Modeling Impaired Coaptation Effects on Mitral Leaflet Homeostasis Using a Flow-Culture Bioreactor

Abstract

Mitral valve (MV) regurgitation constitutes an increasing burden of adult and pediatric cardiac disease tending to worsen over time. Whether altered mechanical forces on leaflets cause valve disease is unknown. Here we show that MV leaflet coaptive strain disruption alters expression of genes critical to leaflet homeostasis. We used a flow-culture bioreactor of rat MVs with flow-induced cyclic coaptation (cycling valve group; n= 4) or in a sustained open state (open valve group; n= 4). After 3 days of culture, leaflet RNA expression was profiled. More than 48 genes exhibited markedly changed expression when coaptive leaflet strain was disrupted for 3 days (change >fourfold; p < 0.05; cycling vs open valves). Genes exhibiting highly altered expression included Angpt2, Vegf, Cd74, RT1-Da (HLA-DRA), and Igfbp3. Pathway analysis indicated the most significant signaling pathways regulating the expression changes were Hif1α and Tnfα when MV closure was disrupted. Disruption of normal MV coaptive strain markedly alters the expression of leaflet genes, demonstrating that cyclic strain is critically important to leaflet homeostasis. We demonstrate a pattern of MV gene expression changes in which hypoxia signaling is prominently increased in response to disrupted strain cycles. Coaptive strain regulation of MV leaflet homeostasis implicates altered strain as a mechanism potentially initiating valve disease. Early repair may prevent progression of disease driven by altered coaptation.