Deciphering links between Leukocyte Activation and Infections in VAD patients

Project Summary Heart disease is a leading cause of death in the United States with 6.5 million individuals having heart failure and resulting in over 270,00 deaths annually. Furthermore, heart disease is also one of the most expensive diseases to treat with an annual financial burden of over $30 billion. The good news is that ventricular assist devices (VADs) have significantly improved the survival rate of end-stage congestive heart failure (CHF) patients, However, due to cost, complexity, and complications, VAD use remains limited. A persistent and serious complication in VAD recipients is an increased vulnerability to infection with infections rates ranging from 20- 60%. At this time the causes of this increased infection rate are not well known. Studies have reported that persistent inflammation and neutrophil activation occurs after VAD implantation, which should lead to a heightened response to fighting microorganisms and not an increased infection rate. The overall goals of this project are to (i) identify pre-implant biomarkers that are predictive of post- implant infection; (ii) determine whether the high infection rates in VAD recipients are related to changes in leukocyte phenotype and function, (ii) develop novel microfluidic devices that allow for leukocyte functional assays in the clinic; and (iii) determine whether treatment of neutrophils from VAD patients with specialized pro- resolving lipid mediators (SPMs) can restore their antibacterial fighting and immunosuppressive capacities. In Specific Aim 1 we will measure pre-operative leukocyte profiles and plasma biomarkers that describe an advance heart failure (AHF) patient’s compromised inflammatory response and determine whether these correlate with post-implant infection risk. In Aim 2, we will develop novel microfluidic assays to determine how the leukocyte profile and function change upon VAD implantation. We hypothesize that the development of immune suppression observed in VAD patents during systemic inflammation is a result of a less functional, immature neutrophils and myeloid derived suppressor cells being released from the bone marrow resulting in a heterogenous population of leukocytes that can simultaneously mediate tissue damage and be dysfunctional in antimicrobial defense. In Aim 3, we will determine whether exposing neutrophils from VAD patients to specialized pro-resolving lipid mediators (SPMs) can restore their antibacterial fighting and immunosuppressive capacities. The new experimental platforms and knowledge gained from these studies should aid in the development of targeted and personalized therapies that will reduce infection rates, as well as guide VAD therapy to reduce the trauma on leukocytes and other blood cells in these devices.