Document Detail


Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression: whole heart and cellular mechanisms.
MedLine Citation:
PMID:  22327339     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cardiac Na(+)/Ca(2+) exchanger (NCX) generates an inward electrical current during SR-Ca(2+) release, thus possibly promoting afterdepolarizations of the action potential (AP). We used transgenic mice 12.5 weeks or younger with cardiomyocyte-directed overexpression of NCX (NCX-Tg) to study the proarrhythmic potential and mechanisms of enhanced NCX activity. NCX-Tg exhibited normal echocardiographic left ventricular function and heart/body weight ratio, while the QT interval was prolonged in surface ECG recordings. Langendorff-perfused NCX-Tg, but not wild-type (WT) hearts, developed ventricular tachycardia. APs and ionic currents were measured in isolated cardiomyocytes. Cell capacitance was unaltered between groups. APs were prolonged in NCX-Tg versus WT myocytes along with voltage-activated K(+) currents (K(v)) not being reduced but even increased in amplitude. During abrupt changes in pacing cycle length, early afterdepolarizations (EADs) were frequently recorded in NCX-Tg but not in WT myocytes. Next to EADs, delayed afterdepolarizations (DAD) triggering spontaneous APs (sAPs) occurred in NCX-Tg but not in WT myocytes. To test whether sAPs were associated with spontaneous Ca(2+) release (sCR), Ca(2+) transients were recorded. Despite the absence of sAPs in WT, sCR was observed in myocytes of both genotypes suggesting a facilitated translation of sCR into DADs in NCX-Tg. Moreover, sCR was more frequent in NCX-Tg as compared to WT. Myocardial protein levels of Ca(2+)-handling proteins were not different between groups except the ryanodine receptor (RyR), which was increased in NCX-Tg versus WT. We conclude that NCX overexpression is proarrhythmic in a non-failing environment even in the absence of reduced K(V). The underlying mechanisms are: (1) occurrence of EADs due to delayed repolarization; (2) facilitated translation from sCR into DADs; (3) proneness to sCR possibly caused by altered Ca(2+) handling and/or increased RyR expression.
Authors:
Christian Pott; Adam Muszynski; Matthias Ruhe; N Bögeholz; Jan S Schulte; Peter Milberg; Gerold Mönnig; Larissa Fabritz; Joshua I Goldhaber; Günter Breithardt; Wilhelm Schmitz; Kenneth D Philipson; Lars Eckardt; Paulus Kirchhof; Frank U Müller
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-02-11
Journal Detail:
Title:  Basic research in cardiology     Volume:  107     ISSN:  1435-1803     ISO Abbreviation:  Basic Res. Cardiol.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-02-13     Completed Date:  2012-05-23     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0360342     Medline TA:  Basic Res Cardiol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  247     Citation Subset:  IM    
Affiliation:
Division of Experimental and Clinical Electrophysiology, Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany. christian.pott@ukmuenster.de
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MeSH Terms
Descriptor/Qualifier:
Action Potentials / physiology*
Animals
Arrhythmias, Cardiac / genetics,  metabolism*
Blotting, Western
Disease Models, Animal
Electrocardiography
Heart / physiology*
Homeodomain Proteins / genetics,  metabolism*
Mice
Myocytes, Cardiac / metabolism*
Organ Culture Techniques
Grant Support
ID/Acronym/Agency:
R01 HL070828/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Homeodomain Proteins; 0/Tlx2 protein, mouse
Comments/Corrections

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