Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation

Abstract

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.

Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset

“…There is some evidence that fetal reprogramming is a pathological contributor because β blocker-treated patients recovering from heart failure partially reverse the fetal gene reactivation, but the recovery of fetal gene expression was only correlative and is not seen in the partial recovery of patients on a LV assist device support (5,32,33). Indeed, Histone deacetylase (HDAC) inhibitors, which are classic dedifferentiation agents, show some effectiveness in experimental models of cardiomyopathy, but clinical use of multiple HDAC inhibitors to treat cancer is associated with adverse cardiac side effects (34)(35)(36)(37). HDAC inhibitors are broad-acting epigenetic transcription regulators that affect the expression of many genes, suggesting that effective use of transcription modulators may require more specific drugs.…”

Overlapping and Divergent Actions of Structurally Distinct Histone Deacetylase Inhibitors in Cardiac Fibroblasts

“…TSA, an apicidin derivative, and MGCD0103 have all been shown to block cardiac fibrosis in multiple mouse models (Kook et al, 2003;Kee et al, 2006;Kong et al, 2006;Gallo et al, 2008;Liu et al, 2008;Nural-Guvener et al, 2014;Williams et al, 2014). Furthermore, another benzamide class I HDAC inhibitor, CI-994 [4-acetamido-N-(2-aminophenyl)benzamide], was recently found to reduce cardiac fibrosis in mouse and dog models of heart remodeling (Seki et al, 2016). How can benzamide class I HDAC inhibitors block cardiac fibrosis in vivo, yet stimulate a subset of fibrosis-associated genes in cardiac fibroblasts?…”

Genetics and Epigenetics of Atrial Fibrillation

“…In this context, emerging evidence is demonstrating a pivotal role of HDACs influencing post-transcriptional regulation of distinct proteins in cardiomyocytes in the context of AF [ 214 , 215 ], particularly on cytoskeletal [ 213 ] and conductive proteins [ 216 ], while their role in contractile and ion channels remains unclear [ 217 ]. Additionally, HDAC inhibition can significantly block or halt AF progression [ 216 , 218 , 219 , 220 , 221 ], further supporting the important role of HDAC in AF, yet the molecular mechanisms remain to be further explored.…”