Translational Study of Cardiac Dysfunction

描述（由申请人提供）：心血管疾病是美国发病率和死亡率的主要原因。持续的心脏肥厚是导致心力衰竭最常见的原因之一。一旦发生心力衰竭，这种情况是不可逆转的，并且与非常高的死亡率有关。此外，心脏肥厚和心力衰竭与心房和室性心律失常以及心源性猝死的增加有关。在我们上一个融资周期中，我们已经证明了一类新型可溶性环氧化物水解酶（sEH）抑制剂在心脏肥大和心力衰竭的临床相关模型中的有益作用。在压力过载和心肌梗死模型中，使用sEH抑制剂（sEHIs）治疗可预防心室肌细胞肥大和电重构。我们的初步研究结果进一步表明，sEHIs治疗可防止心脏成纤维细胞增殖和纤维化。这些结果令人兴奋，因为它们首次证明了这类新型化合物在心脏重塑中具有更广泛的有益作用（不仅限于心肌细胞肥大）。因此，这种竞争性更新的中心目标是通过改变心脏纤维化来测试sEHIs在心脏重塑中的有益作用。此外，由于心房纤维化在房颤（AF）中起着核心作用，我们进一步提出sEH可能是房颤治疗的一个新的治疗靶点。事实上，房颤是临床上最常见的心律失常之一，并且与发病率和死亡率的显著增加有关。因此，新的房颤治疗模式可能会产生很大的影响。

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.