{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:20:30Z","timestamp":1762867230670,"version":"3.37.3"},"reference-count":84,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2017,10,29]],"date-time":"2017-10-29T00:00:00Z","timestamp":1509235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004815","name":"Isaac Newton Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004815","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/15\/12\/31280","PG\/14\/79\/31102"],"award-info":[{"award-number":["PG\/15\/12\/31280","PG\/14\/79\/31102"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M001288\/1"],"award-info":[{"award-number":["MR\/M001288\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["105727\/Z\/14\/Z"],"award-info":[{"award-number":["105727\/Z\/14\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:sec><jats:title>New Findings<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p><jats:bold>What is the central question of this study?<\/jats:bold><\/jats:p>\n<jats:p>Can we experimentally replicate atrial pro\u2010arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis?<\/jats:p>\n<\/jats:list-item>\n<jats:list-item><jats:p><jats:bold>What is the main finding and its importance?<\/jats:bold><\/jats:p>\n<jats:p>Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age\u2010dependent atrial arrhythmic phenotypes in Langendorff\u2010perfused murine <jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro\u2010arrhythmic changes in chronic metabolic disease.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12\u201316\u00a0week) and aged (&gt;52\u00a0week) wild\u2010type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)\u2010deficient (<jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) Langendorff\u2010perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole\u2010heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged <jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (d<jats:italic>V<\/jats:italic>\/d<jats:italic>t<\/jats:italic><jats:sub>max<\/jats:sub>) were reduced in <jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hearts. Action potential latencies were increased by the <jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD<jats:sub>90<\/jats:sub>) were shorter in <jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and <jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hearts. Limiting slopes of restitution curves of APD<jats:sub>90<\/jats:sub> against diastolic interval were correspondingly reduced interactively by <jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> genotype and age. In contrast, reduced AP wavelengths were associated with <jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged <jats:italic>Pgc1\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here.<\/jats:p><\/jats:sec>","DOI":"10.1113\/ep086589","type":"journal-article","created":{"date-parts":[[2017,9,28]],"date-time":"2017-09-28T15:47:56Z","timestamp":1506613676000},"page":"1619-1634","source":"Crossref","is-referenced-by-count":13,"title":["Pro\u2010arrhythmic atrial phenotypes in incrementally paced murine <i>Pgc1\u03b2<\/i><sup>\u2212\/\u2212<\/sup> hearts: effects of age"],"prefix":"10.1113","volume":"102","author":[{"given":"Haseeb","family":"Valli","sequence":"first","affiliation":[{"name":"Physiological Laboratory University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiraz","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Physiological Laboratory University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-1883","authenticated-orcid":false,"given":"James A.","family":"Fraser","sequence":"additional","affiliation":[{"name":"Physiological Laboratory University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6232-388X","authenticated-orcid":false,"given":"Kamalan","family":"Jeevaratnam","sequence":"additional","affiliation":[{"name":"Physiological Laboratory University of Cambridge  Cambridge UK"},{"name":"PU\u2010RCSI School of Medicine Perdana University  Serdang Selangor Darul Ehsan Malaysia"},{"name":"Faculty of Health and Medical Sciences University of Surrey  Guildford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9553-6112","authenticated-orcid":false,"given":"Christopher L.\u2010H.","family":"Huang","sequence":"additional","affiliation":[{"name":"Physiological Laboratory University of Cambridge  Cambridge UK"},{"name":"Department of Biochemistry University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,10,29]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2014-306238"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25371"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2011.04.005"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2005.03.002"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.96.9.3157"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.108.817320"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(99)00178-9"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.11.011"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.3181\/0706-RM-155"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvn274"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.77.6.1166"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(90)90450-3"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27794"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)68422-4"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201110617"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12114"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2828(78)90364-4"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.045104"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.285.18.2370"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.2008.01865.x"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00041"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2010.02.013"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr155"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2007.00956.x"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1586\/erc.11.112"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4157(77)90003-X"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00007.2016"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00234"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0079-6107(76)90007-9"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1109\/TBME.2014.2363669"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(02)01760-6"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2013.00154"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt141"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12006"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2006.04.026"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.123.2.539"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1095-6433(02)00124-1"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0040369"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1101\/sqb.2011.76.011965"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/1440-1681.12751"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2005.05.004"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2003.07.002"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.220673"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.197277"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq334"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.55.4.545"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00034.2011"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2011-300953"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00039.2012"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2013.254938"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.2010.02138.x"},{"key":"e_1_2_5_54_1","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.3909\/ricm0693","article-title":"Cardiometabolic risk factors and atrial fibrillation","volume":"14","author":"Menezes AR","year":"2013","journal-title":"Rev Cardiovasc Med"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.595140"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi9912600"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.785626"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-0939"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-015-1750-0"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1968.25.2.191"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.1995.tb06966.x"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.300158"},{"volume-title":"R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna","year":"2015","author":"R Core Team","key":"e_1_2_5_63_1"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-007-0255-x"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-007-0217-3"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-007-0327-y"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-007-0326-z"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39740"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.113.000311"},{"key":"e_1_2_5_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.02.029"},{"key":"e_1_2_5_71_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.184457"},{"key":"e_1_2_5_72_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.121921"},{"key":"e_1_2_5_73_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.2001.00844.x"},{"key":"e_1_2_5_74_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-006-0132-z"},{"key":"e_1_2_5_75_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.221911"},{"key":"e_1_2_5_76_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C400025200"},{"key":"e_1_2_5_77_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.744466"},{"key":"e_1_2_5_78_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.529545"},{"key":"e_1_2_5_79_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-98141-3"},{"key":"e_1_2_5_80_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb737"},{"key":"e_1_2_5_81_1","first-page":"2302","article-title":"[Electrophysiological properties and mechanism of aging for the susceptibility of left atrium to arrhythmogenesis in rabbits]","volume":"95","author":"Yang S","year":"2015","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"e_1_2_5_82_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.4.408"},{"key":"e_1_2_5_83_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq229"},{"key":"e_1_2_5_84_1","doi-asserted-by":"publisher","DOI":"10.1111\/jce.12015"},{"key":"e_1_2_5_85_1","doi-asserted-by":"publisher","DOI":"10.2147\/CLEP.S47385"}],"container-title":["Experimental Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FEP086589","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/EP086589","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T16:12:39Z","timestamp":1696176759000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/EP086589"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,29]]},"references-count":84,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2017,12]]}},"alternative-id":["10.1113\/EP086589"],"URL":"https:\/\/doi.org\/10.1113\/ep086589","archive":["Portico"],"relation":{},"ISSN":["0958-0670","1469-445X"],"issn-type":[{"type":"print","value":"0958-0670"},{"type":"electronic","value":"1469-445X"}],"subject":[],"published":{"date-parts":[[2017,10,29]]}}}