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| Verfasst von: | Fakuade, Funsho E. [VerfasserIn]  |
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| | Hubricht, Dominik [VerfasserIn] |
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| | Möller, Vanessa [VerfasserIn] |
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| | Sobitov, Izzatullo [VerfasserIn] |
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| | Liutkute, Aiste [VerfasserIn] |
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| | Döring, Yannic [VerfasserIn] |
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| | Seibertz, Fitzwilliam [VerfasserIn] |
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| | Gerloff, Marcus [VerfasserIn] |
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| | Pronto, Julius Ryan D. [VerfasserIn] |
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| | Haghighi, Fereshteh [VerfasserIn] |
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| | Brandenburg, Sören [VerfasserIn] |
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| | Alhussini, Khaled [VerfasserIn] |
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| | Ignatyeva, Nadezda [VerfasserIn] |
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| | Bonhoff, Yara [VerfasserIn] |
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| | Kestel, Stefanie [VerfasserIn] |
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| | El-Essawi, Aschraf [VerfasserIn] |
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| | Jebran, Ahmad Fawad [VerfasserIn] |
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| | Großmann, Marius [VerfasserIn] |
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| | Danner, Bernhard C. [VerfasserIn] |
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| | Baraki, Hassina [VerfasserIn] |
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| | Schmidt, Constanze [VerfasserIn] |
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| | Sossalla, Samuel [VerfasserIn] |
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| | Kutschka, Ingo [VerfasserIn] |
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| | Bening, Constanze [VerfasserIn] |
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| | Maack, Christoph [VerfasserIn] |
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| | Linke, Wolfgang A. [VerfasserIn] |
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| | Heijman, Jordi [VerfasserIn] |
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| | Lehnart, Stephan Elmar [VerfasserIn] |
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| | Kensah, George [VerfasserIn] |
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| | Ebert, Antje [VerfasserIn] |
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| | Mason, Fleur E. [VerfasserIn] |
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| | Voigt, Niels [VerfasserIn] |
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| Titel: | Impaired intracellular calcium buffering contributes to the arrhythmogenic substrate in atrial myocytes from patients with atrial fibrillation |
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| Verf.angabe: | Funsho E. Fakuade, PhD, Dominik Hubricht, Vanessa Möller, Izzatullo Sobitov, MSc, Aiste Liutkute, MSc, Yannic Döring, MSc, Fitzwilliam Seibertz, PhD, Marcus Gerloff, Julius Ryan D. Pronto, PhD, Fereshteh Haghighi, PhD, Sören Brandenburg, MD, Khaled Alhussini, MD, Nadezda Ignatyeva, PhD, Yara Bonhoff, Stefanie Kestel, Aschraf El-Essawi, MD, Ahmad Fawad Jebran, MD, Marius Großmann, MD, Bernhard C. Danner, MD, Hassina Baraki, MD, Constanze Schmidt, MD, Samuel Sossalla, MD, Ingo Kutschka, MD, Constanze Bening, MD, Christoph Maack, MD, Wolfgang A. Linke, PhD, Jordi Heijman, PhD, Stephan E. Lehnart, MD, George Kensah, PhD, Antje Ebert, PhD, Fleur E. Mason, PhD, and Niels Voigt, MD |
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| E-Jahr: | 2024 |
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| Jahr: | 24 June 2024 |
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| Umfang: | 16 S. |
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| Illustrationen: | Illustrationen |
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| Fussnoten: | Gesehen am 17.04.2025 |
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| Titel Quelle: | Enthalten in: Circulation |
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| Ort Quelle: | Philadelphia, Pa. : Lippincott, Williams & Wilkins, 1950 |
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| Jahr Quelle: | 2024 |
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| Band/Heft Quelle: | 150(2024), 7, Seite 544-559 |
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| ISSN Quelle: | 1524-4539 |
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| Abstract: | BACKGROUND: - Alterations in the buffering of intracellular Ca2+, for which myofilament proteins play a key role, have been shown to promote cardiac arrhythmia. It is interesting that although studies report atrial myofibrillar degradation in patients with persistent atrial fibrillation (persAF), the intracellular Ca2+ buffering profile in persAF remains obscure. Therefore, we aimed to investigate the intracellular buffering of Ca2+ and its potential arrhythmogenic role in persAF. - METHODS: - Transmembrane Ca2+ fluxes (patch-clamp) and intracellular Ca2+ signaling (fluo-3-acetoxymethyl ester) were recorded simultaneously in myocytes from right atrial biopsies of sinus rhythm (Ctrl) and patients with persAF, alongside human atrial subtype induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Protein levels were quantified by immunoblotting of human atrial tissue and induced pluripotent stem cell-derived cardiac myocytes. Mouse whole heart and atrial electrophysiology were measured on a Langendorff system. - RESULTS: - Cytosolic Ca2+ buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca2+ buffers. In agreement, protein levels of selected Ca2+ binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca2+ buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)-mediated knockdown of cTnC (si-cTNC) in atrial iPSC-CM phenocopied the reduced cytosolic Ca2+ buffering observed in persAF. Si-cTnC treated atrial iPSC-CM exhibited a higher predisposition to spontaneous Ca2+ release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca2+ buffering using blebbistatin in an ex vivo mouse whole heart model increased vulnerability to tachypacing-induced atrial arrhythmia, validating the direct mechanistic link between impaired cytosolic Ca2+ buffering and atrial arrhythmogenesis. - CONCLUSIONS: - Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca2+ buffering in persAF, thereby potentiating the occurrence of spontaneous Ca2+ release events and atrial fibrillation susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in persAF management. |
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| DOI: | doi:10.1161/CIRCULATIONAHA.123.066577 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext: https://doi.org/10.1161/CIRCULATIONAHA.123.066577 |
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| | Volltext: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.066577 |
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| | DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.066577 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| K10plus-PPN: | 1923190679 |
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| Verknüpfungen: | → Zeitschrift |
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Impaired intracellular calcium buffering contributes to the arrhythmogenic substrate in atrial myocytes from patients with atrial fibrillation / Fakuade, Funsho E. [VerfasserIn]; 24 June 2024 (Online-Ressource)
