Project Abstract: The goal of this proposal is to develop long-term cardiopulmonary support for patients with chronic, severe pulmonary arterial hypertension (PAH) and associated RV failure. Patients with severe PAH will die of RV failure without lung transplant. Unfortunately many of these patients experience long waiting times, are unstable, and become transplant ineligible, due to poor cardiac output and end-organ dysfunction. To prevent this, our team has used innovative modes of venoarterial (VA) ECMO as a temporary bridge to recovery (BTR) or transplantation (BTT) to support the RV, facilitate ambulation, and ensure uniform perfusion of the whole body. Our approach has led to excellent survival rates, but it would be better to intervene prior to RV failure, to support patients for longer periods, and to offer support to non-transplant eligible patients. The goal of this proposal is to extend and improve our successful approach for temporary ECMO support for PAH patients toward permanent, destination therapy support. To accomplish this, we need more compact portable ECMO systems for enhanced mobility, with oxygenators that have slower clot formation, greater durability, and limited blood damage to eliminate the need for transfusions. We plan to test a new pulmonary assist device (PAD) being developed by our group in a sheep pulmonary hypertension (PH)/RV failure model. The PAD consists of two parallel, highly biocompatible gas exchanger modules that can be driven by conventional magnetically levitated pumps for BTR or BTT or a small, VAD-quality pump for destination therapy. The fluid mechanical design and surface treatments of the device slow clot formation and reduce shear stress damage of blood cells, allowing for longer-term support with minimal systemic anticoagulation, no transfusions, and minimized end-organ dysfunction. Patients could potentially be supported initially in the hospital, transitioned to home, and return for gas exchanger replacements every 2-3 months. For Aim 1, we will determine the mode of ECMO attachment that provides optimal RV support in a sheep model of chronic PH/RV failure. Attachment modes include: 1) pumped right atrium (RA) to pulmonary artery (PA), 2) pumped RA to left atrium (LA), 3) pumpless PA to LA, 4) pumped RA – innominate artery, and 5) pumped venovenous (negative control). In each case, the support will be maintained for 4 hours while examining the effect of PAD flow rate on hemodynamics, RV function, and PAD function. These results will inform which mode(s) could be most beneficial to PAH patients. For Aim 2, we will examine changes in RV function and durability of the PAD system over a month of support. Either the PAD system or a Maquet Cardiohelp (MC) system will be attached in sheep with chronic PH/RV failure for one month. The PAD will be attached in the optimal configuration determined from Aim 1, while the MC system will use the optimal pumped configuration, since its high resistance preclude...