Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation
2010 | journal article. A publication with affiliation to the University of Göttingen.
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Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation
Sedej, S.; Heinzel, F. R.; Walther, S.; Dybkova, N.; Wakula, P.; Groborz, J. & Gronau, P. et al. (2010)
Cardiovascular Research, 87(1) pp. 50-59. DOI: https://doi.org/10.1093/cvr/cvq007
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- Authors
- Sedej, Simon; Heinzel, Frank R.; Walther, Stefanie; Dybkova, Nataliya; Wakula, Paulina; Groborz, Jan; Gronau, Phillip; Maier, Lars. S.; Vos, Marc A.; Lai, F. Anthony; Napolitano, Carlo; Priori, Silvia G.; Kockskaemper, Jens; Pieske, Burkert M.
- Abstract
- Mutations in the cardiac ryanodine receptor Ca2+ release channel, RyR2, underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited life-threatening arrhythmia. CPVT is triggered by spontaneous RyR2-mediated sarcoplasmic reticulum (SR) Ca2+ release in response to SR Ca2+ overload during beta-adrenergic stimulation. However, whether elevated SR Ca2+ content-in the absence of protein kinase A activation-affects RyR2 function and arrhythmogenesis in CPVT remains elusive. Isolated murine ventricular myocytes harbouring a human RyR2 mutation (RyR2(R4496C+/-)) associated with CPVT were investigated in the absence and presence of 1 mu mol/L JTV-519 (RyR2 stabilizer) followed by 100 mu mol/L ouabain intervention to increase cytosolic [Na+] and SR Ca2+ load. Changes in membrane potential and intracellular [Ca2+] were monitored with whole-cell patch-clamping and confocal Ca2+ imaging, respectively. At baseline, action potentials (APs), Ca2+ transients, fractional SR Ca2+ release, and SR Ca2+ load were comparable in wild-type (WT) and RyR2(R4496C+/-) myocytes. Ouabain evoked significant increases in diastolic [Ca2+], peak systolic [Ca2+], fractional SR Ca2+ release, and SR Ca2+ content that were quantitatively similar in WT and RyR2(R4496C+/-) myocytes. Ouabain also induced arrhythmogenic events, i.e. spontaneous Ca2+ waves, delayed afterdepolarizations and spontaneous APs, in both groups. However, the ouabain-induced increase in the frequency of arrhythmogenic events was dramatically larger in RyR2(R4496C+/-) when compared with WT myocytes. JTV-519 greatly reduced the frequency of ouabain-induced arrhythmogenic events. The elevation of SR Ca2+ load-in the absence of beta-adrenergic stimulation-is sufficient to increase the propensity for triggered arrhythmias in RyR2(R4496C+/-) cardiomyocytes. Stabilization of RyR2 by JTV-519 effectively reduces these triggered arrhythmias.
- Issue Date
- 2010
- Status
- published
- Publisher
- Oxford Univ Press
- Journal
- Cardiovascular Research
- ISSN
- 0008-6363