcification.
CONCLUSIONS: TGF-ß1 is characteristically present within calcific aortic stenosis cusps, and mediates the calcification of aortic valve interstitial cells in culture through mechanisms involving apoptosis.
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