{"id":14738,"date":"2024-07-02T09:34:08","date_gmt":"2024-07-02T09:34:08","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=14738"},"modified":"2024-07-02T09:34:08","modified_gmt":"2024-07-02T09:34:08","slug":"2024-impaired-intracellular-calcium-buffering-contributes-to-the-arrhythmogenic-substrate-in-atrial-myocytes-from-patients-with-atrial-fibrillation","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2024-impaired-intracellular-calcium-buffering-contributes-to-the-arrhythmogenic-substrate-in-atrial-myocytes-from-patients-with-atrial-fibrillation\/","title":{"rendered":"2024 &#8211; Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation"},"content":{"rendered":"<section id=\"abs-sec-1\">Background:<\/p>\n<p role=\"paragraph\">Alterations in the buffering of intracellular Ca<sup>2+<\/sup>, 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<sup>2+<\/sup>\u00a0buffering profile in persAF remains obscure. Therefore, we aim to investigate the intracellular buffering of calcium and its potential arrhythmogenic role in persAF.<\/p>\n<\/section>\n<p>Methods:<\/p>\n<div role=\"paragraph\">Simultaneous transmembrane fluxes (patch-clamp) and intracellular Ca<sup>2+<\/sup>\u00a0signaling (fluo-3-acetoxymethyl ester) were recorded in myocytes from right atrial biopsies of sinus rhythm (control) 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 was measured on a Langendorff system.<\/div>\n<p>Results:<\/p>\n<div role=\"paragraph\">Cytosolic Ca<sup>2+<\/sup>\u00a0buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca<sup>2+<\/sup>\u00a0buffers. In agreement, protein levels of selected Ca<sup>2+<\/sup>\u00a0binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca<sup>2+<\/sup>\u00a0buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)\u2013mediated knockdown of cTnC in induced pluripotent stem cell\u2013derived cardiac myocytes (si-cTnC) phenocopied the reduced cytosolic Ca<sup>2+<\/sup>\u00a0buffering observed in persAF. Si-cTnC induced pluripotent stem cell\u2013derived cardiac myocytes exhibited a higher predisposition to spontaneous Ca<sup>2+<\/sup>\u00a0release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca<sup>2+<\/sup>\u00a0buffering 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<sup>2+<\/sup>\u00a0buffering and atrial arrhythmogenesis.<\/div>\n<section id=\"abs-sec-4\">Conclusions:<\/p>\n<p role=\"paragraph\">Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca<sup>2+<\/sup>\u00a0buffering in persAF, thereby potentiating the occurrence of spontaneous Ca<sup>2+<\/sup>\u00a0release events and AF susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in AF management.<\/p>\n<\/section>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,77],"therapeutic_areas":[143],"target_categories":[],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-14738","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","application_areas-cell-ipscs-profiling","therapeutic_areas-assay-development-and-validation"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/14738","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=14738"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=14738"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=14738"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=14738"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=14738"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=14738"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=14738"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=14738"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=14738"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}