{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T18:40:48Z","timestamp":1777315248245,"version":"3.51.4"},"reference-count":76,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Germline\n              <jats:italic toggle=\"yes\">HRAS<\/jats:italic>\n              gain-of-function pathogenic variants cause Costello syndrome (CS). During early childhood, 50% of patients develop multifocal atrial tachycardia, a treatment-resistant tachyarrhythmia of unknown pathogenesis. This study investigated how overactive HRAS activity triggers arrhythmogenesis in atrial-like cardiomyocytes (ACMs) derived from human-induced pluripotent stem cells bearing CS-associated\n              <jats:italic toggle=\"yes\">HRAS<\/jats:italic>\n              variants.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              <jats:italic toggle=\"yes\">HRAS<\/jats:italic>\n              Gly12 mutations were introduced into a human-induced pluripotent stem cells-ACM reporter line. Human-induced pluripotent stem cells were generated from patients with CS exhibiting tachyarrhythmia. Calcium transients and action potentials were assessed in induced pluripotent stem cell-derived ACMs. Automated patch clamping assessed funny currents. HCN inhibitors targeted pacemaker-like activity in mutant ACMs. Transcriptomic data were analyzed via differential gene expression and gene ontology. Immunoblotting evaluated protein expression associated with calcium handling and pacemaker-nodal expression.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              ACMs harboring\n              <jats:italic toggle=\"yes\">HRAS<\/jats:italic>\n              variants displayed higher beating rates compared with healthy controls. The hyperpolarization activated cyclic nucleotide gated potassium channel inhibitor ivabradine and the Na\n              <jats:sub>v<\/jats:sub>\n              1.5 blocker flecainide significantly decreased beating rates in mutant ACMs, whereas voltage-gated calcium channel 1.2 blocker verapamil attenuated their irregularity. Electrophysiological assessment revealed an increased number of pacemaker-like cells with elevated funny current densities among mutant ACMs. Mutant ACMs demonstrated elevated gene expression (ie,\n              <jats:italic toggle=\"yes\">ISL1<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">TBX3<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">TBX18<\/jats:italic>\n              ) related to intracellular calcium homeostasis, heart rate, RAS signaling, and induction of pacemaker-nodal-like transcriptional programming. Immunoblotting confirmed increased protein levels for genes of interest and suppressed MAPK (mitogen-activated protein kinase) activity in mutant ACMs.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              CS-associated gain-of-function\n              <jats:italic toggle=\"yes\">\n                HRAS\n                <jats:sup>G12<\/jats:sup>\n              <\/jats:italic>\n              mutations in induced pluripotent stem cells-derived ACMs trigger transcriptional changes associated with enhanced automaticity and arrhythmic activity consistent with multifocal atrial tachycardia. This is the first human-induced pluripotent stem cell model establishing the mechanistic basis for multifocal atrial tachycardia in CS.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.123.012022","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T10:00:23Z","timestamp":1709114423000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["<i>HRAS<\/i>\n            -Mutant Cardiomyocyte Model of Multifocal Atrial Tachycardia"],"prefix":"10.1161","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4757-379X","authenticated-orcid":true,"given":"Nelson A.","family":"Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Mindich Child Health &amp; Development Institute (N.A.R., N.P., S.N., A.G.A., M.R., B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-3097","authenticated-orcid":true,"given":"Nihir","family":"Patel","sequence":"additional","affiliation":[{"name":"Mindich Child Health &amp; Development Institute (N.A.R., N.P., S.N., A.G.A., M.R., B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0957-1259","authenticated-orcid":true,"given":"Rafael","family":"Dariolli","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences &amp; Systems Biology Center New York (R.D., J.Q.X.G., E.A.S.), Icahn School of Medicine at Mount Sinai, New York, NY."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Ng","sequence":"additional","affiliation":[{"name":"Mindich Child Health &amp; Development Institute (N.A.R., N.P., S.N., A.G.A., M.R., B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5518-6450","authenticated-orcid":true,"given":"Angelika G.","family":"Aleman","sequence":"additional","affiliation":[{"name":"Mindich Child Health &amp; Development Institute (N.A.R., N.P., S.N., A.G.A., M.R., B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7401-0119","authenticated-orcid":true,"given":"Jingqi Q.X.","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences &amp; Systems Biology Center New York (R.D., J.Q.X.G., E.A.S.), Icahn School of Medicine at Mount Sinai, New York, NY."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3176-6570","authenticated-orcid":true,"given":"Hung-Mo","family":"Lin","sequence":"additional","affiliation":[{"name":"Yale Center for Analytical Sciences (YCAS), New Haven, CT (H.-M.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0871-9892","authenticated-orcid":true,"given":"Matthew","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Mindich Child Health &amp; Development Institute (N.A.R., N.P., S.N., A.G.A., M.R., B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4106-589X","authenticated-orcid":true,"given":"Rebecca","family":"Josowitz","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA (R.J.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katia","family":"Sol-Church","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA (K.S.-C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8200-1733","authenticated-orcid":true,"given":"Karen W.","family":"Gripp","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics; Al duPont Hospital for Children\/Nemours, Wilmington, DE (K.W.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-8137","authenticated-orcid":true,"given":"Xianming","family":"Lin","sequence":"additional","affiliation":[{"name":"Leon H. Charney Division of Cardiology, New York University School of Medicine (X.L., G.I.F.