Abstract 18043: Time Divergence Between Osteoblast Transformation and Aortic Valve Calcification; an Important Insight Into the Possible Treatment for Valve Calcification
Introduction: Aortic valve calcification (AVC) is a highly regulated process involving osteoblast transformation in valve tissue. Medical therapy has thus far failed to stop or revert this process. We sought to assess osteoblast maturation markers at different phases of the calcification process using our unique animal model of renal failure associated AVC.
Hypothesis: We assessed the hypothesis that osteoblast transformation occurs at early stages of the calcification process.
Methods: Forty rats were fed exclusively with a high-adenine (0.75%), high-phosphate (1.5%) uremia-inducing diet for 2, 3, 4, 5, and 6 weeks (8 rats in each time period). Additional 8 control rats were fed with normal chow. At the end of the mentioned periods, serum electrolytes, renal function and aortic valves were evaluated. Valves were examined using histology and western blot analysis for osteoblast markers: RUNX-2, osteocalcin, and osteopontin.
Results: All rats fed with the uremic diet developed renal failure and hyperphosphatemia. The metabolic abnormalities were worsened with time (creatinine 213±32 mmol/L at 6 weeks versus 38±2 mmol/L in controls, p<0.01).Von-Kossa staining revealed valvular calcium deposits only in rats fed with the uremic diet for 6 weeks. No calcification was seen at earlier stages or in the controls. However, the early transcription factor -Runx-2 and the early osteoblast marker osteocalcin were already significantly elevated (7 times higher, p<0.01) after 2 weeks diet as compared with controls. These markers reached their peak levels after 3 weeks diet and gradually decreased at 5 and at 6 weeks. Similarly, osteopontin -the major marker for mature osteoblast- levels was significantly elevated (2.5 times higher, p<0.01) after 3 weeks diet as compared with controls and reached peak levels after 5 weeks diet.
Conclusions: In conclusion, osteoblast transformation is a preliminary stage in AVC; it precedes the calcification and is completed before the valve is calcified. This novel observation might explain the current ineffectiveness of medical approaches in AVC. It is crucial to define the different phases of AVC in order to determine the optimal timing for intervention, as well as the point in which medical treatment might not be effective anymore.
- © 2010 by American Heart Association, Inc.