Abstract 13340: Contractility and Local Stress Patterns Depend on Directionality of Fibrosis Progression: Insights From Microscale Biomechanical Simulations

Abstract

Introduction: Cardiac fibrosis, a common pathological process in heart disease, leads to reduced contractility and increased myocardial stiffness. However, it remains unclear how various cellular and subcellular events individually contribute to these changes. Hypothesis: Tissue-scale biomechanical effects resulting from cellular and subcellular changes, such as myocyte loss and increased ECM stiffness, are anisotropic and depend on the prevailing direction of fibrosis progression. Methods: We used a mechanical modeling framework allowing for explicit geometrical representation of individual myocytes embedded in ECM. We used a transversely isotropic hyperelastic formulation for the cells while assuming the ECM to be isotropic. Contraction was imposed in each cell using an active stress model. In a simulated tissue domain (6х12 cells), we explored different cellular configurations (Fig. 1A) representing longitudinal, transverse, and random fibrosis progression (i.e., myocyte loss). In each configuration, we examined tissue shortening and stress distributions subject to original and 10х increased ECM stiffness. Results: Myocyte loss perpendicular to the myofiber direction had the largest impact on contractility (Fig. 1B and 1C; as low as 10.8% shortening vs. 15.4% at baseline). In particular, transverse stresses were greatly perturbed in areas near where remaining cells met replacement matrix. Longitudinal and random fibrosis progression had less impact on contractility but led to dramatic heterogeneity in stress distributions. Increased matrix stiffness (Fig. 1C) led to increased magnitude of all stress values. Conclusions: Tissue-scale changes depend on both ECM stiffening and the directionality of myocyte loss. Our model predicts that transverse fibrosis progression has the greatest impact on myocardial contraction, while longitudinal and random progression induce higher local maxima in myocardial stress distributions.