title: 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-amino-phenyl) 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.
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seki
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Ryan
authors.initials: R
authors.lastname: LaCanna
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Jeffery C
authors.initials: JC
authors.lastname: Powers
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Christine
authors.initials: C
authors.lastname: Vrakas
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Remus
authors.initials: R
authors.lastname: Berretta
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Geena
authors.initials: G
authors.lastname: Chacko
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: John
authors.initials: J
authors.lastname: Holten
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Pooja
authors.initials: P
authors.lastname: Jadiya
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Arkles
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Copper
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.).
authors.forename: Jianhe
authors.initials: J
authors.lastname: Huang
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.) fabio.recchia@temple.edu vickas.patel@temple.edu.
authors.forename: Vickas V
authors.initials: VV
authors.lastname: Patel
authors.affiliation: Cardiovascular Research Center (M.S., R.L.C., J.C.P., C.V., R.B., G.C., Jo.H., P.J., T.W., S.R.H., Ji.H., V.V.P., F.A.R.), and Section of Clinical Cardiac Electrophysiology (J.S.A., J.M.C., V.V.P.), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (F.L.) fabio.recchia@temple.edu vickas.patel@temple.edu.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Recchia
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D064752:Atrial Remodeling / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001549:Benzamides; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004285:Dogs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010655:Phenylenediamines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001549:Benzamides; D015415:Biomarkers; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D010655:Phenylenediamines; C081895:tacedinaline