Partial Heart Transplantation: Clinically Relevant Aspects of Transplant Biology

About This Grant

PROJECT SUMMARY Heart valve replacement in children is marred with problems because state-of-the art heart valve implants do not grow. This commits affected children to serial re-operations to replace outgrown valve implants. Partial heart transplantation (PHT) is a new approach to deliver growing heart valve implants that is based on transplantation. PHT differs from heart transplantation (HT) because only the part of the heart containing the necessary heart valve is transplanted, while the native ventricles are spared. Sparing the native ventricles eliminates ventricular dysfunction from chronic rejection or ischemic injury and increases the donor pool. Importantly, PHTs grow adap- tively with recipient children. This avoids morbid re-operations to replace outgrown valve implants. However, PHT transplant biology remains unexplored. This is a critical barrier to progress of the field. Without knowledge of PHT transplant biology, clinical protocols cannot be tailored to children with PHTs. Instead, children with PHTs are empirically treated according to HT clinical protocols because the valves contained in HTs are known to grow. The proposed project seeks to advance the field by exploring clinically relevant aspects of PHT transplant biology. This will contribute the evidence-base for clinical protocols tailored to children with PHTs. The central hypothesis is that the transplant biology of PHT differs from HT, which allows for longer donor ischemia times (Aim 1), less stringent recipient immunosuppression (Aim 2) and ABO incompatible transplantation (Aim 3). This hypothesis is based on preliminary data. The approach for the proposed project leverages a unique piglet model and innovative outcome measures for valve growth including leaflet length echocardiography. The central hy- pothesis will be tested by completing the following specific aims: (1) model the effect of ischemia time on PHT growth potential and function; (2) determine the optimal immunosuppression strategy for PHT; (3) determine the effect of donor antigen variability on PHT growth potential and function. Achieving these aims will contribute evidence-based protocols specifically tailored to PHT. Protocols tailored to PHT will improve clinical practice by decreasing the morbidity and mortality of PHT. This is significant because PHT is a game-changer for children with unrepairable heart valve defects. It is also innovative because it is non-derivative, and a radical departure from the status quo for growing heart valve implants. The proposed project shifts research and clinical paradigms for growing heart valve implants using this new theoretical concept based on transplantation. This new clinical intervention opens new horizons for children who need heart valve replacements because it eliminates the mor- bidity and mortality of serial implant exchanges as the children grow.