Ryanodine Receptor–Mediated Calcium Leak Drives Progressive Development of an Atrial Fibrillation Substrate in a Transgenic Mouse Model

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  • Na Li
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • David Y. Chiang
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Sufen Wang
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Qiongling Wang
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Liang Sun
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Niels Voigt
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Jonathan L. Respress
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Sameer Ather
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Darlene G. Skapura
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Valerie K. Jordan
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Frank T. Horrigan
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Wilhelm Schmitz
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Frank U. Müller
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Miguel Valderrabano
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Stanley Nattel
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Dobromir Dobrev
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...
  • Xander H.T. Wehrens
    From the Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics (N.L., D.Y.C., L.S., J.L.R., S.A., D.G.S., V.K.J., F.T.H., X.H.T.W.), Translational Biology and Molecular Medicine Program (D.Y.C.), and Department of Medicine, Cardiology (X.H.T.W.), Baylor College of Medicine, Houston, TX; Department of Cardiology, The Methodist Hospital, Houston, TX (S.W., M.V.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.);...

Description

<jats:sec> <jats:title>Background—</jats:title> <jats:p> The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca <jats:sup>2+</jats:sup> leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca <jats:sup>2+</jats:sup> release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca <jats:sup>2+</jats:sup> release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca <jats:sup>2+</jats:sup> /calmodulin-dependent protein kinase II–mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca <jats:sup>2+</jats:sup> release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca <jats:sup>2+</jats:sup> -dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> RyR2-mediated SR Ca <jats:sup>2+</jats:sup> leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca <jats:sup>2+</jats:sup> release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate. </jats:p> </jats:sec>

Journal

  • Circulation

    Circulation 129 (12), 1276-1285, 2014-03-25

    Ovid Technologies (Wolters Kluwer Health)

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