Systematic computational assessment of atrial function impairment due to fibrotic remodeling in electromechanical properties
Åshild Telle, Ahmad Kassar, Nadia Chamoun, Romanos Haykal, Alejandro Gonzalo, Tori Hensley, Yaacoub Chahine, Oscar Flores, Juan C. del Álamo, Nazem Akoum, Christoph M. Augustin, Patrick M. Boyle
Abstract
Cardiac fibrosis is a pathological condition associated with many cardiovascular diseases. Atrial fibrosis leads to reduced atrial function, resulting in diminished blood flow and an increased risk of stroke. This reduced function arises from altered myocardial electrophysiological and mechanical properties.
Introduction
Cardiac fibrosis is prevalent in cardiovascular disease and contributes to left atrial (LA) dysfunction. LA fibrosis is strongly associated with atrial fibrillation (AF) and ischemic stroke [1–3]. Fibrotic remodeling encompasses a series of complex pathological events involving myocyte death, expansion of the extracellular matrix, and subcellular electromechanical changes [4,5]. These alterations reduces LA function, in which relative reduction can be quantified to support mechanistic insight and clinical risk stratification.
Materials and method
2.1 Ethics statement
The study was approved by the Institutional Review Board of the University of Washington (STUDY00015081). A written statement of consent was obtained from each patient.
Results
In this section, we present findings from individual patient-specific simulations, using Patient 1 as a representative example, and statistical analysis of aggregated data. We begin by presenting an overview of the simulation pipeline, PV loops with derived metrics for all three patients, followed by OFAT analysis results.
Discussion
4.1 Impact of fibrotic-associated parameter changes on the atrial function
In the present study, we combined a multi-scale, multiphysics modeling framework with patient-specific LA geometries and fibrosis maps to investigate the impact of fibrotic remodeling. We investigated the influence of nine electromechanical parameters altered in fibrosis, and assessed LA function using five volume- and pressure-based metrics.
Conclusions
In our study, we used a computational model combined with patient-specific LA geometries to analyze the impact of nine parameters related to fibrotic remodeling. Our sensitivity analysis predicted that impairment of ICaL and IK1 were most consequential in terms of changes in LA function, having respectively decreased and improved effect. Future research focusing on these may greatly improve our understanding of fibrotic remodeling and its effects on atrial function. We found that reduction in ICaL and IK1 had a dispersive effect impacting non-fibrotic tissue, and that an increase in fibrosis burden produced a comparably moderate reduction in LA function, potentially related to fibrosis density (scattered versus dense). In the future, modeling frameworks with larger cohorts could better elucidate relationships between fibrosis burden, spatial patterns, and LA function impairment. Modeling efforts could include spatiotemporal analysis of thrombogenic risk subject from fibrotic remodeling, ultimately improving risk assessment and prevention strategies.
Citation: Telle Å, Kassar A, Chamoun N, Haykal R, Gonzalo A, Hensley T, et al. (2025) Systematic computational assessment of atrial function impairment due to fibrotic remodeling in electromechanical properties. PLoS Comput Biol 21(12): e1013265. https://doi.org/10.1371/journal.pcbi.1013265
Editor: Anna Grosberg, UCI BME: University of California Irvine Department of Biomedical Engineering, UNITED STATES OF AMERICA
Received: June 23, 2025; Accepted: November 3, 2025; Published: December 5, 2025
Copyright: © 2025 Telle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The organ-level simulations were performed using proprietary software (CARPentry, Numericor; https://numericor.at), which cannot be made publicly available. The related openCARP software (https://opencarp.org/) is freely available for non-commercial use (https://opencarp.org). Supplementary Data for this study are published in a Dryad Repository (https://doi.org/10.5061/dryad.g79cnp62q), including: geometries used in the simulations, for all three patients and both fibrosis levels; the script used to calibrate CV values for all fibrotic combinations; all parameter combinations used in the two sensitivity analysis setups (OFAT and FFD); scripts used to perform all simulations with CARPentry, including both unloading and sensitivity analysis scripts; pressure and volume data from all cycles from all of the above-mentioned simulations for all three patients and both fibrosis levels. The code for performing the post-simulation sensitivity analysis is publicly available via Zenodo (https://doi.org/10.5281/zenodo.15693590), as is the code for material parameter estimation (https://doi.org/10.5281/zenodo.15693906).
Funding: This study was supported by the US National Institutes of Health grants R01-HL158667 (NA, JCA, CMA, PMB) and R01-HL160024 (JCA), and by the Austrian Science Fund grant 10.55776/P37063 (CMA). The funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
