{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:16:41Z","timestamp":1788495401743,"version":"build-2803163510"},"reference-count":74,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","license":[{"start":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T00:00:00Z","timestamp":1723507200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,8,13]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Alterations in the buffering of intracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              , 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 Ca\n              <jats:sup>2+<\/jats:sup>\n              buffering profile in persAF remains obscure. Therefore, we aimed to investigate the intracellular buffering of Ca\n              <jats:sup>2+<\/jats:sup>\n              and its potential arrhythmogenic role in persAF.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Transmembrane Ca\n              <jats:sup>2+<\/jats:sup>\n              fluxes (patch-clamp) and intracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              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\u2013derived cardiac myocytes (iPSC-CMs). Protein levels were quantified by immunoblotting of human atrial tissue and induced pluripotent stem cell\u2013derived cardiac myocytes. Mouse whole heart and atrial electrophysiology were measured on a Langendorff system.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Cytosolic Ca\n              <jats:sup>2+<\/jats:sup>\n              buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca\n              <jats:sup>2+<\/jats:sup>\n              buffers. In agreement, protein levels of selected Ca\n              <jats:sup>2+<\/jats:sup>\n              binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca\n              <jats:sup>2+<\/jats:sup>\n              buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)\u2013mediated knockdown of cTnC (si-cTNC) in atrial iPSC-CM phenocopied the reduced cytosolic Ca\n              <jats:sup>2+<\/jats:sup>\n              buffering observed in persAF. Si-cTnC treated atrial iPSC-CM exhibited a higher predisposition to spontaneous Ca\n              <jats:sup>2+<\/jats:sup>\n              release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca\n              <jats:sup>2+<\/jats:sup>\n              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 Ca\n              <jats:sup>2+<\/jats:sup>\n              buffering and atrial arrhythmogenesis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca\n              <jats:sup>2+<\/jats:sup>\n              buffering in persAF, thereby potentiating the occurrence of spontaneous Ca\n              <jats:sup>2+<\/jats:sup>\n              release events and atrial fibrillation susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in persAF management.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.123.066577","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T09:00:35Z","timestamp":1719219635000},"page":"544-559","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation"],"prefix":"10.1161","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6683-6079","authenticated-orcid":true,"given":"Funsho E.","family":"Fakuade","sequence":"first","affiliation":[{"name":"Cluster of Excellence \u201cMultiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells\u201d (F.E.F., A.L., F.S., F.H., S.E.L., A.E., N.V.), Georg-August-University G\u00f6ttingen, Germany."},{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Hubricht","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9942-9246","authenticated-orcid":true,"given":"Vanessa","family":"M\u00f6ller","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izzatullo","family":"Sobitov","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8855-4870","authenticated-orcid":true,"given":"Aiste","family":"Liutkute","sequence":"additional","affiliation":[{"name":"Cluster of Excellence \u201cMultiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells\u201d (F.E.F., A.L., F.S., F.H., S.E.L., A.E., N.V.), Georg-August-University G\u00f6ttingen, Germany."},{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5060-8610","authenticated-orcid":true,"given":"Yannic","family":"D\u00f6ring","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8554-5186","authenticated-orcid":true,"given":"Fitzwilliam","family":"Seibertz","sequence":"additional","affiliation":[{"name":"Cluster of Excellence \u201cMultiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells\u201d (F.E.F., A.L., F.S., F.H., S.E.L., A.E., N.V.), Georg-August-University G\u00f6ttingen, Germany."},{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5291-196X","authenticated-orcid":true,"given":"Marcus","family":"Gerloff","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3556-5637","authenticated-orcid":true,"given":"Julius Ryan D.","family":"Pronto","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1345-8814","authenticated-orcid":true,"given":"Fereshteh","family":"Haghighi","sequence":"additional","affiliation":[{"name":"Cluster of Excellence \u201cMultiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells\u201d (F.E.F., A.L., F.S., F.H., S.E.L., A.E., N.V.), Georg-August-University G\u00f6ttingen, Germany."},{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Department of Thoracic and Cardiovascular Surgery (F.H., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., G.K.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5148-0997","authenticated-orcid":true,"given":"S\u00f6ren","family":"Brandenburg","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Department of Cardiology and Pneumology (S.B., N.I., W.A.L., S.E.L., A.E.), Heart Research Center G\u00f6ttingen, University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled","family":"Alhussini","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery (K.A., C.B.), University Clinic W\u00fcrzburg, Germany."},{"name":"Comprehensive Heart Failure Center W\u00fcrzburg (K.A., C.B., C.M.), University Clinic W\u00fcrzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadezda","family":"Ignatyeva","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Department of Cardiology and Pneumology (S.B., N.I., W.A.L., S.E.L., A.E.), Heart Research Center G\u00f6ttingen, University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara","family":"Bonhoff","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Kestel","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Institute of Pharmacology and Toxicology (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., Y.B., S.K., F.E.M., N.V.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5583-039X","authenticated-orcid":true,"given":"Aschraf","family":"El-Essawi","sequence":"additional","affiliation":[{"name":"Cluster of Excellence \u201cMultiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells\u201d (F.E.F., A.L., F.S., F.H., S.E.L., A.E., N.V.), Georg-August-University G\u00f6ttingen, Germany."},{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Department of Thoracic and Cardiovascular Surgery (F.H., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., G.K.), University Medical Center G\u00f6ttingen, Germany."},{"name":"Department of Thoracic and Cardiovascular Surgery, Klinikum Braunschweig, Germany (A.E.-E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Fawad","family":"Jebran","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Department of Thoracic and Cardiovascular Surgery (F.H., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., G.K.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Gro\u00dfmann","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Department of Thoracic and Cardiovascular Surgery (F.H., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., G.K.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard C.","family":"Danner","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Department of Thoracic and Cardiovascular Surgery (F.H., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., G.K.), University Medical Center G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3938-6484","authenticated-orcid":true,"given":"Hassina","family":"Baraki","sequence":"additional","affiliation":[{"name":"DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Germany (F.E.F., D.H., V.M., I.S., A.L., Y.D., F.S., M. Gerloff, J.R.D.P., F.H., S.B., N.I., Y.B., S.K., A.E.-E., A.F.J., M. Gro\u00dfmann, B.C.D., H.B., I.K., W.A.L., S.E.L., G.K., A.E., F.E.M., N.V.)."},{"name":"Department of Thoracic and Cardiovascular Surgery (F.H., A.E.-E., A.F.J., M. 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