Simulation guidance of ablation therapy for persistent atrial fibrillation (U01-HL-141074)

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)
Contact info (email)
ntrayanova@jhu.edu
1. Define context(s)
aid in clinical decision making
aid in clinical trial design
identify/explore new therapies
reveal new biological insights
Current Conformance Level / Target Conformance Level
Extensive
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 baseline model calibrated from literature sources (see: 10.1093/cvr/cvw073) Adequate
ex vivo (excised tissues)
in vivo pre-clinical (lower-level organism or small animal)
in vivo pre-clinical (large animal)
Human subjects/clinical x baseline model calibrated from literature sources (see: 10.1093/cvr/cvw073) Adequate
Other: ________________________
Data for validating the model Published? Private? How is credibility checked? Current Conformance Level / Target Conformance Level
in vitro (primary cells cell, lines, etc.) x Establish baseline ion channel expression levels (i.e., maximal conductances) by measuring mRNA levels In Progress (Will be Extensive)
ex vivo (excised tissues) 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)
in vivo pre-clinical (large animal)
Human subjects/clinical
Other: ________________________
3. Validate within context(s)
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:__________
Additional Comments
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
5. Version control
Current Conformance Level / Target Conformance Level
Adequate
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
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 10.1161/CIRCEP.119.008213 – (pre-procedure machine-learning + simulations)
Models 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)
Software 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)
Results 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)
Implications of results 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)
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
10. Conform to standards
Current Conformance Level / Target Conformance Level
In Progress (Will be Extensive)
Yes or No (briefly summarize)
Are there operating procedures, guidelines, or standards for this type of multiscale modeling? Yes
How do your modeling efforts conform? We have not yet carried out this part of the work; eventually, independent assessment of our modeling strategy in consultation with IMAG and the MSM consortium will lend additional credibility to simulation predictions