Novel Targets for Treating Congenital Bicuspid Aortic Valve Disease
Abstract
Bicuspid aortic valve (BAV) is the most common congenital heart disease, affecting 1%-2% of adults worldwide with an estimated prevalence of four million people in the United States. In patients with bicuspid aortic valve disease, the valve becomes thickened and calcified as early as the fourth decade of life. Calcification leads to narrowing or aortic valve stenosis, and bicuspid aortic valve alone is the underlying cause of 100% of patients with aortic stenosis below the age of 50. Even in patients over the age of 50, bicuspid aortic valve is the underlying cause of more than two-thirds of patients with aortic stenosis, illustrating the immense morbidity imposed by this disease. Once calcification and valve stenosis occur, it is usually a progressive condition, and there currently exist no therapies to retard or reverse aortic valve calcification, and surgical or percutaneous replacement of the valve is the only option. Bicuspid aortic valve disease is prevalent in the military population in approximately similar frequencies as the general population. Recent data from the U.S. Department of Veterans Affairs (VA) medical centers suggests that aortic stenosis from underlying bicuspid aortic valve disease comprises almost 12% of all valve surgeries performed at VA hospitals, again illustrating the high prevalence and morbidity imposed by this congenital cardiac condition. Moreover, patients with bicuspid aortic valve disease exhibit aortic root dilatation and aneurysm formation and are susceptible to suffering from aortic dissection. Persons with bicuspid aortic valve disease and aortopathy serving in the Air Force often are subject to high G forces and are particularly susceptible to sudden aortic dilatation and a catastrophic aortic dissection. The cause of aortopathy in bicuspid aortic valve disease is not known, and there are no reliable clinical or molecular markers to predict progression of disease or complications. In this proposal, we investigate mechanisms of calcification in bicuspid aortic valve disease and present novel targets to retard calcification in bicuspid aortic valve disease. Using mouse models, human specimens, and modeling of bicuspid aortic valve disease with induced pluripotent human stem cells, we investigate underlying causes of aortopathy and identify new imaging parameters to predict progress of bicuspid aortic valve disease. Our proposal would identify novel pharmacologic targets for treating or preventing valve calcification and dysfunction in bicuspid aortic valve disease and identify patients at higher risk for developing complications. Such therapeutic and prognostic strategies would significantly lower the morbidity of this condition in the general and military population and identify patients who would benefit from earlier intervention.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710464
Entities
People
- Arjun Deb
Organizations
- United States Army
- University of California, Los Angeles