Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression: whole heart and cellular mechanisms.
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.
Division of Experimental and Clinical Electrophysiology, Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany. christian.pott@ukmuenster.de
Christian
C
Pott
Adam
A
Muszynski
Matthias
M
Ruhe
N
N
Bögeholz
Jan S
JS
Schulte
Peter
P
Milberg
Gerold
G
Mönnig
Larissa
L
Fabritz
Joshua I
JI
Goldhaber
Günter
G
Breithardt
Wilhelm
W
Schmitz
Kenneth D
KD
Philipson
Lars
L
Eckardt
Paulus
P
Kirchhof
Frank U
FU
Müller
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004562:Electrocardiography; D006321:Heart / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009924:Organ Culture Techniques
D018398:Homeodomain Proteins; C107836:Tlx2 protein, mouse