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Multiphoton Imaging of Ca2+ Instability in Acute Myocardial Slices from a RyR2R2474S Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia
- Source :
- Journal of Clinical Medicine, Vol 10, Iss 2821, p 2821 (2021), Journal of Clinical Medicine, Volume 10, Issue 13
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca2+ release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca2+ dynamics in single cells from murine CPVT models has increased our understanding of the disease pathogenesis, questions remain on the mechanisms triggering the lethal arrhythmias at tissue level. Here, we combined subcellular analysis of Ca2+ signals in isolated cardiomyocytes and in acute thick ventricular slices of RyR2R2474S knock-in mice, electrically paced at different rates (1–5 Hz), to identify arrhythmogenic Ca2+ dynamics, from the sub- to the multicellular perspective. In both models, RyR2R2474S cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca2+ alternans and synchronous Ca2+ release events in neighboring cardiomyocytes. Analysis of Ca2+ dynamics in multiple cells in the tissue suggests that SCRs beget SCRs in contiguous cells, overcoming the protective electrotonic myocardial coupling, and potentially generating arrhythmia triggering foci. We suggest that intercellular interactions may underscore arrhythmic propensity in CPVT hearts with ‘leaky’ RyR2.
- Subjects :
- Diastole
cardiomyocytes
030204 cardiovascular system & hematology
Catecholaminergic polymorphic ventricular tachycardia
Ryanodine receptor 2
Article
03 medical and health sciences
0302 clinical medicine
Ca2+ imaging
ryanodine receptor 2
medicine
cardiac slices
Multiphoton imaging
030304 developmental biology
0303 health sciences
catecholaminergic polymorphic ventricular tachycardia
business.industry
Endoplasmic reticulum
General Medicine
arrhythmias
medicine.disease
Cell biology
Coupling (electronics)
Murine model
cardiovascular system
Medicine
business
Intracellular
Subjects
Details
- Language :
- English
- ISSN :
- 20770383
- Volume :
- 10
- Issue :
- 2821
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Medicine
- Accession number :
- edsair.doi.dedup.....06c803fe98d668e5fef89d6741a01404