Computational modeling identifies embolic stroke of undetermined source patients with potential arrhythmic substrate
- University of Washington, United States
- King's College London, United Kingdom
- Klinikum Coburg, Germany
Abstract
Cardiac magnetic resonance imaging (MRI) has revealed fibrosis in embolic stroke of undetermined source (ESUS) patients comparable to levels seen in atrial fibrillation (AFib). We used computational modeling to understand the absence of arrhythmia in ESUS despite the presence of putatively pro-arrhythmic fibrosis. MRI-based atrial models were reconstructed for 45 ESUS and 45 AFib patients. The fibrotic substrate's arrhythmogenic capacity in each patient was assessed computationally. Reentrant drivers were induced in 24/45 (53%) ESUS and 22/45 (49%) AFib models. Inducible models had more fibrosis (16.7±5.45%) than non-inducible models (11.07±3.61%; P<0.0001); however, inducible subsets of ESUS and AFib models had similar fibrosis levels (P=0.90), meaning the intrinsic pro-arrhythmic substrate properties of fibrosis in ESUS and AFib are indistinguishable. This suggests some ESUS patients have latent pre-clinical fibrotic substrate that could be a future source of arrhythmogenicity. Thus, our work prompts the hypothesis that ESUS patients with fibrotic atria are spared from AFib due to an absence of arrhythmia triggers.
Data availability
Where possible (Figs. 2, 3, 5, 6), raw numerical data underlying figures are available via figshare: https://doi.org/10.6084/m9.figshare.14348042. Patient-derived data related to this article, including processed versions thereof, are not publicly available out of respect for the privacy of the patients involved. Interested parties wishing to obtain these data for non-commercial reuse should contact the co-corresponding authors via email. Upon all reasonable requests for access to these data, the co-corresponding authors will work to pursue negotiation of a Data Transfer and Use Agreement with the requesting party; administrators at the requesting party's institution, the University of Washington, and Klinikum Coburg; and relevant Institutional Review Boards at all the latter institutions. Source files for a complete example of computational modeling and simulation of the fibrotic atria, using publicly available data sets and software tools only, can be found via the following permanent link: https://doi.org/10.6084/m9.figshare.14347979. Documentation provided with this example includes instructions on the use of the openCARP cardiac electrophysiology simulator and the meshalyzer visualization software (both available via https://opencarp.org/) to precisely reproduce the computational protocol applied to patient-specific left atria models in this study.
Article and author information
Author details
Funding
Achievement Rewards for College Scientists Foundation
- Savannah F Bifulco
National Institutes of Health (T32-EB001650)
- Savannah F Bifulco
Medical Research Council (MR/S015086/1)
- Caroline H Roney
National Institutes of Health (R01-HL152256)
- Steven A Niederer
H2020 European Research Council (PREDICT-HF (864055))
- Steven A Niederer
British Heart Foundation (RG/20/4/34803)
- Steven A Niederer
Engineering and Physical Sciences Research Council (EP/P01268X/1)
- Steven A Niederer
Wellcome Trust (203148/Z/16/Z)
- Steven A Niederer
National Institutes of Health (NIH 5-U01-NS095869)
- David Tirschwell
- W T Longstreth Jr
John Locke Charitable Trust
- Nazem Akoum
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Noriaki Emoto, Kobe Pharmaceutical University, Japan
Ethics
Human subjects: This study was approved by the Institutional Review Board (IRB) of the University of Washington (UW) and the Ethikkommission der Bayerischen Ländesärztekammer München, Bayern, Deutschland; all participants provided written informed consent. Associated reference numbers: IRB5350 for ESUS patients; IRB8763 for AFib patients.
Version history
- Received: October 21, 2020
- Accepted: April 16, 2021
- Accepted Manuscript published: May 4, 2021 (version 1)
- Version of Record published: May 24, 2021 (version 2)
Copyright
© 2021, Bifulco et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Computational modeling identifies embolic stroke of undetermined source patients with potential arrhythmic substrate
eLife 10:e64213.
https://doi.org/10.7554/eLife.64213
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