The Next Step: Regadenoson mitigates ischemia reperfusion injury and is renal protective in a 48 hour porcine model of resuscitative ECMO

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This is an application for a career development award to provide the PI with training in translation research. Building on ischemia reperfusion injury research performed by his mentors, the PI will use his acute resuscitative porcine animal model and extend it to 48 hours to look at end organ injury/recovery. This will further separate his career path from his mentors and set him up for funding for a clinical trial. Cardiac arrest is one of the leading causes of death worldwide, and resuscitative extracorporeal membrane oxygenation (ECMO) has emerged as a therapeutic option for refractory cardiac arrest, which was reported in almost 4,000 patients worldwide in 2017. The focus of the current proposal is to build upon our successful 6- hour ECMO porcine model and extend it to 48 hours to fully assess organ injury and recovery. We are also using an FDA-approved A2AR agonist (Regadenoson) to maximize the clinical translatability and to bring this therapy to patients. This project represents a paradigm shift in the management of ECMO from a supportive role to active treatment of the underlying problem, IRI organ injury. Resuscitatve ECMO is the most extreme example of IRI, but this treatment will be applied to all future resuscitative mechanical circulatory support. Specific Aim 1A will show that Regadenoson attenuates systemic organ injury in a 48-model of resuscitative ECMO. We will look at several markers of CNS, cardiac, liver, kidney, and intestinal injury as well as cytokine levels. CD3+ and CD4+ T cells, monocytes and neutrophils, and several damage-associated molecular pattern (DAMP) molecules will be assessed including HMGB1, cell-free DNA fragments and mitochondrial DNA. Aim 1B will show improved organ function in the groups treated with Regadenoson. Cardiac function will be assessed by cardiac index measured by a Swan-Ganz catheter and echocardiographs (ECHO) as well as the amount of inotropic support, IV fluid requirement and ECMO flows. Urine output will be collected and measured, and intestinal permeability will be determined via fluorescein isothiocyanate (FITC) gavage. Specific Aim2 will show how Regadenoson attenuates organ injury and improves organ function through several mechanisms including attenuation of neutrophil activation with reduced apoptosis, decreased membrane barrier permeability and fewer reactive oxygen species in the liver, kidney, intestine, heart, and brain. This mechanistic aim will provide additional scientific support for the use of A2AR activation to attenuate IRI in multiple organ systems. Dr Laubach is a senior researcher who has studied IRI for more than two decades and will serve as a mentor for this aim of the grant. Specific Aim3 will propose a clinical trial to determine if Regadenoson provides a durable clinical improvement in multiple organ systems in patients with post-arrest reperfusion with resuscitative ECMO. I will use the skills obtained from my course work and mentoring from Drs. Lau and Kron to submit a FDA investigational new drug application during the fourth year of this project, so I can submit an R01 proposal for clinical trial funding during the final year.