{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:53:46Z","timestamp":1784328826700,"version":"3.55.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              CaM (calmodulin) is a ubiquitously expressed, multifunctional Ca\n              <jats:sup>2+<\/jats:sup>\n              sensor protein that regulates numerous proteins. Recently, CaM missense variants have been identified in patients with malignant inherited arrhythmias, such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the exact mechanism of CaM-related CPVT in human cardiomyocytes remains unclear. In this study, we sought to investigate the arrhythmogenic mechanism of CPVT caused by a novel variant using human induced pluripotent stem cell (iPSC) models and biochemical assays.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We generated iPSCs from a patient with CPVT bearing\n              <jats:italic>CALM2<\/jats:italic>\n              p.E46K. As comparisons, we used 2 control lines including an isogenic line, and another iPSC line from a patient with long QT syndrome bearing\n              <jats:italic>CALM2<\/jats:italic>\n              p.N98S (also reported in CPVT). Electrophysiological properties were investigated using iPSC-cardiomyocytes. We further examined the RyR2 (ryanodine receptor 2) and Ca\n              <jats:sup>2+<\/jats:sup>\n              affinities of CaM using recombinant proteins.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We identified a novel de novo heterozygous variant,\n              <jats:italic>CALM2<\/jats:italic>\n              p.E46K, in 2 unrelated patients with CPVT accompanied by neurodevelopmental disorders. The E46K-cardiomyocytes exhibited more frequent abnormal electrical excitations and Ca\n              <jats:sup>2+<\/jats:sup>\n              waves than the other lines in association with increased Ca\n              <jats:sup>2+<\/jats:sup>\n              leakage from the sarcoplasmic reticulum via RyR2. Furthermore, the [\n              <jats:sup>3<\/jats:sup>\n              H]ryanodine binding assay revealed that E46K-CaM facilitated RyR2 function especially by activating at low [Ca\n              <jats:sup>2+<\/jats:sup>\n              ] levels. The real-time CaM-RyR2 binding analysis demonstrated that E46K-CaM had a 10-fold increased RyR2 binding affinity compared with wild-type CaM which may account for the dominant effect of the mutant CaM. Additionally, the E46K-CaM did not affect CaM-Ca\n              <jats:sup>2+<\/jats:sup>\n              binding or L-type calcium channel function. Finally, antiarrhythmic agents, nadolol and flecainide, suppressed abnormal Ca\n              <jats:sup>2+<\/jats:sup>\n              waves in E46K-cardiomyocytes.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>We, for the first time, established a CaM-related CPVT iPSC-CM model which recapitulated severe arrhythmogenic features resulting from E46K-CaM dominantly binding and facilitating RyR2. In addition, the findings in iPSC-based drug testing will contribute to precision medicine.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.122.011387","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T10:01:27Z","timestamp":1677837687000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Novel Calmodulin Variant p.E46K Associated With Severe Catecholaminergic Polymorphic Ventricular Tachycardia Produces Robust Arrhythmogenicity in Human Induced Pluripotent Stem Cell\u2013Derived Cardiomyocytes"],"prefix":"10.1161","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1599-7803","authenticated-orcid":true,"given":"Jingshan","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9471-5335","authenticated-orcid":true,"given":"Takeru","family":"Makiyama","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."},{"name":"Department of Community Medicine Supporting System (T. Makiyama), Kyoto University Graduate School of Medicine, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6129-9745","authenticated-orcid":true,"given":"Yuta","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."},{"name":"Department of Bioscience &amp; Genetics (Y. Yamamoto, S.O.), National Cerebral &amp; Cardiovascular Center, Suita, Japan."},{"name":"Now with Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA (Y. Yamamoto)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3992-1889","authenticated-orcid":true,"given":"Takuya","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan (T. Kobayashi, N.K., T. Murayama, T.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisaaki","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Osaka Women\u2019s &amp; Children\u2019s Hospital, Osaka, Japan (H.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9686-2400","authenticated-orcid":true,"given":"Thomas L.","family":"Maurissen","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers (T.L.M., K.W.), Center for iPS Cell Research &amp; Application (CiRA), Kyoto University, Kyoto, Japan."},{"name":"Now with Roche Pharma Research &amp; Early Development, Immunology, Infectious Diseases &amp; Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (T.L.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Wuriyanghai","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."},{"name":"Now with Department of Internal medicine, Peking University Third Hospital, Beijing, China (Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9562-8981","authenticated-orcid":true,"given":"Asami","family":"Kashiwa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-0597","authenticated-orcid":true,"given":"Tomohiko","family":"Imamura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-3962","authenticated-orcid":true,"given":"Takanori","family":"Aizawa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2693-6993","authenticated-orcid":true,"given":"Hai","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8281-8396","authenticated-orcid":true,"given":"Hirohiko","family":"Kohjitani","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misato","family":"Nishikawa","sequence":"additional","affiliation":[{"name":"Department of Cell Growth &amp; Differentiation (M.N., K.C., Y. Yoshida), Center for iPS Cell Research &amp; Application (CiRA), Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4825-5857","authenticated-orcid":true,"given":"Kazuhisa","family":"Chonabayashi","sequence":"additional","affiliation":[{"name":"Department of Hematology &amp; Oncology (K.C.), Kyoto University Graduate School of Medicine, Kyoto, Japan."},{"name":"Department of Cell Growth &amp; Differentiation (M.N., K.C., Y. Yoshida), Center for iPS Cell Research &amp; Application (CiRA), Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3990-4053","authenticated-orcid":true,"given":"Megumi","family":"Fukuyama","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (M.F., K.K., M.H.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Manabe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Asahikawa Kosei General Hospital (H.M.), Asahikawa Medical University, Asahikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouichi","family":"Nakau","sequence":"additional","affiliation":[{"name":"Asahikawa, Japan and Department of Pediatrics (K.N.), Asahikawa Medical University, Asahikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Wada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Sapporo Medical University Hospital, Sapporo, Japan (T.