This career development award will provide training to Marcos Lopez, MD, MS and help him advance towards his long-term goal of becoming an independent physician-scientist testing hypotheses to reduce organ injury in surgical patients. Dr. Lopez is an anesthesiologist and intensivist at Vanderbilt University Medical Center (VUMC). He is establishing a research niche characterizing the contribution of endothelial dysfunction to perioperative brain and kidney injury. Dr. Lopez assembled a multidisciplinary mentorship committee to facilitate achievement of his goals. Primary mentor Frederic T. Billings IV MD, MSCI is an anesthesiologist and intensivist who conducts clinical trials to reduce kidney injury after cardiac surgery. Co-mentor David Harrison, MD, is a cardiologist and leader in the study of the endothelium. Co-mentor Pratik Pandharipande MD, MSCI, is an anesthesiologist, intensivist, and leader in the study of ICU delirium. Dr. Lopez will combine vascular biology training in the Harrison lab with perioperative clinical trial design and outcome assessments training from Drs. Billings and Pandharipande to achieve independence. VUMC is a tertiary academic hospital that prioritizes the development of physician-scientists like Dr. Lopez. Core research facilities, expert faculty renowned for collaboration, and research career development programs directly contribute to his success. Dr. Lopez's research will assess endothelium-mediated vascular reactivity prior to and following cardiac surgery in patients enrolled in an RCT of intraoperative oxygen treatment (R01GM112871; PI: Billings) to test the hypotheses that normoxia during cardiac surgery improves vascular reactivity compared to hyperoxia and that impaired vascular reactivity correlates with intraoperative oxidative stress (Aim 1), that vascular reactivity in arterioles dissected from the pericardial fat of normoxia-treated patients will be increased compared to hyperoxia-treated patients (Aim 2), and that endothelial dysfunction is associated with increased brain and kidney injury (Aim 3). The study benefits from the subject recruitment, randomization, sampling, and outcomes assessment of the parent trial but tests its own independent hypotheses, providing a route to scientific independence. Dr. Lopez will measure brachial artery flow-mediated dilation, peripheral artery tonometry, and plasma concentrations of plasminogen activator inhibitor-1 and E-selectin pre and postoperatively. He will measure vascular reactivity in pericardial fat arterioles at the end of surgery using wire myography. He will compare these data with oxygenation groups, markers of oxidative stress, and with measured brain and kidney injury to test his hypotheses. Dr. Lopez will gain experience recruiting patients into a clinical trial, prospectively collecting data, and managing a clinical research team. Dr. Lopez will progress to independence by completing career development training and this study. He will initiate a research program to reduce perioperative organ injury by targeting endothelial dysfunction.
Five hundred thousand patients undergo cardiac surgery each year, and 25% develop acute kidney injury, 30% develop brain injury manifested as delirium, and 32% develop new onset atrial fibrillation. This study measures endothelial dysfunction as a mechanism of organ injury following cardiac surgery so that novel therapies for postoperative brain and kidney injury can be developed.
