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
Further reading
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Background:
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB.
Methods:
Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations.
Results:
Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (<34 weeks) sPTB.
Conclusions:
The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes.
Funding:
This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.
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Runs of homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE, to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 SNPs and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended HLA region and autoimmune disorders. We found an association between a diplotype covering the HFE gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (P-value=1.82×10-11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.
