Multiphoton Imaging of Ca<sup>2+</sup> Instability in Acute Myocardial Slices from a <i>RyR2</i><sup>R2474S</sup> Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (<i>RyR</i>2), the sarcoplasmic reticulum (SR) Ca<sup>2+</sup> release channel in cardiomyocytes. Pathogenetic mut...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/10/13/2821 |
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| author | Giulia Borile Tania Zaglia Stephan E. Lehnart Marco Mongillo |
| author_facet | Giulia Borile Tania Zaglia Stephan E. Lehnart Marco Mongillo |
| author_sort | Giulia Borile |
| collection | DOAJ |
| description | Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (<i>RyR</i>2), the sarcoplasmic reticulum (SR) Ca<sup>2+</sup> release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca<sup>2+</sup> release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca<sup>2+</sup> 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 Ca<sup>2+</sup> signals in isolated cardiomyocytes and in acute thick ventricular slices of <i>RyR2</i><sup>R2474S</sup> knock-in mice, electrically paced at different rates (1–5 Hz), to identify arrhythmogenic Ca<sup>2+</sup> dynamics, from the sub- to the multicellular perspective. In both models, <i>RyR2</i><sup>R2474S</sup> cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca<sup>2+</sup> alternans and synchronous Ca<sup>2+</sup> release events in neighboring cardiomyocytes. Analysis of Ca<sup>2+</sup> 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. |
| first_indexed | 2024-03-09T04:52:49Z |
| format | Article |
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| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-09T04:52:49Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Clinical Medicine |
| spelling | doaj.art-4a6cf5e892d1476fa003a6291ef20a622023-12-03T13:08:44ZengMDPI AGJournal of Clinical Medicine2077-03832021-06-011013282110.3390/jcm10132821Multiphoton Imaging of Ca<sup>2+</sup> Instability in Acute Myocardial Slices from a <i>RyR2</i><sup>R2474S</sup> Murine Model of Catecholaminergic Polymorphic Ventricular TachycardiaGiulia Borile0Tania Zaglia1Stephan E. Lehnart2Marco Mongillo3Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, ItalyDepartment of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, ItalyHeart Research Heart Research Center Göttingen, Cellular Biophysics and Translational Cardi-Ology Section, Department of Cardiology & Pulmonology, University Medical Center Göttingen, 37073 Göttingen, GermanyDepartment of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, ItalyCatecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (<i>RyR</i>2), the sarcoplasmic reticulum (SR) Ca<sup>2+</sup> release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca<sup>2+</sup> release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca<sup>2+</sup> 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 Ca<sup>2+</sup> signals in isolated cardiomyocytes and in acute thick ventricular slices of <i>RyR2</i><sup>R2474S</sup> knock-in mice, electrically paced at different rates (1–5 Hz), to identify arrhythmogenic Ca<sup>2+</sup> dynamics, from the sub- to the multicellular perspective. In both models, <i>RyR2</i><sup>R2474S</sup> cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca<sup>2+</sup> alternans and synchronous Ca<sup>2+</sup> release events in neighboring cardiomyocytes. Analysis of Ca<sup>2+</sup> 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.https://www.mdpi.com/2077-0383/10/13/2821catecholaminergic polymorphic ventricular tachycardiaarrhythmiasryanodine receptor 2Ca<sup>2+</sup> imagingcardiomyocytescardiac slices |
| spellingShingle | Giulia Borile Tania Zaglia Stephan E. Lehnart Marco Mongillo Multiphoton Imaging of Ca<sup>2+</sup> Instability in Acute Myocardial Slices from a <i>RyR2</i><sup>R2474S</sup> Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia Journal of Clinical Medicine catecholaminergic polymorphic ventricular tachycardia arrhythmias ryanodine receptor 2 Ca<sup>2+</sup> imaging cardiomyocytes cardiac slices |
| title | Multiphoton Imaging of Ca<sup>2+</sup> Instability in Acute Myocardial Slices from a <i>RyR2</i><sup>R2474S</sup> Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia |
| title_full | Multiphoton Imaging of Ca<sup>2+</sup> Instability in Acute Myocardial Slices from a <i>RyR2</i><sup>R2474S</sup> Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia |
| title_fullStr | Multiphoton Imaging of Ca<sup>2+</sup> Instability in Acute Myocardial Slices from a <i>RyR2</i><sup>R2474S</sup> Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia |
| title_full_unstemmed | Multiphoton Imaging of Ca<sup>2+</sup> Instability in Acute Myocardial Slices from a <i>RyR2</i><sup>R2474S</sup> Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia |
| title_short | Multiphoton Imaging of Ca<sup>2+</sup> Instability in Acute Myocardial Slices from a <i>RyR2</i><sup>R2474S</sup> Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia |
| title_sort | multiphoton imaging of ca sup 2 sup instability in acute myocardial slices from a i ryr2 i sup r2474s sup murine model of catecholaminergic polymorphic ventricular tachycardia |
| topic | catecholaminergic polymorphic ventricular tachycardia arrhythmias ryanodine receptor 2 Ca<sup>2+</sup> imaging cardiomyocytes cardiac slices |
| url | https://www.mdpi.com/2077-0383/10/13/2821 |
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