Heart Rhythm
Volume 5, Issue 7 , Pages 1047-1054, July 2008

Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation

  • Subeena Sood, PhD

      Affiliations

    • Department of Molecular Physiology and Biophysics, Houston, Texas
    • ,
  • Mihail G. Chelu, MD, PhD

      Affiliations

    • Department of Molecular Physiology and Biophysics, Houston, Texas
    • ,
  • Ralph J. van Oort, PhD

      Affiliations

    • Department of Molecular Physiology and Biophysics, Houston, Texas
    • ,
  • Darlene Skapura, BSc

      Affiliations

    • Department of Molecular Physiology and Biophysics, Houston, Texas
    • ,
  • Marco Santonastasi, MEng

      Affiliations

    • Department of Molecular Physiology and Biophysics, Houston, Texas
    • ,
  • Dobromir Dobrev, MD

      Affiliations

    • Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany
    • ,
  • Xander H.T. Wehrens, MD, PhD, FESC

      Affiliations

    • Department of Molecular Physiology and Biophysics, Houston, Texas
    • Department of Medicine, Division of Cardiology, Baylor College of Medicine, Houston, Texas.
    • Corresponding Author InformationAddress reprint requests and correspondence: Dr. Xander H. T. Wehrens, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, BCM335, Houston, Texas 77030.

Received 15 February 2008; accepted 21 March 2008. published online 28 March 2008.

Background

Although defective Ca2+ homeostasis may contribute to arrhythmogenesis in atrial fibrillation (AF), the underlying molecular mechanisms remain poorly understood. Studies in patients with AF revealed that impaired diastolic closure of sarcoplasmic reticulum (SR) Ca2+-release channels (ryanodine receptors, RyR2) is associated with reduced levels of the RyR2-inhibitory subunit FKBP12.6.

Objective

The objective of the present study was to test the hypothesis that Ca2+ leak from the SR through RyR2 increases the propensity for AF in FKBP12.6-deficient (−/−) mice.

Methods

Surface electrocardiogram and intracardiac electrograms were recorded simultaneously in FKBP12.6−/− mice and wild-type (WT) littermates. Right atrial programmed stimulation was performed before and after injection of RyR2 antagonist tetracaine (0.5 mg/kg). Intracellular Ca2+ transients were recorded in atrial myocytes from FKBP12.6−/− and WT mice.

Results

FKBP12.6−/− mice had structurally normal atria and unaltered expression of key Ca2+-handling proteins. AF episodes were inducible in 81% of FKBP12.6−/−, but in only 7% of WT mice (P <.05), and were prevented by tetracaine in all FKBP12.6−/− mice. SR Ca2+ leak in FKBP12.6−/− myocytes was 53% larger than in WT myocytes, and FKBP12.6−/− myocytes showed increased incidence of spontaneous SR Ca2+ release events, which could be blocked by tetracaine.

Conclusion

The increased vulnerability to AF in FKBP12.6−/− mice substantiates the notion that defective SR Ca2+ release caused by abnormal RyR2 and FKBP12.6 interactions may contribute to the initiation or maintenance of atrial fibrillation.

Keywords: Atrial fibrillation, Calcium, Electrical remodeling, Focal activity, Ryanodine receptors

To access this article, please choose from the options below

Login to an existing account or Register a new account.

  • Purchase this article for 31.50 USD (You must login/register to purchase this article)

    Online access for 24 hours. The PDF version can be downloaded as your permanent record.

  • Subscribe to this title

    Get unlimited online access to this article and all other articles in this title 24/7 for one year.

  • Claim access now

    For current subscribers with Society Membership or Account Number.

  • Visit SciVerse ScienceDirect to see if you have access via your institution.
 

 Supported by a national Scientist Development Grant from the American Heart Association (0535310N) and NIH/NHLBI grant 1R01-HL089598-01 (XHTW), the 2007–2008 Michael Bilitch Fellowship in Cardiac Pacing and Electrophysiology from the Heart Rhythm Society (MGC), and the German Federal Ministry of Education and Research through the Atrial Fibrillation Competence Network (grant 01Gi0204; projects C3 and C4) and a grant of Fondation Leducq (07 CVD 03) (DD).

PII: S1547-5271(08)00334-2

doi:10.1016/j.hrthm.2008.03.030

Heart Rhythm
Volume 5, Issue 7 , Pages 1047-1054, July 2008

Article Tools

* Image Usage & Resolution