{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:34:20Z","timestamp":1774647260633,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011708","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T00:00:00Z","timestamp":1704153600000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL115580"],"award-info":[{"award-number":["HL115580"]}],"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":["HL135109"],"award-info":[{"award-number":["HL135109"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bob and Corrine Frick Center for Heart Failure and Arrhythmia"},{"DOI":"10.13039\/100006928","name":"Ohio State University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006928","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["21\/355"],"award-info":[{"award-number":["21\/355"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001509","name":"Royal Society Te Ap\u0101rangi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001509","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001516","name":"National Heart Foundation of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001516","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The sinoatrial node (SAN), the primary pacemaker of the heart, is responsible for the initiation and robust regulation of sinus rhythm. 3D mapping studies of the ex-vivo human heart suggested that the robust regulation of sinus rhythm relies on specialized fibrotically-insulated pacemaker compartments (head, center and tail) with heterogeneous expressions of key ion channels and receptors. They also revealed up to five sinoatrial conduction pathways (SACPs), which electrically connect the SAN with neighboring right atrium (RA). To elucidate the role of these structural-molecular factors in the functional robustness of human SAN, we developed comprehensive biophysical computer models of the SAN based on 3D structural, functional and molecular mapping of ex-vivo human hearts. Our key finding is that the electrical insulation of the SAN except SACPs, the heterogeneous expression of I<jats:sub>f<\/jats:sub>, I<jats:sub>Na<\/jats:sub> currents and adenosine A1 receptors (A1R) across SAN pacemaker-conduction compartments are required to experimentally reproduce observed SAN activation patterns and important phenomena such as shifts of the leading pacemaker and preferential SACP. In particular, we found that the insulating border between the SAN and RA, is required for robust SAN function and protection from SAN arrest during adenosine challenge. The heterogeneity in the expression of A1R within the human SAN compartments underlies the direction of pacemaker shift and preferential SACPs in the presence of adenosine. Alterations of I<jats:sub>Na<\/jats:sub> current and fibrotic remodelling in SACPs can significantly modulate SAN conduction and shift the preferential SACP\/exit from SAN. Finally, we show that disease-induced fibrotic remodeling, I<jats:sub>Na<\/jats:sub> suppression or increased adenosine make the human SAN vulnerable to pacing-induced exit blocks and reentrant arrhythmia. In summary, our computer model recapitulates the structural and functional features of the human SAN and can be a valuable tool for investigating mechanisms of SAN automaticity and conduction as well as SAN arrhythmia mechanisms under different pathophysiological conditions.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011708","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T18:42:37Z","timestamp":1702924957000},"page":"e1011708","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mechanistic insight into the functional role of human sinoatrial node conduction pathways and pacemaker compartments heterogeneity: A computer model analysis"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3303-0401","authenticated-orcid":true,"given":"Jichao","family":"Zhao","sequence":"first","affiliation":[]},{"given":"Roshan","family":"Sharma","sequence":"additional","affiliation":[]},{"given":"Anuradha","family":"Kalyanasundaram","sequence":"additional","affiliation":[]},{"given":"James","family":"Kennelly","sequence":"additional","affiliation":[]},{"given":"Jieyun","family":"Bai","sequence":"additional","affiliation":[]},{"given":"Ning","family":"Li","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2643-642X","authenticated-orcid":true,"given":"Alexander","family":"Panfilov","sequence":"additional","affiliation":[]},{"given":"Vadim V.","family":"Fedorov","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2023,12,18]]},"reference":[{"issue":"400","key":"pcbi.1011708.ref001","doi-asserted-by":"crossref","first-page":"eaam5607","DOI":"10.1126\/scitranslmed.aam5607","article-title":"Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure","volume":"9","author":"N Li","year":"2017","journal-title":"Science Translational Medicine"},{"key":"pcbi.1011708.ref002","article-title":"Three-dimensional functional anatomy of human sinoatrial node for epicardial and endocardial mapping and ablation","author":"A Kalyanasundaram","year":"2022","journal-title":"Heart Rhythm; In press"},{"key":"pcbi.1011708.ref003","first-page":"172","article-title":"The form and nature of the muscular connections between the primary divisions of the vertebrate heart","volume":"41","author":"A Keith","year":"1907","journal-title":"J Anat Physiol"},{"key":"pcbi.1011708.ref004","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1002\/ar.21379","article-title":"Computer three-dimensional anatomical reconstruction of the human sinus node and a novel paranodal area","volume":"294","author":"N Chandler","year":"2011","journal-title":"Anat Rec"},{"key":"pcbi.1011708.ref005","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.pbiomolbio.2015.12.011","article-title":"Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways","volume":"120","author":"TA Csepe","year":"2016","journal-title":"Progress in Biophysics and Molecular Biology"},{"key":"pcbi.1011708.ref006","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1093\/ehjci\/jew304","article-title":"Novel application of 3D contrast-enhanced CMR to define fibrotic structure of the human sinoatrial node in vivo","volume":"18","author":"TA Csepe","year":"2017","journal-title":"European Heart Journal-Cardiovascular Imaging"},{"key":"pcbi.1011708.ref007","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1161\/CIRCULATIONAHA.120.051583","article-title":"Fibroblast-specific proteotranscriptomes reveal distinct fibrotic signatures of human sinoatrial node in nonfailing and failing hearts","volume":"144","author":"A Kalyanasundaram","year":"2021","journal-title":"Circulation"},{"key":"pcbi.1011708.ref008","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1161\/CIRCEP.115.003070","article-title":"Molecular mapping of sinoatrial node HCN channel expression in the human heart","volume":"8","author":"N Li","year":"2015","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"pcbi.1011708.ref009","first-page":"1","article-title":"Impaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node","volume":"11","author":"N Li","year":"2020","journal-title":"Nature Communications"},{"key":"pcbi.1011708.ref010","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1016\/S0006-3495(86)83559-7","article-title":"Propagation through electrically coupled cells. 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