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6125-0789","authenticated-orcid":true,"given":"Koichi","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (M.F., K.K., M.H.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8412-6481","authenticated-orcid":true,"given":"Futoshi","family":"Toyoda","sequence":"additional","affiliation":[{"name":"Department of Physiology (F.T.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5511-9090","authenticated-orcid":true,"given":"Yoshinori","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Cell Growth &amp; Differentiation (M.N., K.C., Y. Yoshida), Center for iPS Cell Research &amp; Application (CiRA), Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1807-672X","authenticated-orcid":true,"given":"Naomasa","family":"Makita","sequence":"additional","affiliation":[{"name":"Omics Research Center (N.M.), National Cerebral &amp; Cardiovascular Center, Suita, Japan."},{"name":"Now with Department of Cardiology, Sapporo Teishinkai Hospital, Sapporo, Japan (N.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2293-1183","authenticated-orcid":true,"given":"Knut","family":"Woltjen","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers (T.L.M., K.W.), Center for iPS Cell Research &amp; Application (CiRA), Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1209-8896","authenticated-orcid":true,"given":"Seiko","family":"Ohno","sequence":"additional","affiliation":[{"name":"Department of Bioscience &amp; Genetics (Y. Yamamoto, S.O.), National Cerebral &amp; Cardiovascular Center, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5005-9698","authenticated-orcid":true,"given":"Nagomi","family":"Kurebayashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan (T. Kobayashi, N.K., T. Murayama, T.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3845-2980","authenticated-orcid":true,"given":"Takashi","family":"Murayama","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan (T. Kobayashi, N.K., T. Murayama, T.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan (T. Kobayashi, N.K., T. Murayama, T.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9029-2339","authenticated-orcid":true,"given":"Minoru","family":"Horie","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (M.F., K.K., M.H.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5665-4076","authenticated-orcid":true,"given":"Takeshi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (J.G., T. Makiyama, Y. Yamamoto, Y.W., A.K., T.I., T.A., H.H., H.K., T. Kimura), Kyoto University Graduate School of Medicine, Kyoto, Japan."},{"name":"Now with Department of Cardiology, Hirakata Kohsai Hospital, Osaka, Japan (T. Kimura)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bb.24.060195.000505"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.12337"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.85.2.247"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(04)74155-7"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.001216"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2014.10.035"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.08.015"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx073"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.04.022"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.303391"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.116.004161"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)37497-0"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euab250"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16643-5"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.019"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06894"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2018.05.028"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2022.08.021"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201611624"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202112869"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.255240"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(02)75286-7"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1374"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.113.000459"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0153851"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.09.013"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311920"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr073"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000036914.12686.28"},{"key":"e_1_3_3_32_2","first-page":"735","article-title":"Ryanodine as a probe for the functional state of the skeletal muscle sarcoplasmic reticulum calcium release channel.","volume":"37","author":"Chu A","year":"1990","unstructured":"Chu, A, Diaz-Munoz, M, Hawkes, MJ, Brush, K, Hamilton, SL. Ryanodine as a probe for the functional state of the skeletal muscle sarcoplasmic reticulum calcium release channel. Mol Pharmacol. 1990;37:735\u2013741.","journal-title":"Mol Pharmacol"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2006.07.011"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.13764"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(84)90501-0"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0164795"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1086\/324565"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.301783"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1377-y"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2018.08.025"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.71.1606"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.09.011"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euu063"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1357-2725(01)00030-9"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.279"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.05.014"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2015.09.029"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.316819"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.134368"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2022.02.008"}],"container-title":["Circulation: Arrhythmia and Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCEP.122.011387","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:25:46Z","timestamp":1715563546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCEP.122.011387"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3]]},"references-count":49,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,3]]}},"alternative-id":["10.1161\/CIRCEP.122.011387"],"URL":"https:\/\/doi.org\/10.1161\/circep.122.011387","relation":{},"ISSN":["1941-3149","1941-3084"],"issn-type":[{"value":"1941-3149","type":"print"},{"value":"1941-3084","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3]]},"assertion":[{"value":"2022-07-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}