Translational Study of Cardiac Dysfunction

描述(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。持续性心肌肥厚是导致心力衰竭的最常见原因之一。一旦心力衰竭发展，这种情况是不可逆转的，并与非常高的死亡率相关。此外，心脏肥厚和衰竭与房性和室性心律失常以及心脏性猝死的增加有关。在我们的上一个资助周期中，我们展示了一类新型的可溶性环氧化物水解酶(SEH)抑制剂在临床相关的心肌肥厚和衰竭模型中的有益效果。在压力超负荷和心肌梗死模型中，使用sEH抑制剂(SEHIs)可防止心肌细胞肥大和电重构。我们的初步研究结果进一步表明，sEHIs治疗可以预防心脏成纤维细胞的增殖和纤维化。这些结果是令人兴奋的，因为他们首次证明了这种新型化合物在心脏重塑(不仅限于心肌细胞肥大)方面具有更广泛的有益作用。因此，这一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影响。此外，由于心房纤维化在心房颤动(房颤)中起核心作用，我们进一步提出sEH可能成为治疗房颤的新靶点。事实上，房颤是临床上最常见的心律失常之一，与发病率和死亡率的显著增加有关。因此，房颤的新治疗模式很可能是非常有效的。

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.