Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Sci Transl Med. 2018 Feb 7;10(427). doi: 10.1126/scitranslmed.aao0144.
There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor-mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte-autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans.
目前尚无治疗射血分数保留的心力衰竭（HFpEF）的药物，HFpEF 的特征为左心室（LV）舒张功能障碍。我们证明 ITF2357（givinostat），一种组蛋白去乙酰化酶（HDAC）催化活性的临床阶段抑制剂，在两种具有 EF 保留的不同舒张功能障碍的小鼠模型中均有效。ITF2357 可阻断由于高血压引起的 Dahl 盐敏感（DSS）大鼠的 LV 舒张功能障碍，并抑制在正常血压小鼠中的衰老诱导的舒张功能障碍。HDAC 抑制剂介导的功效不是由于降低血压或抑制与舒张功能障碍通常相关的细胞和分子事件，包括心脏纤维化、心脏肥大或肌球蛋白同工型表达的变化。相反，离体研究揭示了心肌纤维松弛受损，这是一种以前未被认识的、心肌细胞自主的舒张功能障碍机制，可通过 HDAC 抑制得到改善。将这些发现转化为人类，舒张功能障碍和 EF 保留的患者的心肌纤维也表现出松弛受损。这些数据表明，增强心肌纤维松弛的药物（如 HDAC 抑制剂）有望用于治疗人类的 HFpEF。
