Alterations in the mechanical environment of the mitral valve induces regionalized superimposed tissue formation and thickening of the leaflets

Understanding the regulation of native tissue organization is crucial for the development of tissue engineered heart valves (TEHV). The mechanical environment is a major determinant of the remodeling process of TEHV in vivo. Little, however, is known about the influence of the mechanical environment on the morphology of the intact native valve, whose great heterogeneity suggests a region-specific response to mechanical stimuli. To obtain more insight in the mechanobiology of the cardiac valves we have created an ex vivo flow model in which mouse cardiac valves can be cultured ex vivo in their native environment inside the heart. In this study, mitral valves are continuously subjected to mechanical stresses as experienced during a specific part of the cardiac cycle. By culturing the mitral valve in the closed position (as during systole) the leaflets were subjected to pressure at the ventricular side and stretch at the atrial side. As a result the leaflets became thicker and superimposed tissue (SIT), an additional layer of tissue that is formed on the outside of the original leaflet, is formed. With increasing pressure in left ventricle more SIT is formed at the atrial side of the leaflets. By culturing the valve in the open position (diastole) the atrial sides of the leaflets were exposed to a continuous flow. Loosely arranged SIT formed of which the thickness depended on the flow speed. To mimic mitral regurgitation, the mitral valve was cultured in the prolapsed position by disrupting the papillary muscle and with a retrograde flow through the prolapsed valve creating a disturbed flow. In this position the mitral valve developed a thicker free edge similar as seen in prolapsing human mitral valves. Together, these observations show that the type of remodeling in the leaflet depends on the type and location of mechanical forces experienced. Insights in the mechanobiology of the cardiac valves can prove valuable for the generation of TEHV.