The influence of cellular and extracellular perturbations on cardiomyocyte contractility

The main components of the myocardium are cardiomyocytes and cardiac fibroblasts. In cardiomyopathy, synchronized beating of the heart is often hampered by fibrosis. Cardiac fibrosis is characterized by deterioration of cell... [ view full abstract ]

The main components of the myocardium are cardiomyocytes and cardiac fibroblasts. In cardiomyopathy, synchronized beating of the heart is often hampered by fibrosis. Cardiac fibrosis is characterized by deterioration of cell and matrix alignment due to fibroblast proliferation and increased matrix production. However, it remains unclear how these changes influence contractility on the cellular level.

An in vitro cardiac microtissue system was used to unravel the effects of cellular and extracellular perturbations on cardiac beating. A mixture of mouse neonatal cardiomyocytes and cardiac fibroblasts were seeded in collagen/matrigel hydrogel in arrays of microwells containing flexible posts. By manipulating the number of fibroblasts and collagen concentration, proliferation of fibroblasts and fibrosis was mimicked.

Microtissues started beating rhythmically after 2 days of culture. The deflection of the post was used to calculate beating frequency and dynamic contraction forces as measure for contractility. Our results showed that an increase in number of fibroblasts hampered contractility of the microtissues. Interestingly, only a fibroblasts density higher than 50% inhibited spontaneous beating of the microtissues. Collagen content did not affect beating frequency and contraction force corrected for compaction of the microtissues, indicating normal functionality.

Together, our results suggest that increased cardiac fibroblasts density and not collagen content is most detrimental for cardiomyocyte beating. For treatment of fibrosis, it is therefore more important to restore the cellular composition of the heart. This study presented an in vitro tissue model that is suitable for investigating pathophysiological events associated with cardiac fibrosis and thereby facilitates optimization of new therapies.