Arrhythmogenesis in Catecholaminergic Polymorphic Ventricular Tachycardia

  • Nian Liu
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.
  • Barbara Colombi
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.
  • Mirella Memmi
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.
  • Spyros Zissimopoulos
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.
  • Nicoletta Rizzi
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.
  • Sara Negri
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.
  • Marcello Imbriani
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.
  • Carlo Napolitano
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.
  • F. Anthony Lai
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.
  • Silvia G. Priori
    From Molecular Cardiology (N.L., B.C., M.M., N.R., C.N., S.G.P.) and Lab studi inquinanti aereiformi (S.N., M.I.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; the Wales Heart Research Institute (S.Z., F.A.L.), Department of Cardiology, Cardiff University School of Medicine, UK; and the Department of Cardiology (S.G.P.), University of Pavia, Italy.

書誌事項

タイトル別名
  • Insights From a RyR2 R4496C Knock-In Mouse Model

抄録

<jats:p> Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by life threatening arrhythmias and mutations in the gene encoding the ryanodine receptor (RyR2). Disagreement exists on whether (1) RyR2 mutations induce abnormal calcium transients in the absence of adrenergic stimulation; (2) decreased affinity of mutant RyR2 for FKBP12.6 causes CPVT; (3) K201 prevent arrhythmias by normalizing the FKBP12.6-RyR2 binding. We studied ventricular myocytes isolated from wild-type (WT) and knock-in mice harboring the R4496C mutation (RyR2 <jats:sup>R4496C+/−</jats:sup> ). Pacing protocols did not elicit delayed afterdepolarizations (DADs) (n=20) in WT but induced DADs in 21 of 33 (63%) RyR2 <jats:sup>R4496C+/−</jats:sup> myocytes ( <jats:italic>P</jats:italic> =0.001). Superfusion with isoproterenol (30 nmol/L) induced small DADs (45%) and no triggered activity in WT myocytes, whereas it elicited DADs in 87% and triggered activity in 60% of RyR2 <jats:sup>R4496C+/−</jats:sup> myocytes ( <jats:italic>P</jats:italic> =0.001). DADs and triggered activity were abolished by ryanodine (10 μmol/L) but not by K201 (1 μmol/L or 10 μmol/L). In vivo administration of K201 failed to prevent induction of polymorphic ventricular tachycardia (VT) in RyR2 <jats:sup>R4496C+/−</jats:sup> mice. Measurement of the FKBP12.6/RyR2 ratio in the heavy sarcoplasmic reticulum membrane showed normal RyR2–FKBP12.6 interaction both in WT and RyR2 <jats:sup>R4496C+/−</jats:sup> either before and after treatment with caffeine and epinephrine. We suggest that (1) triggered activity is the likely arrhythmogenic mechanism of CPVT; (2) K201 fails to prevent DADs in RyR2 <jats:sup>R4496C+/−</jats:sup> myocytes and ventricular arrhythmias in RyR2 <jats:sup>R4496C+/−</jats:sup> mice; and (3) RyR2–FKBP12.6 interaction in RyR2 <jats:sup>R4496C+/−</jats:sup> is identical to that of WT both before and after epinephrine and caffeine, thus suggesting that it is unlikely that the R4496C mutation interferes with the RyR2/FKBP12.6 complex. </jats:p>

収録刊行物

  • Circulation Research

    Circulation Research 99 (3), 292-298, 2006-08-04

    Ovid Technologies (Wolters Kluwer Health)

被引用文献 (10)*注記

もっと見る

詳細情報

問題の指摘

ページトップへ