PROJECT SUMMARY/ABSTRACT The long term goal of the proposal is to determine the role of pulsatility during cardiopulmonary bypass (CPB) for preserving endothelial function and preventing organ injury after cardiac surgery. More than 400,000 people undergo cardiac surgery in the United States each year which allows them to live longer and more fulfilling lives, but if the surgery is complicated by acute kidney injury (AKI) mortality increases up to 10-fold. Dr. Clendenen is a Cardiothoracic Anesthesiologist dedicated to improving clinical outcomes after cardiac procedures and this K23 proposal is designed to provide him with the structured mentorship and training necessary to become a leader in innovative clinical trials designed to improve patient outcomes. He has developed a collaborative mentorship team led by Dr. Adit Ginde who is an Emergency Medicine Physician and national PI for a large PETAL network clinical trial with 3,000 participants, with co-mentorship provided by Dr. Sarah Faubel, an expert in renal disease research, and Dr. Kristen Jablonski Nowak, a recognized leader in endothelial function. Methodological advisors include Dr. Alex Kaizer (Biostatistics) and Dr. Kerrie Moreau (Vascular Biology). This proposal leverages the collective expertise of an established mentorship team and the unique environment at the University of Colorado Anschutz Medical Center that incorporates a tertiary referral center for cardiac surgery in the setting of a large public research University. These ample resources will allow Dr. Clendenen to address key barriers to reducing morbidity and mortality after cardiac surgery with an adaptive clinical trial comparing the incidence of AKI after cardiac surgery with pulsatile versus non-pulsatile CPB. He will accomplish this by determining the effect of pulsatile CPB on post-operative endothelial function in a prospective observational cohort (Aim 1), determining the timing of endothelial dysfunction and renal injury after cardiac surgery in the same cohort (Aim 2), and determining the optimal level and efficacy of pulsatility during CPB to prevent AKI with an adaptive seamless phase IIa/IIb clinical trial (Aim 3). These specific aims require Dr. Clendenen to develop expertise in assessing clinical endothelial function and AKI risk and designing and completing an adaptive clinical trial. He will accomplish this with a focused career development plan including coursework on clinical trial design and biostatistics alongside structured training in assessing endothelial function to measure the effects of CPB. Completion of the proposed project will provide the necessary mentorship, training, and experience required to allow Dr. Clendenen to become a leader in adaptive clinical trials to improve outcomes after cardiac surgery.

PROJECT NARRATIVE Cardiac surgery is effective for improving the health of patients with cardiovascular disease, but many patients experience complications such as acute kidney injury (AKI) that result in an increased risk of death after surgery. Maintaining normal pulsatile blood flow with the heart lung machine during cardiac surgery may prevent AKI after cardiac surgery even though increased mechanical pulsatility damages red blood cells. This trial will identify to best level of pulsatility during cardiac surgery for minimizing red blood cell damage while preventing AKI.