Protection of transplanted heart function by regulation of Na/K pump activity

The objective of this proposal is to examine a novel technique called improved Synchronization Modulation Electric Field (i-SMEF) in the protection of donor hearts and improvement of transplanted graft functions. We will apply the i-SMEF on donor hearts during static cold storage and evaluate the transplanted graft function following heart transplantation in mice.Heart transplantation (HTx) remains the best therapeutic option for advanced-stage heart failure, as well as for complex congenital heart disease, restrictive cardiomyopathy, and some infectious diseases. However, the long-term survival rate of the heart graft has only shown a small improvement during the past decades, with a median survival about 12.5 years. In addition, the maximal time for static cold storage is usually about 5 hours. Longer storage time is associated with higher rates of both early and late graft failure. The development of new strategy for extension of storage time thereby increasing the donor pool and improvement of the transplanted graft function are unmet needs.One of the prominent challenges in HTx is ischemia reperfusion injury (IRI) to the graft. IRI is a major factor for both early and late graft failure and mortality. Following hypoxia, due to poor ATP supply, activity of the Na+/K+-ATPase (Na/K pump) slows down or stops, which is one of the earliest and critical impairments following ischemia. Reduction in the Na/K pump function disrupts the equilibrium of cellular ion concentrations, cell volume and membrane potential, which can cause damage to all cellular components (e.g., mitochondria), apoptosis and necrosis. Therefore, maintaining the Na/K pump function following ischemia could be a vital initial strategy for the protection or prevention of the ischemic injury.We have developed a novel technique, named the i-SMEF (patent pending, Chen and Liu), which can not only maintain the pump functions, but also generate ATP molecules.Based on strong preliminary findings, we propose to test this technique in a mouse HTx model. We will test our hypothesis that application of the i-SMEF on donor hearts during cold storage protects against ischemic injury and improves the transplanted graft functions.