Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation
Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation
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DOI：
10.1124/jpet.116.234591
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发表时间：
2016-09-01
影响因子：
3.5
通讯作者：
Recchia, Fabio A.
中科院分区：
文献类型：
--
作者：
Seki, Mitsuru;LaCanna, Ryan;Recchia, Fabio A.
目前的治疗方法对于治疗持续性/永久性房颤（AF）的效果不如阵发性房颤（AF）。我们和其他人先前已经表明，组蛋白脱乙酰酶（HDAC）抑制逆转了诱导型阵发性房颤小鼠的结构和电心房重构。I类HDAC抑制剂N-乙酰地那林在确定持续性AF期间心房结构改变中的特定作用。（乙酰氨基）-N-（2-氨基苯基）苯甲酰胺]（CI-994）给药2周（1 mg/kg/天）给予具有心房重构和可诱导AF的Hopx转基因小鼠和具有心房快速起搏的犬，I类HDAC抑制剂可防止小鼠心房纤维化和心律失常诱导。将狗分为三组：1）窦性心律，2）持续AF加媒介物，和3）持续AF加CI-994。在第3组中，与第2组相比，2周以上的AF时间减少了30%，沿着减弱的心房纤维化和心房内脂肪细胞浸润。此外，与组1和组3相比，组2犬具有更高的心房和血清炎性细胞因子、脂肪因子以及心房免疫细胞和脂肪细胞。另一方面，第2组和第3组显示出相似的左心房大小、心室功能和二尖瓣返流。重要的是，在患有持续性AF的狗中发现的并被CI-994逆转的相同组织学改变也存在于患有慢性AF的移植患者的心房组织中。这是第一个证据，表明在持续性AF中，I类HDAC抑制可以减少颤动、心房纤维化、心房内脂肪细胞和免疫细胞浸润的总时间，而对心脏功能没有显著影响。
Current therapies are less effective for treating sustained/permanent versus paroxysmal atrial fibrillation (AF). We and others have previously shown that histone deacetylase (HDAC) inhibition reverses structural and electrical atrial remodeling in mice with inducible, paroxysmal-like AF. Here, we hypothesize an important, specific role for class I HDACs in determining structural atrial alterations during sustained AF. The class I HDAC inhibitor N-acetyldinaline [ 4-(acetylamino)-N-(2-aminophenyl) benzamide] (CI-994) was administered for 2 weeks (1 mg/kg/day) to Hopx transgenic mice with atrial remodeling and inducible AF and to dogs with atrial tachypacing-induced sustained AF. Class I HDAC inhibition prevented atrial fibrosis and arrhythmia inducibility in mice. Dogs were divided into three groups: 1) sinus rhythm, 2) sustained AF plus vehicle, and 3) sustained AF plus CI-994. In group 3, the time in AF over 2 weeks was reduced by 30% compared with group 2, along with attenuated atrial fibrosis and intra-atrial adipocyte infiltration. Moreover, group 2 dogs had higher atrial and serum inflammatory cytokines, adipokines, and atrial immune cells and adipocytes compared with groups 1 and 3. On the other hand, groups 2 and 3 displayed similar left atrial size, ventricular function, and mitral regurgitation. Importantly, the same histologic alterations found in dogs with sustained AF and reversed by CI-994 were also present in atrial tissue from transplanted patients with chronic AF. This is the first evidence that, in sustained AF, class I HDAC inhibition can reduce the total time of fibrillation, atrial fibrosis, intra-atrial adipocytes, and immune cell infiltration without significant effects on cardiac function.