Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation

Sedej, Simon, Heinzel, Frank R., Walther, Stefanie, Dybkova, Nataliya, Wakula, Paulina, Groborz, Jan, Gronau, Phillip, Maier, Lars S., Vos, Marc A., Lai, Francis Anthony ORCID: https://orcid.org/0000-0003-2852-8547, Napolitano, Carlo., Priori, Silvia G., Kockskamper, Jens. and Pieske, Burkert 2010. Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation. Cardiovascular Research 87 (1) , pp. 50-59. 10.1093/cvr/cvq007

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Abstract

Aims 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 β-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. Methods and results Isolated murine ventricular myocytes harbouring a human RyR2 mutation (RyR2R4496C+/−) associated with CPVT were investigated in the absence and presence of 1 µmol/L JTV-519 (RyR2 stabilizer) followed by 100 µmol/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 RyR2R4496C+/− 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 RyR2R4496C+/− 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 RyR2R4496C+/− when compared with WT myocytes. JTV-519 greatly reduced the frequency of ouabain-induced arrhythmogenic events. Conclusion The elevation of SR Ca2+ load—in the absence of β-adrenergic stimulation—is sufficient to increase the propensity for triggered arrhythmias in RyR2R4496C+/− cardiomyocytes. Stabilization of RyR2 by JTV-519 effectively reduces these triggered arrhythmias.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Ryanodine receptor; ouabain; delayed after depolarization; sodium; JTV-519
Publisher:	Elsevier
ISSN:	0008-6363
Last Modified:	20 Oct 2022 08:04
URI:	https://orca.cardiff.ac.uk/id/eprint/27121

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