NEW INSIGHT INTO TREATMENT OF AORTIC STENOSIS: LIGHT AT THE END OF THE TUNNEL
Donald D. Heistad, M.D., University of Iowa, IA, USA
No medical therapy for fibro-calcific aortic valve stenosis (FCAVS) is effective. We have developed experimental models of severe FCAVS in mice, and are using these models to examine interventions that may be useful in slowing the development or progression of FCAVS.
First, we have examined effects on FCAVS of osteoprotegerin (OPG), an endogenous decoy receptor of receptor-activator of NFKB ligand (RANKL). OPG effectively suppresses calcification of the aortic valve, by both inhibition of the osteogenic pathway and reduction of apoptosis, and preserves aortic valve function. The mechanism of action of denosumab, which is used for treatment of osteoporosis and boney metastases, is similar to OPG. We speculate that inhibition of the RANKL/RANK mechanism might be useful in prevention or treatment of FCAVS.
Second, we have examined effects of pioglitazone (a PPARgamma ligand) on FCAVS. PPARG is antiinflammatory and antioxidant, and both effects may protect against FCAVS. Pioglitazone attenuated lipid deposition as well as calcification in the aortic valve.
Third, we have studied mice (Egfr knockdown-wave) with a 90 percent reduction in epidermal growth factor receptor, which modulates semilunar valvulogenesis. The aortic valve develops fibrosis and calcification. About 80 percent of the mice have moderate or severe aortic regurgitation. The mice also develop dilated cardiomyopathy. Thus, severe fibrocalcific disease of the aortic valve can produce aortic regurgitation with volume overload cardiomyopathy.