Translational Study of Cardiac Dysfunction

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DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Sustained cardiac hypertrophy represents one of the most common causes leading to heart failure. Once heart failure develops, the condition is irreversible and is associated with a very high mortality rate. Moreover, cardiac hypertrophy and failure are associated with an increase in both atrial and ventricular arrhythmias and sudden cardiac death. During our last funding cycle, we have demonstrated the beneficial effects of a novel class of soluble epoxide hydrolase (sEH) inhibitors in clinically relevant models of cardiac hypertrophy and failure. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and MI models. Our preliminary findings further demonstrate that treatment with sEHIs prevents cardiac fibroblast proliferation and fibrosis. These results are exciting because they demonstrate for the first time a broader salutary effects in cardiac remodeling (not limited to just myocyte hypertrophy) of this novel class of compounds. Thus, the central objective of this competing renewal is to test the beneficial effects of sEHIs in cardiac remodeling by modifying cardiac fibrosis. Additionally, since atrial fibrosis plays a central role in atrial fibrillation (AF), we urther propose that sEH may represent a new therapeutic target for the treatment of AF. Indeed, AF represents one the most common arrhythmias clinically and is associated with a significant increase in morbidity and mortality. Hence, new treatment paradigms for AF are likely to be highly impactful.