pmjboyle@uw.edu

MRI-Based Computational Modeling of Fibrotic Substrate in

Cryptogenic Stroke (ESUS)PATRICK BOYLE • UNIVERSITY OF WASHINGTON

Western AFib Symposium • February 29, 2020

•Conventional wisdom:•Fibrosis exacerbates AFib•AFib increases stroke risk

•Alternative hypothesis:•Fibrosis directly increases stroke risk, regardless of whether patient has AFib

•ESUS patients have extensive atrial fibrosis but no arrhythmia

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Atrial Fibrosis, AFib, and Stroke

AMA Ed Hub: Stroke Prevention in Atrial Fibrillation

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•10 ESUS patients had LGE-MRI post-stroke

•Full workup including 30+ days monitoring prior to recruitment

•Comparison to controls from UW database

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Pilot Study at UW (Nazem Akoum)

K Tandon, [...] N Akoum (2019) Neurology 93(4):e381-7

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•No difference in LA fibrosis burden between ESUS and AFib groups

•Both were significantly more fibrotic than Ctrl

•LA fibrosis by quartile was the only variable associated with ESUS

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Atrial Fibrosis in ESUS Patients

Unexpected!

Data from LGE-MRI

pmjboyle@uw.edu

K Tandon, [...] N Akoum (2019) Neurology 93(4):e381-7

•Which ESUS patients will have recurrent stroke?

•Not feasible with current computational tools (yet)

•Which ESUS patients will have incident AFib?

•If ESUS patients have so much fibrosis, why don’t they have AFib?

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

How can modeling & simulation help?

•Possibility #1: something is fundamentally different about fibrotic substrate

•e.g., spatial pattern•Possibility #2: fibrotic substrate is the same but there is a lack of triggers

•Simulations can help clarify this ambiguity!

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State-of-the-Art in Atrial EP Modeling

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Late Gadolineum Enhancement (LGE)-MRI

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S Zahid*, H Cochet*, PM Boyle*, [...] NA Trayanova (2016) Cardiovasc Res

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

EP model parameterizationNon-fibrotic myocardium: human atrial model w/ changes for “chronic” AFib

Fibrotic myocardium: altered EP due to fibrotic remodeling (impaired excitability and conduction) mediated by TGF-β1

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S Zahid*, H Cochet*, PM Boyle*, [...] NA Trayanova (2016) Cardiovasc Res

Evolution of Vm(t) Map of activation times

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Computational “substrate stress test”

Phase singularities of reentrant driver

For this individual, this region within the fibrotic substrate

has the necessary properties to initiate & sustain persistent

reentrant driver activity

pmjboyle@uw.edu

S Zahid*, H Cochet*, PM Boyle*, [...] NA Trayanova (2016) Cardiovasc Res

Each patient has a subset of regions within the fibrotic substrate that are significantly more likely to harbor AF-sustaining reentrant drivers

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Key insight from our mechanistic studies

Example: n = 4 pro-RD regions

1

2

3

4

pmjboyle@uw.edu

S Zahid*, H Cochet*, PM Boyle*, [...] NA Trayanova (2016) Cardiovasc Res

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Substrate stress test for ESUS

AFib LGE-MRI scans (n = 45)UW only (pre-ablation, first timers)

ESUS LGE-MRI scans (n = 45)UW + Klinikum Coburg

pmjboyle@uw.edu

•Fully automated workflow for reconstructing bi-layer models of the left atrium

•Feasible to go from segmented images to results in ~3-4 hours

•In ESUS patients with fibrotic atria, does the substrate stress test show reentrant drivers?

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Simplified atrial modeling frameworkModel from ESUS LGE-MRI

pmjboyle@uw.edu

ESUS (n = 45) AFib (n = 45)

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patientspmjboyle@uw.edu

ESUS (n = 45) AFib (n = 45)

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

In some models (both ESUS + AFib) rapid atrial pacing induced reentry

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ESUS (n = 45) AFib (n = 45)

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

In others, pacing never engaged the substrate (n = 15 sites per model)

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ESUS (n = 45)

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Ree

ntry

No

Ree

ntry

AFib (n = 45)

22/45 ESUS models were inducible (48.9%)29/45 AFib models were inducible (64.4%)

Within inducible models, was fibrosis different?

pmjboyle@uw.edu

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Reentry inducibility and atrial fibrosis

Inducible despitelow fibrosis

Non-inducible despite high fibrosis

pmjboyle@uw.edu

Atr

ial f

ibro

sis

(%)

n = 29 n = 22

n = 16 n = 23

# reentry-inducing pacing sites # distinct reentrant drivers

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Arrhythmia dynamics: ESUS vs. AFib

pmjboyle@uw.edu

pmjboyle@uw.edu Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Mechanistic Implications•Possibility #1: something is fundamentally different about fibrotic substrate

•Possibility #2: fibrotic substrate is the same but there is a lack of triggers

NOT SUPPORTED

SUPPORTED

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Atrial Fibrosis in ESUS PatientsKey Takeaways from Computational Modeling & Simulation

Fibrotic substrate in ESUS has same capacity to

sustain reentry as in AFib“Absence of triggers”

hypothesis is supportedArrhythmogenic substrate was more prevalent in AFib

Visit our poster at HRS!pmjboyle@uw.edu

Western-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients

Atrial Fibrosis in ESUS PatientsKey Takeaways from Computational Modeling & Simulation

Fibrotic substrate in ESUS has same capacity to

sustain reentry as in AFib“Absence of triggers”

hypothesis is supportedArrhythmogenic substrate was more prevalent in AFib

Visit our poster at HRS!pmjboyle@uw.edu

Savannah BifulcoBioE PhD Student

The Cardiac Systems Simulation (CardSS) Lab

Zih-Hua(Amber) Chen

MS student

SavannahBifulco

PhD student

KirstenKwanJunior

PatrickBoyle

PI

GriffinScott

Sophomore

KellyZhang

Sophomore

AlexOchs

PhD student

MattHalimJunior

FarzanaMohamedali

Senior

• Funding: AHA SDG16-30440006 (Boyle), NIH U01-HL141074 (Trayanova)• Collaborators: Nazem Akoum, Arun Sridhar (UW Cardiology), Juan Carlos del Alamo

(UW Mech E), Chuck Murry (UW BioE/Pathology), Natalia Trayanova (JHU BME), Edward Vigmond (Bordeaux), Steven Niederer (King’s College London)

• Coburg ESUS MRI team: Christian Mahnkopf, Peter Kuhnlein, Marcel MitlacherWestern-AF: Computational Modeling of Fibrotic Substrate in ESUS Patients https://cardsslab.org/

ChelseaGibbs

PhD student

Cartoonist!

pmjboyle@uw.edu