BACKGROUND The development of heart failure is accompanied by complex changes in cardiac electrophysiology and functional properties of cardiomyocytes and fibroblasts. Histone deacetylase (HDAC) inhibitors hold great promise for the pharmaceutical therapy of several malignant diseases. Here, we describe novel effects of the class I HDAC inhibitor Entinostat on electrical and structural remodeling in an in vivo model of pacing induced heart failure. METHODS Rabbits were implanted a pacemaker system, subjected to rapid ventricular pacing and treated with Entinostat or placebo, respectively. Following stimulation, rabbit hearts were explanted and subsequently subjected to electrophysiological studies and further immunohistological analyses of left ventricles. RESULTS In vivo, rapid ventricular stimulation caused a significant prolongation of monophasic action potential duration compared to sham hearts (from 173 ± 26 ms to 250 ± 41 ms; cycle length 900 ms; p < 0.05) and an increased incidence of Early afterdepolarisations (+ 150%), while treatment with Entinostat in failing hearts could partially prevent this effect (from 250 ± 41 ms to 170 ± 53 ms, p < 0.05; reduction in EAD by 50%). Entinostat treatment partially restored KCNH2 and Cav1.3 gene expressions in failing hearts, and inhibited the development of cardiac fibrosis in vivo. CONCLUSION In a rabbit model of heart failure, Entinostat diminishes heart failure related prolongation of repolarization and partially restores KCNH2 and Cav1.3 expression. In addition, Entinostat exerts antifibrotic properties both in vitro and in vivo. Thus, Entinostat might be an interesting candidate for the pharmaceutical therapy of heart failure directed against structural and electrical remodeling.

中文翻译：

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Entinostat抑制组蛋白脱乙酰基酶，以预防心力衰竭中的电和结构重塑。

背景技术心力衰竭的发展伴随着心脏电生理以及心肌细胞和成纤维细胞功能特性的复杂变化。组蛋白脱乙酰基酶（HDAC）抑制剂在几种恶性疾病的药物治疗中具有广阔的前景。在这里，我们描述了起搏诱发心力衰竭的体内模型中，I类HDAC抑制剂恩替司他对电和结构重塑的新型作用。方法兔植入起搏器系统，快速起搏并分别用恩替司他或安慰剂治疗。刺激后，将兔心脏移出，然后进行电生理研究和左心室的进一步免疫组织学分析。结果在体内，与假心脏相比，快速的心室刺激导致单相动作电位持续时间显着延长（从173±26 ms增至250±41 ms；周期长度900 ms； p <0.05），早期除极后发生率增加（+ 150％），而在心脏衰竭的患者中使用恩替司他治疗可以部分预防这种影响（从250±41 ms到170±53 ms，p <0.05； EAD降低50％）。恩替司他治疗可部分恢复衰竭心脏中KCNH2和Cav1.3基因的表达，并抑制体内心脏纤维化的发展。结论在兔子的心力衰竭模型中，恩替司他减少了与心力衰竭有关的复极化延长，并部分恢复了KCNH2和Cav1.3的表达。另外，恩替司他在体外和体内均具有抗纤维化特性。从而，