1. Computational and Systems Biology
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Computational modeling identifies embolic stroke of undetermined source patients with potential arrhythmic substrate

  1. Savannah F Bifulco
  2. Griffin D Scott
  3. Sakher Sarairah
  4. Zeinab Birjandian
  5. Caroline H Roney
  6. Steven A Niederer
  7. Christian Mahnkopf
  8. Peter Kuhnlein
  9. Marcel Mitlacher
  10. David Tirschwell
  11. W T Longstreth Jr
  12. Nazem Akoum  Is a corresponding author
  13. Patrick M Boyle  Is a corresponding author
  1. University of Washington, United States
  2. King's College London, United Kingdom
  3. Klinikum Coburg, Germany
Research Article
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Cite this article as: eLife 2021;10:e64213 doi: 10.7554/eLife.64213

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

  1. Savannah F Bifulco

    Bioengineering, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Griffin D Scott

    Bioengineering, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sakher Sarairah

    Cardiology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Zeinab Birjandian

    Cardiology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Caroline H Roney

    School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Steven A Niederer

    School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Christian Mahnkopf

    Cardiology, Klinikum Coburg, Coburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Peter Kuhnlein

    Cardiology, Klinikum Coburg, Coburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Marcel Mitlacher

    Cardiology, Klinikum Coburg, Coburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. David Tirschwell

    Neurology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. W T Longstreth Jr

    Neurology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Nazem Akoum

    Cardiology, University of Washington, Seattle, United States
    For correspondence
    nakoum@cardiology.washington.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2001-6806
  13. Patrick M Boyle

    Bioengineering, University of Washington, Seattle, United States
    For correspondence
    pmjboyle@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9048-1239

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.

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.

Reviewing Editor

  1. Noriaki Emoto, Kobe Pharmaceutical University, Japan

Publication history

  1. Received: October 21, 2020
  2. Accepted: April 16, 2021
  3. Accepted Manuscript published: May 4, 2021 (version 1)

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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