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Research ArticleCardiovascular

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

Mitsuru Seki, Ryan LaCanna, Jeffery C. Powers, Christine Vrakas, Fang Liu, Remus Berretta, Geena Chacko, John Holten, Pooja Jadiya, Tao Wang, Jeffery S. Arkles, Joshua M. Copper, Steven R. Houser, Jianhe Huang, Vickas V. Patel and Fabio A. Recchia
Journal of Pharmacology and Experimental Therapeutics September 2016, 358 (3) 441-449; DOI: https://doi.org/10.1124/jpet.116.234591
Mitsuru Seki
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.)
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Ryan LaCanna
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.)
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Jeffery C. Powers
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.)
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Christine Vrakas
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.)
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Fang Liu
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.)
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Remus Berretta
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.)
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Geena Chacko
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.)
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John Holten
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.)
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Pooja Jadiya
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.)
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Tao Wang
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.)
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Jeffery S. Arkles
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.)
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Joshua M. Copper
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.)
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Steven R. Houser
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.)
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Jianhe Huang
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.)
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Vickas V. Patel
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.)
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Fabio A. Recchia
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.)
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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.

Footnotes

    • Received April 23, 2016.
    • Accepted June 22, 2016.
  • ↵1 M.S., R.L., J.C.P., and C.V. contributed equally to this work.

  • This work was supported by the National Institutes of Health [Grants R01 HL105734 to V.V.P. and R01 HL108213 to F.A.R.] and unrestricted funds from the Lewis Katz School of Medicine at Temple University.

  • dx.doi.org/10.1124/jpet.116.234591.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 358 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 3
1 Sep 2016
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Research ArticleCardiovascular

Class I HDAC Inhibition in Atrial Fibrillation

Mitsuru Seki, Ryan LaCanna, Jeffery C. Powers, Christine Vrakas, Fang Liu, Remus Berretta, Geena Chacko, John Holten, Pooja Jadiya, Tao Wang, Jeffery S. Arkles, Joshua M. Copper, Steven R. Houser, Jianhe Huang, Vickas V. Patel and Fabio A. Recchia
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 441-449; DOI: https://doi.org/10.1124/jpet.116.234591

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Research ArticleCardiovascular

Class I HDAC Inhibition in Atrial Fibrillation

Mitsuru Seki, Ryan LaCanna, Jeffery C. Powers, Christine Vrakas, Fang Liu, Remus Berretta, Geena Chacko, John Holten, Pooja Jadiya, Tao Wang, Jeffery S. Arkles, Joshua M. Copper, Steven R. Houser, Jianhe Huang, Vickas V. Patel and Fabio A. Recchia
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 441-449; DOI: https://doi.org/10.1124/jpet.116.234591
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