Skip Navigation


European Heart Journal Advance Access originally published online on March 8, 2007
European Heart Journal 2007 28(9):1135-1142; doi:10.1093/eurheartj/ehl543
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
28/9/1135    most recent
ehl543v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in EHJ
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Paavola, J.
Right arrow Articles by Laine, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Paavola, J.
Right arrow Articles by Laine, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves

Jere Paavola1, Matti Viitasalo2, Päivi J. Laitinen-Forsblom3, Michael Pasternack1, Heikki Swan2, Ilkka Tikkanen1,3, Lauri Toivonen2, Kimmo Kontula3 and Mika Laine1,2,*

1 Minerva Foundation Institute for Medical Research, FIN-00290, Helsinki, Finland
2 Department of Cardiology, Helsinki University Central Hospital, University of Helsinki, FIN-00290, Haartmaninkatu 4, PO Box 340, HUS 00029, Helsinki, Finland
3 Department of Medicine, University of Helsinki, FIN-00290, Helsinki, Finland

Received 7 October 2006; revised 9 January 2007; accepted 25 January 2007; online publish-ahead-of-print 8 March 2007.

* Corresponding author. Tel: +358 40 5245735; fax: +358 9 471 74574. E-mail address: Mika.Laine{at}hus.fi

See page 1054 for the editorial comment on this article (doi:10.1093/eurheartj/ehm068)

Aims: Mutations in cardiac ryanodine receptors (RyR2s) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), characterized by risk of polymorphic ventricular tachyarrhythmias and sudden death during exercise. Arrhythmias are caused by gain-of-function defects in RyR2, but cellular arrhythmogenesis remains elusive.

Methods and results: We recorded endocardial monophasic action potentials (MAPs) at right ventricular septum in 15 CPVT patients with a RyR2 mutation (P2328S, Q4201R, and V4653F) and in 12 control subjects both at baseline and during epinephrine infusion (0.05 µg/kg/min). At baseline 3 and during epinephrine infusion, four CPVT patients, but none of the control subjects, showed delayed afterdepolarizations (DADs) occasionally coinciding with ventricular premature complexes. In order to study the underlying mechanisms, we expressed two types of mutant RyR2 (P2328S and V4653F) causing CPVT as well as wild-type RyR2 in HEK 293 cells. Confocal microscopy of Fluo-3 loaded cells transfected with any of the three RyR2s showed no spontaneous subcellular Ca2+ release events at baseline. Membrane permeable cAMP analogue (Dioctanoyl-cAMP) triggered subcellular Ca2+ release events as Ca2+ sparks and waves. Cells expressing mutant RyR2s showed spontaneous Ca2+ release events at lower concentrations of cAMP than cells transfected with wild-type RyR2.

Conclusion: CPVT patients show DADs coinciding with premature action potentials in MAP recordings. Expression studies suggest that DADs are caused by increased propensity of abnormal RyR2s to generate spontaneous Ca2+ waves in response to cAMP stimulation. Increased sensitivity of mutant RyR2s to cAMP may explain the occurrence of arrhythmias during exercise or emotional stress in CPVT.

Key Words: Arrhythmia • Calcium • Mutation • cAMP • HEK293 cells • Heart failure • Sudden death


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?

Related articles in EHJ:

Leaky ryanodine receptors cause delayed afterdepolarizations and ventricular arrhythmias
Xander H.T. Wehrens
EHJ 2007 28: 1054-1056. [Extract] [Full Text]  



This article has been cited by other articles:


Home page
 Biophys. JHome page
A. Koop, P. Goldmann, S. R. W. Chen, R. Thieleczek, and M. Varsanyi
ARVC-Related Mutations in Divergent Region 3 Alter Functional Properties of the Cardiac Ryanodine Receptor
Biophys. J., June 15, 2008; 94(12): 4668 - 4677.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
N. Liu and S. G. Priori
Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin
Cardiovasc Res, January 15, 2008; 77(2): 293 - 301.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D. R. Gonzalez, F. Beigi, A. V. Treuer, and J. M. Hare
Deficient ryanodine receptor S-nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes
PNAS, December 18, 2007; 104(51): 20612 - 20617.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. E. Lehnart, M. J. Ackerman, D. W. Benson Jr, R. Brugada, C. E. Clancy, J. K. Donahue, A. L. George Jr, A. O. Grant, S. C. Groft, C. T. January, et al.
Inherited Arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function
Circulation, November 13, 2007; 116(20): 2325 - 2345.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.