Excitation and mechanical contraction of a 3D cardiomyocyte model.

Abstract

Cardiomyocyte ultrastructure and pathological disruptions, such as myofibrillar disarray and mitochondrial disorganization, are important determinants of contractile function and dysfunction. Our previous model simulation assumed idealized periodicity and symmetry of cardiomyocyte structures limiting their ability to replicate pathological abnormalities. Utilizing image-based modeling, here we extend previous simulations by incorporating realistic 3D structures based on mouse cardiomyocyte images from serial block-face scanning electron microscopy. Segmentation from a quarter cross section of three sarcomeres in series allowed modeling of mitochondria, myofibrils, transverse-axial tubular system, and dyads. We integrate membrane electrophysiology, spatially resolved calcium handling and diffusion, and force generation within the same mesh to simulate local Ca²⁺ dynamics and mechanics simultaneously. The image-based model successfully reproduces heterogeneous electrophysiological, calcium, and mechanical strain as well as whole-cell action potential and calcium transients. In the healthy myocyte, the standard deviation of axial myofibril strain was estimated at 1.87%, arising from heterogeneous Ca²⁺ distributions, structural irregularities, or differing mechanical constraints. Comparing half-volumes with and without axially oriented transverse-axial tubular system shows minimal overall differences in force generation and mechanical outcome. Image-based, multiphysics finite element simulation of cardiomyocyte excitation-contraction coupling promises to elucidate the mechanisms and functional significance of ultrastructural heterogeneity in cardiac muscle cells.