The Road to Destination Therapy: Developing a Durable Ambulatory Mechanical Cardiopulmonary Support for Pulmonary Hypertension

Project Abstract Pulmonary hypertension (PH), which causes right ventricular failure (RVF), is a life-threatening disease with limited long-term treatment options and a 5-year survival rate of only 50% despite advances in medical therapy, which temporarily ameliorate it. Lung transplant is the only definitive treatment; however, PH patients can acutely deteriorate and become ineligible for transplant. It is difficult to predict and intervene prior to RVF due to the limited physiologic understanding about end-stage PH and also because patients with severe PH do not tolerate exercise testing that would otherwise better predict their prognosis. Mechanical cardiopulmonary support (MCS) technology, notably extracorporeal membrane oxygenation (ECMO), is used sometimes to rescue patients with PH-RVF and has occasionally served as a bridge to lung transplant. However, it is a limited intervention because of its many technological shortcomings: its complexity of operation, poor durability and biocompatibility, and bulky size that limits patient mobility and ambulatory use. Moreover, ECMO does not address the specific physiologic and metabolic deficits incurred by end-stage PH patients, which change drastically between rest and exercise states and remain poorly characterized. Due to the ethical challenges and barriers of studying severe PH in clinical subjects, our team proposes to use a large animal model to address this challenging disease. We will use our group’s high-fidelity large animal model of PH-RVF that utilizes progressive pulmonary artery banding approach in sheep subjects. Our prior work with this animal model has demonstrated that the sheep subjects accurately recapitulate the clinical pathophysiology of PH that spans across multiple organ systems. Using our established expertise with this animal model, we will first reveal the exercise limitations associated with this severe disease, and use this physiologic understanding to develop a more durable, wearable MCS that can support patients with end-stage PH-RVF. Under Aim 1, the PH-RVF sheep subjects will undergo treadmill exercise testing to characterize the longitudinal changes in cardiopulmonary reserve, metabolism, and exercise tolerance during disease progression. Under Aim 2, the PH-RVF sheep will receive 14 days of MCS to address the specific physiologic and metabolic deficits that were characterized under Aim 1. The novel portable MCS system consists of low-resistance, low-profile, highly biocompatible gas exchangers coupled with a ventricular assist device pump. The mode of attachment will be varied between two optimized configurations (right atrium- left atrium, RA-LA, and right atrium-aorta, RA-Ao) that were narrowed down in our team’s previous investigation, R01HL140231. During 14 days of wearable device support, RV and device function will be studied under conditions of dynamic exercise induced stress using multi-scale analysis to assess the impact on RV recovery and end-organ function. We hypothesize that RA-LA will better provide physiologic restoration of blood flow, RV function, and exercise tolerance compared to RA-Ao.