Investigators
Natalia Trayanova, Johns Hopkins University (PI/PD); Hugh Calkins, Johns Hopkins Medicine (PI); Patrick Boyle, University of Washington (Co-I); Adityo Prakosa, Johns Hopkins University (Co-I)
1. Define context(s)
aid in clinical decision making
aid in clinical trial design
identify/explore new therapies
reveal new biological insights
Primary goal of the model/tool/database
The overall objective of this application is to develop and validate a novel personalized multiscale modeling strategy for determining the optimal targets for catheter ablation of the fibrotic substrate in patients with persistent atrial fibrillation (PsAF). The project will culminate with a pilot prospective patient study, where PsAF ablation will be executed directly at simulation-predicted targets.
Biological domain of the model
cardiac electrophysiology
Structure(s) of interest in the model
human atria, cardiomyocytes, fibrosis
Spatial scales included in the model
sub-cellular, cellular, tissue, and organ-scale cardiac features
Time scales included in the model
sub-events of the cardiac action potential, with time courses on the order of 10s or 100s of µs; arrhythmia events at the organ-scale, which evolve over the course of several seconds of rapid electrical stimulation
2. Data for building and validating the model
Data for building the model |
Published? |
Private? |
How is credibility checked? |
Current Conformance Level / Target Conformance Level |
in vitro (primary cells cell, lines, etc.) |
x |
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baseline model calibrated from literature sources (see: 10.1093/cvr/cvw073) |
Adequate |
ex vivo (excised tissues) |
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in vivo pre-clinical (lower-level organism or small animal) |
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in vivo pre-clinical (large animal) |
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Human subjects/clinical |
x |
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baseline model calibrated from literature sources (see: 10.1093/cvr/cvw073) |
Adequate |
Other: ________________________ |
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Data for validating the model |
Published? |
Private? |
How is credibility checked? |
Current Conformance Level / Target Conformance Level |
in vitro (primary cells cell, lines, etc.) |
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x |
Establish baseline ion channel expression levels (i.e., maximal conductances) by measuring mRNA levels |
In Progress (Will be Extensive) |
ex vivo (excised tissues) |
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x |
Adjust mathematical formulations for membrane kinetics to match action potential morphology observed via optical mapping |
In Progress (Will be Extensive) |
in vivo pre-clinical (lower-level organism or small animal) |
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in vivo pre-clinical (large animal) |
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Human subjects/clinical |
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Other: ________________________ |
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3. Validate within context(s)
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Who does it? |
When does it happen? |
How is it done? |
Current Conformance Level / Target Conformance Level |
Verification |
Trayanova & Boyle Labs |
Throughout project |
convergence testing in tissue wedge models extracted from all atrial models; re-running simulations and analysis for a subset of models in a distinct software package |
Extensive |
Validation |
Trayanova & Efimov Labs |
Years 1-2 of project |
Establish baseline ion channel expression levels (i.e., maximal conductances) by measuring mRNA levels; Adjust mathematical formulations for membrane kinetics to match action potential morphology observed via optical mapping; Calibrate conductivity tensor values to match conduction velocities observed via optical mapping |
Extensive |
Uncertainty quantification |
Trayanova & Boyle Labs |
Years 2-3 of project |
Characterize the relationship between cell- and tissue-scale model parameters and primary model outputs (i.e., locations of persistent reentrant drivers within the fibrotic substrate) |
Adequate |
Sensitivity analysis |
Trayanova & Boyle Labs |
Years 1-2 of project |
Calculate sensitivity of reentrant driver target estimation to locations of pacing sites used to elicit reentry (work already done) |
Adequate |
Other:__________ |
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Additional Comments |
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4. Limitations
Disclaimer statement (explain key limitations) |
Who needs to know about this disclaimer? |
How is this disclaimer shared with that audience? |
Current Conformance Level / Target Conformance Level |
an intrinsic limitation of any image-based model is that it can only incorporate what can be imaged (i.e., limitations of the MRI scanner limit the information that can be used to constrain the model) |
all relevant stakeholders |
through dissemination in papers, abstracts, and public lectures |
Adequate |
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5. Version control
Current Conformance Level / Target Conformance Level |
Adequate |
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Naming Conventions? |
Repository? |
Code Review? |
individual modeler |
yes |
yes |
peers |
within the lab |
yes |
yes |
peers |
collaborators |
yes |
yes |
via regular Skype calls |
6. Documentation
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Current Conformance Level / Target Conformance Level |
Code commented? |
Adequate |
Scope and intended use described? |
Adequate |
User’s guide? |
Extensive |
Developer’s guide? |
Extensive |
7. Dissemination
Current Conformance Level / Target Conformance Level |
Extensive |
Target Audience(s): |
“Inner circle” |
Scientific community |
Public |
Simulations |
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10.1161/CIRCEP.119.008213 – (pre-procedure machine-learning + simulations) |
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Models |
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doi:10.1016/j.media.2019.04.004 - (UAC: modeling methodology) doi:10.3389/fphys.2018.01151 - (FIRM vs. modeling: validation methodology) 10.1007/s10439-020-02525-w – (human atrial fibre atlas) |
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Software |
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doi:10.1016/j.jacep.2018.08.016 - (jet vent: analysis tools relevant to project) doi:10.1038/s41551-018-0282-2 - (VAAT: analysis tools relevant to project) doi:10.3389/fphys.2019.00628 - (VT parameter variability: analysis tools relevant to project) doi:10.1016/j.bpj.2019.07.024 - (Characterizing Conduction Channels: analysis tools relevant to project) |
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Results |
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doi:10.1038/s41551-019-0437-9 (OPTIMA) doi:10.1093/cvr/cvz083 (pre/post MRI) doi:10.1093/europace/euy234 - (post-ablation reentry dynamics) |
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Implications of results |
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doi:10.1016/j.ijcard.2019.01.096 (personalized atrial modeling) 10.1016/j.ccep.2020.02.006 – (utility of cMRI in AF Management) |
doi:10.1038/s41569-018-0149-y (developments in precision cardiology) doi:10.1038/s41569-018-0104-y (Computational models in cardiology) |
8. Independent reviews
Current Conformance Level / Target Conformance Level |
In Progress (Will be Extensive) |
Reviewer(s) name & affiliation: |
TBD; the emergence of a new software platform for cardiac EP simulations (OpenCARP: https://opencarp.org/) will pave the way towards identification of new outside groups to validate modeling and simulation methodology developed and used in this project |
When was review performed? |
TBD |
How was review performed and outcomes of the review? |
Comprehensive reproduction of modeling, simulations, and analysis steps of workflow by a different group using a different software platform |
9. Test competing implementations
Current Conformance Level / Target Conformance Level |
In Progress (Will be Extensive) |
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Yes or No (briefly summarize) |
Were competing implementations tested? |
Not yet; however, the emergence of OpenCARP discussed above is a step towards feasibility of comprehensive testing in an alternative platform |
Did this lead to model refinement or improvement? |
n/a |