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soomin C.","family":"Song","sequence":"additional","affiliation":[{"name":"Ion Lab, Department of Pathology, NYU Langone Health, New York, NY (S.C.S.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2366-8527","authenticated-orcid":true,"given":"Glenn I.","family":"Fishman","sequence":"additional","affiliation":[{"name":"Leon H. Charney Division of Cardiology, New York University School of Medicine (X.L., G.I.F.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7327-8538","authenticated-orcid":true,"given":"Eric A.","family":"Sobie","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences &amp; Systems Biology Center New York (R.D., J.Q.X.G., E.A.S.), Icahn School of Medicine at Mount Sinai, New York, NY."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8527-5027","authenticated-orcid":true,"given":"Bruce D.","family":"Gelb","sequence":"additional","affiliation":[{"name":"Mindich Child Health &amp; Development Institute (N.A.R., N.P., S.N., A.G.A., M.R., B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY."},{"name":"Division of Pediatric Cardiology, Department of Pediatrics (B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY."},{"name":"Department of Genetics and Genomic Sciences (B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl197"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2010.09.002"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2009.04.001"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.0b013e31822dd91f"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1641"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31456"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.05.021"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-091212-153523"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2007.054411"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33857"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2012.07.007"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30065"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196808152790703"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199006143222405"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0735-1097(01)01390-0"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.113.1.203"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2015.06.096"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(89)90275-5"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1023\/a:1020077206796"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccep.2010.10.012"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(85)90964-x"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.42.3.397"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(71)90238-9"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0101316"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.03.006"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.150"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv642"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.314578"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-021-02571-w"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3745"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehs442"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.12.005"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.758623"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200464160-00003"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.33594\/000000119"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5273(90)90187-a"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198501033120105"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1993.tb13815.x"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.187062"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2465"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2019.5135"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.416007"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/pace.13402"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1111\/jce.12081"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2016.03.015"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-019-02149-5"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacep.2021.01.020"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1047951120001195"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02425054"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfy299"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfu312"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kft113"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1505670112"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0081633"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt154"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.3349\/ymj.2011.52.2.211"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38854"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.03.050"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-016-0584-z"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.549642"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000122382.19400.14"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.135038"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.00847"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.12.020"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.10.002"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2009.05.002"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-98580-x"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m213132200"}],"container-title":["Circulation: Arrhythmia and Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCEP.123.012022","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T21:07:40Z","timestamp":1748552860000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCEP.123.012022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4]]},"references-count":76,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1161\/CIRCEP.123.012022"],"URL":"https:\/\/doi.org\/10.1161\/circep.123.012022","relation":{},"ISSN":["1941-3149","1941-3084"],"issn-type":[{"value":"1941-3149","type":"print"},{"value":"1941-3084","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4]]},"assertion":[{"value":"2023-03-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}