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SHR Neuro Cancer Cardio Lipid Metab Microb

Fakuade, FE; Hubricht, D; Möller, V; Sobitov, I; Liutkute, A; Döring, Y; Seibertz, F; Gerloff, M; Pronto, JRD; Haghighi, F; Brandenburg, S; Alhussini, K; Ignatyeva, N; Bonhoff, Y; Kestel, S; El-Essawi, A; Jebran, AF; Großmann, M; Danner, BC; Baraki, H; Schmidt, C; Sossalla, S; Kutschka, I; Bening, C; Maack, C; Linke, WA; Heijman, J; Lehnart, SE; Kensah, G; Ebert, A; Mason, FE; Voigt, N.
Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation.
Circulation. 2024; 150(7): 544-559. Doi: 10.1161/CIRCULATIONAHA.123.066577 [OPEN ACCESS]
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Heijman Jordi
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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.
Find related publications in this database (using NLM MeSH Indexing)
Atrial Fibrillation - metabolism, pathology, physiopathology
Humans - administration & dosage
Myocytes, Cardiac - metabolism, pathology
Animals - administration & dosage
Calcium - metabolism
Heart Atria - metabolism, pathology
Mice - administration & dosage
Male - administration & dosage
Induced Pluripotent Stem Cells - metabolism
Female - administration & dosage
Calcium Signaling - administration & dosage
Middle Aged - administration & dosage
Aged - administration & dosage
Action Potentials - administration & dosage

Find related publications in this database (Keywords)
atrial fibrillation
atrial remodeling
calcium signaling
cardiac arrhythmias
electrophysiology
ion channels
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