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  • Book
    Gaurav Krishnamurthy.
    The mitral valve (MV) is a bicuspid valve that allows the unidirectional flow of blood from the left atrium (LA) into the left ventricle (LV). MV disease afflicts millions each year worldwide and if sufficiently severe, surgical therapy is indicated. Surgical repair is currently preferred but valve replacement is often required. Current replacement therapy involves implantation of a mechanical valve, associated with anticoagulation/ thromboembolic complications, or a tissue valve, associated with less than ideal durability. To overcome these limitations, a currently important research goal is to create bioengineered autologous tissue valves. A key component of this thrust is to understand more completely the structure and function of native valves which reliably cycle 100,000 times per day, more than 3 billion times in an average lifetime. Toward this end, this thesis presents, for the first time, the material properties of the anterior mitral leaflet in the beating heart. The methodology used in this research is as follows: Surgical preparation and radiopaque marker data acquisition: 16 miniature radiopaque markers were sewn to the MV annulus, 16 to the anterior MV leaflet, and one on each papillary muscle tip in male sheep. 4-D coordinates were obtained from biplane videofluoroscopic marker images (60f/s) during three complete cardiac cycles. Data were acquired sequentially with repeat control runs between saddlehorn electrical pulse stimulation and intravenous administration of esmolol to study the effect of pharmacological agents on mitral leaflet contractility, and vagal nerve stimulation to assess the potential for central neural control. Inverse finite element analysis: A finite element model of the anterior MV leaflet was developed using marker coordinates at the end of isovolumic relaxation (IVR, when pressure difference across the valve is approximately zero), as the stress-free reference state. Leaflet displacements were simulated during IVR using measured left ventricular and atrial pressures. The elastic moduli in both the commisure-commisure (Ecirc) and radial (Erad) directions were optimized using the Method of Feasible Directions to minimize the difference between simulated and measured displacements. The derived material properties were found to be orders of magnitude greater than previously determined ex vivo material properties. Histologic studies have shown that the mitral leaflets, rather than being simple collagen flaps (as once thought), contain complex networks of contractile elements (smooth and striated muscle; valvular interstitial cells), blood vessels, and both afferent & efferent nerves. The finding of higher stiffness in vivo than ex vivo suggests a mechanistic role for these elements; to modulate the stiffness of the active mitral valve in vivo -- a property necessarily missing in excised, flaccid valves ex vivo. Using the derived material properties, a forward analysis was performed to determine the stress-strain behavior of the anterior leaflet at various trans-mitral pressure gradients during IVR. This analysis showed that the leaflet material behaved linearly over a physiologic range of pressures. It is also shown in this thesis that these leaflet material properties vary over the cardiac cycle; leaflet stiffness is higher during early systole (Isovolumic Contraction, IVC) most likely due to force development in cardiac muscle cells in the annular third of the anterior leaflet, and as this force development wanes during systole, the stiffness of the leaflet drops. Stimulation of the neutrally-rich annular saddlehorn region adjacent to the anterior leaflet was shown to almost double leaflet stiffness, whereas administration of a beta-blocker (Esmolol) eliminated the early systolic increase in anterior leaflet stiffness. The initial homogeneous finite element model of the anterior leaflet was further developed to incorporate regionally varying material properties. This heterogeneous finite element model confirmed that Esmolol selectively reduced leaflet stiffness in the annular region (which contains the slip of cardiac muscle) during IVC and did not affect edge stiffness (which is devoid of cardiac muscle). Saddlehorn stimulation caused an increase in leaflet stiffness values for all regions (edge, belly and annular regions) during both IVC and IVR. Loss of atrial contraction had a similar effect on the anterior leaflet as administration of Esmolol, i.e. without atrial depolarization the leaflet stiffness during IVC in the annular region dropped to baseline IVR values. Finally, the functional role of autonomic nerves in the anterior leaflet was investigated by remote stimulation of the vagus nerve. This study showed that vagal nerve stimulation can result in a decrease in anterior leaflet stiffness during both IVR and IVC. In summary, the findings of this thesis suggest a permanent paradigm shift from one viewing the mitral valve leaflets as passive flaps to one viewing the leaflets as active, potentially adaptive, neurally-controlled tissues whose complex function and dysfunction must be taken into account when considering not only therapeutic approaches to mitral valve disease, but even the definitions of mitral valve disease itself. The improved understanding of the structure-function relationships in these native, active valves could uncover new targets for pharmacologic intervention, as well as provide important insights to improve the future design and durability of tissue-engineered mitral valves.