{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:54:56Z","timestamp":1791806096218,"version":"4.3.4"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2019,10,15]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Atrial fibrillation often occurs in the setting of hypertension and associated atrial dilation with pathologically increased cardiomyocyte stretch. In the setting of atrial dilation, mechanoelectric feedback has been linked to the development of ectopic beats that trigger paroxysmal atrial fibrillation mainly originating from pulmonary veins (\n              <jats:styled-content style=\"fixed-case\">PVs<\/jats:styled-content>\n              ). However, the precise mechanisms remain poorly understood.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We identify mechanosensitive, swelling\u2010activated chloride ion channels (\n              <jats:styled-content style=\"fixed-case\">\n                <jats:italic>I<\/jats:italic>\n                <jats:sub>C<\/jats:sub>\n              <\/jats:styled-content>\n              <jats:sub>l,swell<\/jats:sub>\n              ) as a crucial component of the caveolar mechanosensitive complex in rat and human cardiomyocytes. In vitro optical mapping of rat\n              <jats:styled-content style=\"fixed-case\">PV<\/jats:styled-content>\n              , single rat\n              <jats:styled-content style=\"fixed-case\">PV<\/jats:styled-content>\n              , and human cardiomyocyte patch clamp studies showed that stretch\u2010induced activation of\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Cl,swell<\/jats:sub>\n              leads to membrane depolarization and decreased action potential amplitude, which trigger conduction discontinuities and both ectopic and reentrant activities within the\n              <jats:styled-content style=\"fixed-case\">PV<\/jats:styled-content>\n              . Reverse transcription quantitative polymerase chain reaction, immunofluorescence, and coimmunoprecipitation studies showed that\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Cl,swell<\/jats:sub>\n              likely consists of at least 2 components produced by mechanosensitive ClC\u20103 (chloride channel\u20103) and\n              <jats:styled-content style=\"fixed-case\">SWELL<\/jats:styled-content>\n              1 (also known as LRRC8A [leucine rich repeat containing protein 8A]) chloride channels, which form a macromolecular complex with caveolar scaffolding protein Cav3 (caveolin 3). Downregulation of Cav3 protein expression and disruption of caveolae structures during chronic hypertension in spontaneously hypertensive rats facilitates activation of\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Cl,swell<\/jats:sub>\n              and increases\n              <jats:styled-content style=\"fixed-case\">PV<\/jats:styled-content>\n              sensitivity to stretch 10\u2010 to 50\u2010fold, promoting the development of atrial fibrillation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Our findings identify caveolae\u2010mediated activation of mechanosensitive\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Cl,swell<\/jats:sub>\n              as a critical cause of\n              <jats:styled-content style=\"fixed-case\">PV<\/jats:styled-content>\n              ectopic beats that can initiate atrial arrhythmias including atrial fibrillation. This mechanism is exacerbated in the setting of chronically elevated blood pressures.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.119.012748","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T09:02:22Z","timestamp":1570698142000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":48,"title":["Caveolae\u2010Mediated Activation of Mechanosensitive Chloride Channels in Pulmonary Veins Triggers Atrial Arrhythmogenesis"],"prefix":"10.1161","volume":"8","author":[{"given":"Yuriy V.","family":"Egorov","sequence":"first","affiliation":[{"name":"Laboratory of Heart Electrophysiology Cardiology Research Centre Moscow Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonid","family":"Tyan","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evi","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary D.","family":"Piro","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan J.","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"},{"name":"Department of Pediatrics Pediatric Cardiology University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rylie","family":"Lodin","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric G.","family":"Schmuck","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amish N.","family":"Raval","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carter J.","family":"Ralphe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Pediatric Cardiology University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Kamp","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonid V.","family":"Rosenshtraukh","sequence":"additional","affiliation":[{"name":"Laboratory of Heart Electrophysiology Cardiology Research Centre Moscow Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey V.","family":"Glukhov","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Medicine University of Wisconsin\u2010Madison School of Medicine and Public Health Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2009"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1994.03510350050036"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199809033391003"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.108.847962"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2016.08.026"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6107(03)00011-7"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.114.001894"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2006.089359"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2008.02.008"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008312"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.09.014"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5320(78)90051-5"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00198.2015"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2122"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1997.273.2.C541"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.674945"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00676-4"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aac4296"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/jce.12738"},{"key":"e_1_3_2_21_2","first-page":"e54773","article-title":"High\u2010resolution optical mapping of the mouse sino\u2010atrial node","volume":"118","author":"Lang D","year":"2016","unstructured":"Lang D, Glukhov AV. High\u2010resolution optical mapping of the mouse sino\u2010atrial node. J Vis Exp. 2016;118:e54773.","journal-title":"J Vis Exp"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.192237"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000058461.86339.7E"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.84.2.157"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.046417"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.04.008"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.07.003"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.024"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M608251200"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.4995"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.08.014"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000257123.95372.ab"},{"key":"e_1_3_2_33_2","first-page":"233a","article-title":"Swelling\u2010activated cl current, ICl, swell, is chronically activated in diseased human atrial myocytes","volume":"84","author":"Patel DG","year":"2003","unstructured":"Patel DG, Higgins RS, Baumgarten CM. Swelling\u2010activated cl current, ICl, swell, is chronically activated in diseased human atrial myocytes. Biophys J. 2003;84:233a.","journal-title":"Biophys J"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616393114"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.12.031"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2011.06.002"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00758.2006"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1981.241.3.C121"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrcr.2018.07.002"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.12062SC"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphs.2016.12.006"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(08)80035-1"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0072416"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408288"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.811877"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.305043"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.11.002"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-002-0948-0"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.119.012748","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T11:32:06Z","timestamp":1715599926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.119.012748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,15]]},"references-count":47,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2019,10,15]]}},"alternative-id":["10.1161\/JAHA.119.012748"],"URL":"https:\/\/doi.org\/10.1161\/jaha.119.012748","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,15]]},"assertion":[{"value":"2019-07-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-10-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e012748"}}