Journal
BASIC RESEARCH IN CARDIOLOGY
Volume 107, Issue 2, Pages -Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-012-0247-7
Keywords
Na+/Ca2+ exchanger; Cellular electrophysiology; Transgenic mice; Arrhythmia; Ventricular tachycardia; Sudden cardiac death
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Funding
- Interdisziplinare Medizinische Forschung (IMF) [Po 12 06 07]
- Deutsche Forschungsgemeinschaft (DFG) [Po 1004-1/2, FA 413/3-1]
- IZKF Munster
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The cardiac Na+/Ca2+ exchanger (NCX) generates an inward electrical current during SR-Ca2+ release, thus possibly promoting afterdepolarizations of the action potential younger (AP). We used transgenic mice 12.5 weeks or 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 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 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 Ca2+ handling and/or increased RyR expression.
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