The key results of the study can be summarized as follows: 1) leaflet tissue is selectively more sensitive to alterations in FSS magnitude than frequency; 2) FSS abnormalities promote paracrine signaling via BMP-4 and TGF-β1-dependent pathways and ECM degradation via MMP- and cathepsin-dependent pathways; and 3) the FSS mechanisms of early CAVD development are time-dependent. Here, BMP4 is linked to congenital bilateral aplasia of vas deferens from CFTR mutation.