{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:08:01Z","timestamp":1740146881818,"version":"3.37.3"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2020-04933"],"award-info":[{"award-number":["RGPIN-2020-04933"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Chronic stress among young patients (\u2264 45 years old) could result in autonomic dysfunction. Autonomic dysfunction could be exhibited via sympathetic hyperactivity, sympathetic nerve sprouting, and diffuse adrenergic stimulation in the atria. Adrenergic spatial densities could alter atrial electrophysiology and increase arrhythmic susceptibility. Therefore, we examined the role of adrenergic spatial densities in creating arrhythmogenic substrates in silico. We simulated three 25 <jats:italic>cm<\/jats:italic><jats:sup>2<\/jats:sup> atrial sheets with varying adrenergic spatial densities (ASD), activation rates, and external transmembrane currents. We measured their effects on spatial and temporal heterogeneity of action potential durations (APD) at 50% and 20%. Increasing ASD shortens overall APD, and maximum spatial heterogeneity (31%) is achieved at 15% ASD. The addition of a few (5% to 10%) adrenergic elements decreases the excitation threshold, below 18 <jats:italic>\u03bcA<\/jats:italic>\/<jats:italic>cm<\/jats:italic><jats:sup>2<\/jats:sup>, while ASDs greater than 10% increase their excitation threshold up to 22 <jats:italic>\u03bcA<\/jats:italic>\/<jats:italic>cm<\/jats:italic><jats:sup>2<\/jats:sup>. Increase in ASD during rapid activation increases <jats:italic>APD<\/jats:italic><jats:sub>50<\/jats:sub> and <jats:italic>APD<\/jats:italic><jats:sub>20<\/jats:sub> by 21% and 41%, respectively. Activation times of captured beats during rapid activation could change by as much as 120 ms from the baseline cycle length. Rapidly activated atrial sheets with high ASDs significantly increase temporal heterogeneity of <jats:italic>APD<\/jats:italic><jats:sub>50<\/jats:sub> and <jats:italic>APD<\/jats:italic><jats:sub>20<\/jats:sub>. Rapidly activated atrial sheets with 10% ASD have a high likelihood (0.7 \u00b1 0.06) of fragmenting otherwise uniform wavefronts due to the transient inexcitability of adrenergically stimulated elements, producing an effective functional block. The likelihood of wave fragmentation due to ASD highly correlates with the spatial variations of <jats:italic>APD<\/jats:italic><jats:sub>20<\/jats:sub> (<jats:italic>\u03c1<\/jats:italic> = 0.90, p = 0.04). Our simulations provide a novel insight into the contributions of ASD to spatial and temporal heterogeneities of APDs, changes in excitation thresholds, and a potential explanation for wave fragmentation in the human atria due to sympathetic hyperactivity. Our work may aid in elucidating an electrophysiological link to arrhythmia initiation due to chronic stress among young patients.<\/jats:p>","DOI":"10.1371\/journal.pone.0290676","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T17:23:12Z","timestamp":1692984192000},"page":"e0290676","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pro-arrhythmic role of adrenergic spatial densities in the human atria: An in-silico study"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5846-5327","authenticated-orcid":true,"given":"Karl","family":"Magtibay","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"St\u00e9phane","family":"Mass\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kumaraswamy","family":"Nanthakumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karthikeyan","family":"Umapathy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"issue":"1","key":"pone.0290676.ref001","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1161\/01.RES.0000133678.22968.e3","article-title":"Mechanisms of cardiac nerve sprouting after myocardial infarction in dogs","volume":"95","author":"S Zhou","year":"2004","journal-title":"Circulation research"},{"issue":"5","key":"pone.0290676.ref002","doi-asserted-by":"crossref","first-page":"H1851","DOI":"10.1152\/ajpheart.00083.2005","article-title":"Canine model of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia","volume":"289","author":"M Swissa","year":"2005","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"5","key":"pone.0290676.ref003","first-page":"1010","article-title":"Extracardiac neural remodeling in humans with cardiomyopathy","volume":"5","author":"OA Ajijola","year":"2012","journal-title":"Circulation: Arrhythmia and Electrophysiology"},{"issue":"9","key":"pone.0290676.ref004","doi-asserted-by":"crossref","first-page":"H1838","DOI":"10.1152\/ajpheart.01106.2011","article-title":"Sympathetic stimulation increases dispersion of repolarization in humans with myocardial infarction","volume":"302","author":"M Vaseghi","year":"2012","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"3","key":"pone.0290676.ref005","article-title":"High-resolution structure-function mapping of intact hearts reveals altered sympathetic control of infarct border zones","volume":"7","author":"C Zhu","year":"2022","journal-title":"JCI insight"},{"issue":"1-3","key":"pone.0290676.ref006","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.pbiomolbio.2015.12.015","article-title":"The nervous heart","volume":"120","author":"CM Ripplinger","year":"2016","journal-title":"Progress in biophysics and molecular biology"},{"key":"pone.0290676.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.autneu.2017.03.005","article-title":"The role of the autonomic nervous system in arrhythmias and sudden cardiac death","volume":"205","author":"S Franciosi","year":"2017","journal-title":"Autonomic Neuroscience"},{"issue":"8","key":"pone.0290676.ref008","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1073\/pnas.1400113111","article-title":"Molecular evidence of stress-induced acute heart injury in a mouse model simulating posttraumatic stress disorder","volume":"111","author":"JH Cho","year":"2014","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"11","key":"pone.0290676.ref009","doi-asserted-by":"crossref","first-page":"12240","DOI":"10.1096\/fj.201900100R","article-title":"Contribution of DNA methylation in chronic stress-induced cardiac remodeling and arrhythmias in mice","volume":"33","author":"P Zhang","year":"2019","journal-title":"The FASEB Journal"},{"issue":"3","key":"pone.0290676.ref010","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1113\/JP281118","article-title":"What gets on the nerves of cardiac patients? 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