| Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression: whole heart and cellular mechanisms. | |
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MedLine Citation:
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PMID: 22327339 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-02-11 |
Journal Detail:
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Title: Basic research in cardiology Volume: 107 ISSN: 1435-1803 ISO Abbreviation: Basic Res. Cardiol. Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-02-13 Completed Date: 2012-05-23 Revised Date: 2013-04-15 |
Medline Journal Info:
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Nlm Unique ID: 0360342 Medline TA: Basic Res Cardiol Country: Germany |
Other Details:
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Languages: eng Pagination: 247 Citation Subset: IM |
Affiliation:
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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:
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Action Potentials
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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:
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R01 HL070828/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Homeodomain Proteins; 0/Tlx2 protein, mouse |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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