{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:07:30Z","timestamp":1792674450347,"version":"4.5.0"},"reference-count":44,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2018,8,3]],"date-time":"2018-08-03T00:00:00Z","timestamp":1533254400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RG\/17\/3\/32774"],"award-info":[{"award-number":["RG\/17\/3\/32774"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["Gilliam Fellowship"],"award-info":[{"award-number":["Gilliam Fellowship"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["16GRNT30960054"],"award-info":[{"award-number":["16GRNT30960054"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM099608"],"award-info":[{"award-number":["T32GM099608"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL093056"],"award-info":[{"award-number":["R01HL093056"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL111600"],"award-info":[{"award-number":["R01HL111600"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Ageing results in changes to cardiac electrophysiology, Ca<jats:sup>2+<\/jats:sup> handling, and \u03b2\u2010adrenergic responsiveness.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Sympathetic neurodegeneration also occurs with age, yet detailed action potential and Ca<jats:sup>2+<\/jats:sup> handling responses to physiological sympathetic nerve stimulation (SNS) in the aged heart have not been assessed.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Optical mapping in mouse hearts with intact sympathetic innervation revealed reduced responsiveness to SNS in the aged atria (assessed by heart rate) and aged ventricles (assessed by action potentials and Ca<jats:sup>2+<\/jats:sup> transients).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Sympathetic nerve density and noradrenaline content were reduced in aged ventricles, but noradrenaline content was preserved in aged atria.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results demonstrate that reduced responsiveness to SNS in the atria may be primarily due to decreased \u03b2\u2010adrenergic receptor responsiveness, whereas reduced responsiveness to SNS in the ventricles may be primarily due to neurodegeneration.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The objective of this study was to determine how age\u2010related changes in sympathetic structure and function impact cardiac electrophysiology and intracellular Ca<jats:sup>2+<\/jats:sup> handling. Innervated hearts from young (3\u20104\u00a0months, YWT, <jats:italic>n\u00a0=\u00a0<\/jats:italic>10) and aged (20\u201024\u00a0months, AGED, <jats:italic>n\u00a0=\u00a0<\/jats:italic>11) female mice (C57Bl6) were optically mapped using the voltage (<jats:italic>V<\/jats:italic><jats:sub>m<\/jats:sub>,)\u2010 and calcium (Ca<jats:sup>2+<\/jats:sup>)\u2010sensitive indicators Rh237 and Rhod2\u2010AM. Sympathetic nerve stimulation (SNS) was performed at the spinal cord (T1\u2010T3). \u03b2\u2010Adrenergic responsiveness was assessed with isoproterenol (1\u00a0\u03bcM, ISO). Sympathetic nerve density and noradrenaline content were also quantified. Stimulation thresholds necessary to produce a defined increase in heart rate (HR) with SNS were higher in AGED <jats:italic>vs<\/jats:italic>. YWT hearts (5.4<jats:italic>\u00a0\u00b1\u00a0<\/jats:italic>0.4\u00a0<jats:italic>vs<\/jats:italic>. 3.8<jats:italic>\u00a0\u00b1\u00a0<\/jats:italic>0.4\u00a0Hz, <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>0.05). Maximal HR with SNS was lower in AGED <jats:italic>vs<\/jats:italic>. YWT (20.5<jats:italic>\u00a0\u00b1\u00a0<\/jats:italic>3.41% <jats:italic>vs<\/jats:italic>. 73.0<jats:italic>\u00a0\u00b1\u00a0<\/jats:italic>7.63% increase, <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>0.05). \u03b2\u2010Adrenergic responsiveness of the atria (measured as percentage increase in HR with ISO) was decreased in AGED <jats:italic>vs<\/jats:italic>. YWT hearts (75.3\u00a0\u00b1\u00a022.5% <jats:italic>vs<\/jats:italic>. 148.5<jats:italic>\u00a0\u00b1\u00a0<\/jats:italic>19.8%, <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>0.05). SNS significantly increased action potential duration (APD) in YWT but not AGED. Ca<jats:sup>2+<\/jats:sup> transient durations and rise times were unchanged by SNS, yet AGED hearts had an increased susceptibility to Ca<jats:sup>2+<\/jats:sup> alternans and ventricular arrhythmias. \u03b2\u2010Adrenergic responsiveness of all ventricular parameters were similar between AGED and YWT. Sympathetic nerve density and noradrenaline content were decreased in the AGED ventricle, but not atria, compared to YWT. These data suggest that decreased responsiveness to SNS in the aged atria may be primarily due to decreased \u03b2\u2010adrenergic responsiveness, whereas decreased responsiveness to SNS in the aged ventricles may be primarily due to nerve degeneration.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp276396","type":"journal-article","created":{"date-parts":[[2018,6,25]],"date-time":"2018-06-25T11:56:43Z","timestamp":1529927803000},"page":"3977-3991","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Age\u2010related changes in cardiac electrophysiology and calcium handling in response to sympathetic nerve stimulation"],"prefix":"10.1113","volume":"596","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7462-8912","authenticated-orcid":false,"given":"Samantha D.","family":"Francis Stuart","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of California Davis  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4747-0419","authenticated-orcid":false,"given":"Lianguo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis  Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Woodard","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Oregon Health and Science University  Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5965-0671","authenticated-orcid":false,"given":"G. 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