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Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca2+ exchanger overexpression: whole heart and cellular mechanisms

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Abstract

The cardiac Na+/Ca2+ exchanger (NCX) generates an inward electrical current during SR-Ca2+ 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 (Kv) 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 Ca2+ release (sCR), Ca2+ 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 Ca2+-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 KV. 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 Ca2+ handling and/or increased RyR expression.

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Acknowledgments

We thank Christiane Pott, PhD, for advice on statistical analysis of our results. This study was supported by Interdisziplinäre Medizinische Forschung (IMF Po 12 06 07, to Christian Pott), a returnee fellowship of the Deutsche Forschungsgemeinschaft (DFG Po 1004-1/2 to Christian Pott), and by IZKF Münster (core unit CarTel to Paulus Kirchhof) and the Deutsche Forschungsgesmeinschaft DFG FA 413/3-1 (to Larissa Fabritz). Lars Eckardt holds the Osypka Professorship for Clinical and Experimental Rhythmology. This work contains data from the MD theses of Adam Muszynski and Matthias Ruhe.

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  1. Larissa Fabritz & Paulus Kirchhof

    Present address: Centre for Cardiovascular Sciences, University of Birmingham, Birmingham, UK

Authors and Affiliations

  1. Division of Experimental and Clinical Electrophysiology, Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany

    Christian Pott, Adam Muszynski, Matthias Ruhe, N. Bögeholz, Peter Milberg, Gerold Mönnig, Günter Breithardt & Lars Eckardt

  2. Institute of Pharmacology and Toxicology, University Hospital Münster, Münster, Germany

    Adam Muszynski, Matthias Ruhe, N. Bögeholz, Jan S. Schulte, Wilhelm Schmitz & Frank U. Müller

  3. Department of Cardiology, Cedars Sinai, Los Angeles, CA, USA

    Joshua I. Goldhaber

  4. Cardiovascular Research Laboratories and the Department of Physiology, University of California Los Angeles (UCLA), Los Angeles, CA, USA

    Kenneth D. Philipson

  5. Abteilung für Rhythmologie, Department für Kardiologie und Angiologie, Universitätsklinikum Münster, Albert-Schweitzer Str. 33, 48149, Münster, Germany

    Christian Pott

  6. Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany

    Larissa Fabritz & Paulus Kirchhof

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  1. Christian Pott
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Pott, C., Muszynski, A., Ruhe, M. et al. Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca2+ exchanger overexpression: whole heart and cellular mechanisms. Basic Res Cardiol 107, 247 (2012). https://doi.org/10.1007/s00395-012-0247-7

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