Mechanical Modeling of Cardiac Fibrosis With Explicit Spatial Representation of Cellular Structure and Collagen Alignment.

Cardiac fibrosis is a pathological condition involving remodeling that impairs cardiac function. Common forms include replacement fibrosis, where damaged myocytes are substituted by collagenous tissue, and interstitial fibrosis, involving matrix expansion between the myocytes. These occur alongside other remodeling processes, including myocardial stiffening and collagen alignment. The mechanical impact of each process remains an active area of investigation. In this work, we used a computational model with explicit myocyte and collagen geometries to study the microscale mechanical effects of fibrotic remodeling. Replacement fibrosis was simulated by substituting myocytes with extracellular matrix, while interstitial fibrosis was modeled by increasing transverse spacing between the cells. These geometric changes were combined with increased matrix and myocyte stiffness and collagen alignment to assess individual and combined effects during contraction and stretch. Structural changes alone led to substantially higher myocyte stresses during contraction (53.9 kPa for increased interstitial space and 35.4 kPa for myocyte replacement, versus 30.9 kPa at baseline). Collagen alignment and myocyte stiffening mitigated increased stress levels. Stretch experiments showed less structural differences in resulting tissue-level load values, which combined with stiffening were slightly higher for increased interstitial space. Individual and combined analyzes attributed total tissue stiffening more to myocyte than matrix stiffening. Our findings suggest that fibrotic remodeling leads to elevated stress in surviving myocytes. Myocyte stiffening and collagen alignment may serve compensatory roles, while also increasing tissue-level stiffness. Integrating microscale modeling with experimental data in future studies may offer deeper insights into the mechanical consequences of fibrotic remodeling.