DESCRIPTION (provided by applicant): Although inflammation has been linked to development of several chronic diseases, including of the cardiovascular system, emerging evidence suggests that recently identified endogenous anti-inflammatory molecules may be critical for appropriate control and protection against injury and excessive inflammation. In vitro and animal studies suggest that Mono-Epoxides derived from long-chain polyunsaturated Fatty Acids (MEFAs) are crucial for reducing inflammatory responses to injury, including in the heart. While there is promising evidence in animal disease models, the metabolism and anti-inflammatory function of MEFAs in humans remain largely unexplored. This proposed work will evaluate for the first time the relationships of plasma MEFAs with circulating and urine pro-inflammatory mediators in a human model of acute injury/inflammation, i.e. cardiac surgery. This work represents a highly innovative use of a human model of discrete and well-timed tissue injury to elucidate the biologic roles and relevance of MEFAs in humans. This is made possible by nesting our proposed study in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Trial, a randomized, double-blind, placebo controlled trial among 1516 cardiac surgery patients to test the effects of peri-operative oral fish oil on both biologic endpoints, including pro- inflammatory biomarkers, and clinical endpoints including post-operative atrial fibrillation (POAF). The study has existing funding for subject enrollment, sample collection/storage, and ascertainment/measurement of these endpoints. Although MEFAs are metabolites of fish-oil-derived fatty acids, the impact of dietary fish oil on MEFAs response to acute injury/inflammation in humans is unknown. By nesting this biologic research within OPERA, an existing randomized controlled trial of fish oil, we will be able to directly evaluate the unbiased effects of oral fish oil intake on MEFAs response to injury/inflammation. These results will have tremendous significance for understanding how dietary fatty acids affect MEFAs response, and represent a second highly innovative aspect of this work. Finally, given the focus of OPERA on POAF, we will be able to evaluate at no additional cost the potential relevance of MEFAs response to this clinically relevant outcome, a common and serious complication of cardiac surgery. We will perform this novel work by measuring plasma levels of MEFAs and their metabolites in a randomly selected subset of patients (n=800) in OPERA, and then assessing the interrelationships of MEFAs level with biomarkers of inflammation; the effects of oral fish oil treatment, vs. placebo, on these MEFAs response; and the relationship of MEFAs levels with POAF.

This study will improve our understanding in humans of the possible inter-relation between anti- inflammatory MEFAs and pro-inflammatory mediators; evaluate the unbiased effects of oral fish oil intake on MEFAs response to injury/inflammation, and the potential relevance of MEFAs response to post-operative atrial fibrillation, a common and serious complication of cardiac surgery Thus, the results may help to provide initial novel insights into MEFAs possible role in human health and potentially guide future therapeutic strategies targeting the MEFAs pathway.