dc.contributor.author |
Li, Ning |
en |
dc.contributor.author |
Hansen, Brian J |
en |
dc.contributor.author |
Csepe, Thomas A |
en |
dc.contributor.author |
Zhao, Jichao |
en |
dc.contributor.author |
Ignozzi, Anthony J |
en |
dc.contributor.author |
Sul, Lidiya V |
en |
dc.contributor.author |
Zakharkin, Stanislav O |
en |
dc.contributor.author |
Kalyanasundaram, Anuradha |
en |
dc.contributor.author |
Davis, Jonathan P |
en |
dc.contributor.author |
Biesiadecki, Brandon J |
en |
dc.contributor.author |
Kilic, Ahmet |
en |
dc.contributor.author |
Janssen, Paul ML |
en |
dc.contributor.author |
Mohler, Peter J |
en |
dc.contributor.author |
Weiss, Raul |
en |
dc.contributor.author |
Hummel, John D |
en |
dc.contributor.author |
Fedorov, Vadim V |
en |
dc.date.accessioned |
2018-11-12T21:47:07Z |
en |
dc.date.issued |
2017-07 |
en |
dc.identifier.issn |
1946-6234 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/44136 |
en |
dc.description.abstract |
The human sinoatrial node (SAN) efficiently maintains heart rhythm even under adverse conditions. However, the specific mechanisms involved in the human SAN's ability to prevent rhythm failure, also referred to as its robustness, are unknown. Challenges exist because the three-dimensional (3D) intramural structure of the human SAN differs from well-studied animal models, and clinical electrode recordings are limited to only surface atrial activation. Hence, to innovate the translational study of human SAN structural and functional robustness, we integrated intramural optical mapping, 3D histology reconstruction, and molecular mapping of the ex vivo human heart. When challenged with adenosine or atrial pacing, redundant intranodal pacemakers within the human SAN maintained automaticity and delivered electrical impulses to the atria through sinoatrial conduction pathways (SACPs), thereby ensuring a fail-safe mechanism for robust maintenance of sinus rhythm. During adenosine perturbation, the primary central SAN pacemaker was suppressed, whereas previously inactive superior or inferior intranodal pacemakers took over automaticity maintenance. Sinus rhythm was also rescued by activation of another SACP when the preferential SACP was suppressed, suggesting two independent fail-safe mechanisms for automaticity and conduction. The fail-safe mechanism in response to adenosine challenge is orchestrated by heterogeneous differences in adenosine A1 receptors and downstream GIRK4 channel protein expressions across the SAN complex. Only failure of all pacemakers and/or SACPs resulted in SAN arrest or conduction block. Our results unmasked reserve mechanisms that protect the human SAN pacemaker and conduction complex from rhythm failure, which may contribute to treatment of SAN arrhythmias. |
en |
dc.format.medium |
Print |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Science translational medicine |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Heart Atria |
en |
dc.subject |
Sinoatrial Node |
en |
dc.subject |
Humans |
en |
dc.subject |
Adenosine |
en |
dc.subject |
Electrocardiography |
en |
dc.subject |
Action Potentials |
en |
dc.subject |
Heart Rate |
en |
dc.subject |
Adult |
en |
dc.subject |
Aged |
en |
dc.subject |
Middle Aged |
en |
dc.subject |
Female |
en |
dc.subject |
Arrhythmias, Cardiac |
en |
dc.subject |
In Vitro Techniques |
en |
dc.title |
Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1126/scitranslmed.aam5607 |
en |
pubs.issue |
400 |
en |
pubs.volume |
9 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
28747516 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
research-article |
en |
pubs.subtype |
Journal Article |
en |
pubs.subtype |
Research Support, N.I.H., Extramural |
en |
pubs.elements-id |
644680 |
en |
pubs.org-id |
Bioengineering Institute |
en |
pubs.org-id |
ABI Associates |
en |
dc.identifier.eissn |
1946-6242 |
en |
pubs.record-created-at-source-date |
2017-07-28 |
en |
pubs.dimensions-id |
28747516 |
en |