# Mechanistic Relationships Between Fibrosis, Fibrillation, and Stroke: Multi-Scale, Multi-Physics Simulations

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $611,167

## Abstract

The main goals of this project are to identify mechanisms underlying thrombogenesis in patients with left atrial (LA) fibrosis
and to validate this new knowledge via a prospective proof-of-concept clinical study. Atrial fibrillation (AFib) affects millions
of Americans and carries a five-fold increased risk of stroke, a leading cause of mortality and morbidity. Around 30% of all
ischemic strokes are caused by thromboembolism in AFib patients. In patients without AFib, embolic strokes of undetermined
source (ESUS) account for an additional 30% of ischemic strokes. Current stroke risk stratification tools in AFib and ESUS (e.g.,
CHA2DS2-VASc) are deficient in predictive accuracy, leaving many patients either under-treated for stroke prevention or over-
treated and subjected to unnecessary bleeding risk. The growing evidence that LA fibrosis serves as a mechanistic nexus
between AFib and ESUS is a very promising advance that could open new avenues for stroke prevention. However, taking
advantage of this opportunity requires detailed knowledge of the mechanism(s) by which fibrotic atria are prone to thrombosis,
with or without AFib. Fibrosis has complex structural, electrical, and contractile effects in the LA. These phenomena may
independently or synergistically influence thrombosis risk by altering LA hemodynamics, but prior work has not systematically
assessed inter-dependencies or clarified each factor’s relative importance. This is due to difficulties associated with
experimental manipulation and acquisition of clinical measurements. Advances in computational modeling offer an
unprecedented opportunity to address this critical knowledge gap. Specifically, the stage is set to create a multi-scale, multi-
physics framework that can comprehensively simulate the pro-thrombotic potential of each unique patient-specific LA
fibrosis pattern. Our central hypothesis is that LA fibrosis is a key mechanistic factor in determining each individual’s risk of
thromboembolic stroke due to structural, electrical, and contractile factors. Our approach consists of three specific aims.
Aim 1 will develop and calibrate a computational framework that integrates electrophysiological, biomechanical, and mechano-
fluidic modeling in patient-specific LA models, paying special attention to resolving the effects of fibrosis. We will parameterize
the framework using multi-modality magnetic resonance imaging acquisitions in AFib patients with prior stroke and non-AFib,
non-stroke controls. Aim 2 will use the new computational framework to systematically characterize mechanistic connections
between LA fibrosis and thrombogenesis. We will examine how each individual’s mix of fibrosis extent/pattern, LA anatomy,
and susceptibility to emergent electromechanical phenomena combine (with or without simulated AFib) to create a
thrombogenic milieu that can be characterized by computational modeling. Aim 3 will validate the mechanistic connections
between fibrosis and risk of recurren...

## Key facts

- **NIH application ID:** 10836358
- **Project number:** 5R01HL158667-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Patrick M Boyle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $611,167
- **Award type:** 5
- **Project period:** 2022-05-05 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836358

## Citation

> US National Institutes of Health, RePORTER application 10836358, Mechanistic Relationships Between Fibrosis, Fibrillation, and Stroke: Multi-Scale, Multi-Physics Simulations (5R01HL158667-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10836358. Licensed CC0.

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