Molecular Mechanisms of Heart Valve Development and Disease

The mature heart valves consist of stratified extracellular matrix (ECM) layers, and heart valve disease is characterized by ECM dysregulation and mineralization. There is increasing evidence that regulatory pathways that control heart valve development also are active in disease. In human diseased valves and mouse models, the expression of valve progenitor markers, including Twist1, Msx1/2 and Snail1/2, is induced. Additional markers of osteogenesis, including Runx2, osteocalcin and bone sialoprotein, also are expressed in calcific aortic valve disease (CAVD) in humans and mice. New mouse models have been developed for studies of valve disease mechanisms. Klotho-null mice are a model for premature aging and exhibit calcified nodules in aortic valves with osteogenic gene induction. Osteogenesis Imperfecta mice, bearing a collagen1a2 mutation, develop features of myxomatous valve disease, including thickening, increased proteoglycan deposition and chondrogenic gene induction. Together, these findings demonstrate specific molecular indicators of valve disease progression, including the identification of early disease markers, which represent potential targets for therapeutic intervention.