Surface strains in the anterior leaflet of the functioning mitral valve.

Abstract-The mitral valve (MV) is a complex anatomical structure whose function involves a delicate force balance and synchronized function of each of its components. Elucidation of the role of each component and their interactions is critical to improving our understanding of MV function, and to form the basis for rational surgical repair. In the present study, we present the first known detailed study of the surface strains in the anterior leaflet in the functioning MV. The three-dimensional spatial positions of markers placed in the central region of the MV anterior leaflet in a left ventricle-simulating flow loop over the cardiac cycle were determined. The resulting two-dimensional in-surface strain tensor was computed from the marker positions using a C0 Lagrangian quadratic finite element. Results demonstrated that during valve closure the anterior leaflet experienced large, anisotropic strains with peak stretch rates of 500%-1,000%/s. This rapid stretching was followed by a plateau phase characterized by relatively constant strain state. We hypothesized that the presence of this plateau phase was a result of full straightening of the leaflet collagen fibers upon valve closure. This hypothesis suggests that the MV collagen fibers are designed to allow leaflet coaptation followed by a dramatic increase in stiffness to prevent further leaflet deformation, which would lead to valvular regurgitation. These studies represent a first step in improving our understanding of normal MV function and to help establish the principles for repair and replacement.

Insulin receptor binding kinetics: modeling and simulation studies.

Biological actions of insulin regulate glucose metabolism and other essential physiological functions. Binding of insulin to its cell surface receptor initiates signal transduction pathways that mediate cellular responses. Thus, it is of great interest to understand the mechanisms underlying insulin receptor binding kinetics. Interestingly, negative cooperative interactions are observed at high insulin concentrations while positive cooperativity may be present at low insulin concentrations. Clearly, insulin receptor binding kinetics cannot be simply explained by a classical bimolecular reaction. Mature insulin receptors have a dimeric structure capable of binding two molecules of insulin. The binding affinity of the receptor for the second insulin molecule is significantly lower than for the first bound insulin molecule. In addition, insulin receptor aggregation occurs in response to ligand binding and aggregation may also influence binding kinetics. In this study, we develop a mathematical model for insulin receptor binding kinetics that explicitly represents the divalent nature of the insulin receptor and incorporates receptor aggregation into the kinetic model. Model parameters are based upon published data where available. Computer simulations with our model are capable of reproducing both negative and positive cooperativity at the appropriate insulin concentrations. This model may be a useful tool for helping to understand the mechanisms underlying insulin receptor binding and the coupling of receptor binding to downstream signaling events.