Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression: whole heart and cellular mechanisms

• Published in: Basic research in cardiology 2012-03, Vol.107 (2), p.247-247
• Main Authors: Pott, Christian, Muszynski, Adam, Ruhe, Matthias, Bögeholz, N, Schulte, Jan S, Milberg, Peter, Mönnig, Gerold, Fabritz, Larissa, Goldhaber, Joshua I, Breithardt, Günter, Schmitz, Wilhelm, Philipson, Kenneth D, Eckardt, Lars, Kirchhof, Paulus, Müller, Frank U
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; Blotting, Western; Disease Models, Animal; Electrocardiography; Heart - physiology; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Mice; Myocytes, Cardiac - metabolism; Organ Culture Techniques
• ISSN: 1435-1803
• DOI: 10.1007/s00395-012-0247-7

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.