Class I histone deacetylase inhibition for the treatment of sustained atrial fibrillation

TY - JOUR

T1 - Class I histone deacetylase inhibition for the treatment of sustained atrial fibrillation

AU - Seki, Mitsuru

AU - Lacanna, Ryan

AU - Powers, Jeffery C.

AU - Vrakas, Christine

AU - Liu, Fang

AU - Berretta, Remus

AU - Chacko, Geena

AU - Holten, John

AU - Jadiya, Pooja

AU - Wang, Tao

AU - Arkles, Jeffery S.

AU - Copper, Joshua M.

AU - Houser, Steven R.

AU - Huang, Jianhe

AU - Patel, Vickas V.

AU - Recchia, Fabio A.

N1 - Publisher Copyright: Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

PY - 2016/9

Y1 - 2016/9

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84983803114

UR - https://www.scopus.com/pages/publications/84983803114#tab=citedBy

U2 - 10.1124/jpet.116.234591

DO - 10.1124/jpet.116.234591

M3 - Article

C2 - 27353074

SN - 0022-3565

VL - 358

SP - 441

EP - 449

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

IS - 3

ER -