Adhesion between cardiac myocytes is essential for the heart to function as an electromechanical syncytium. Although cell-matrix and cell–cell adhesions reorganize during development and disease, the hierarchical cooperation between these subcellular structures is poorly understood. We reasoned that, during cardiac development, focal adhesions mechanically stabilize cells and tissues during myofibrillogenesis and intercalated disc assembly. As the intercalated disc matures, we postulated that focal adhesions disassemble as systolic stresses are transmitted intercellularly. Finally, we hypothesized that pathological remodeling of cardiac microenvironments induces excessive mechanical loading of intercalated discs, leading to assembly of stabilizing focal adhesions adjacent to the junction. To test our model, we engineered μtissues composed of two ventricular myocytes on deformable substrates of tunable elasticity to measure the dynamic organization and functional remodeling of myofibrils, focal adhesions, and intercalated discs as cooperative ensembles. Maturing μtissues increased systolic force while simultaneously developing into an electromechanical syncytium by disassembling focal adhesions at the cell–cell interface and forming mature intercalated discs that transmitted the systolic load. We found that engineering the microenvironment to mimic fibrosis resulted in focal adhesion formation adjacent to the cell–cell interface, suggesting that the intercalated disc required mechanical reinforcement. In these pathological microenvironments, μtissues exhibited further evidence of maladaptive remodeling, including lower work efficiency, longer contraction cycle duration, and weakened relationships between cytoskeletal organization and force generation. These results suggest that the cooperative balance between cell-matrix and cell–cell adhesions in the heart is guided by an architectural and functional hierarchy established during development and disrupted during disease.

McCain, M. L., Lee, H., Aratyn-Schaus, Y., Kléber, A. G., & Parker, K. K. (2012). Cooperative coupling of cell-matrix and cell–cell adhesions in cardiac muscle. Proceedings of the National Academy of Sciences, 109(25), 9881–9886.