Understanding the Consequences of Cell-to-Cell Mechanical Variation in the Heart

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The heart is made of millions of individual muscle cells that must contract together in a coordinated way to pump blood. Because the cells must work together, they are electrically connected to one another to synchronize beating. It might have been expected that the strength and speed of contraction would be the same in neighboring cells. However, when cells are separate, their mechanical behavior is surprisingly different. It is not clear how these cells, being so different mechanically, still work together to produce efficient pumping. In this project, cell-to-cell mechanical variation will be measured in small samples of heart tissue. From this information, an accurate computer model of heart tissue can be created. The model will help explain how cell-to-cell variation impacts overall tissue function. Finally, the predictions made by the model will be tested in engineered heart tissues, which allow the amount of cell variability to be adjusted and studied. This work is significant because cell variability tends to increase with aging and in certain diseases. A clearer understanding of how variation contributes to normal and abnormal heart function could ultimately inspire effective treatments for cardiac disorders that are currently incurable. New data suggest that adjacent cells from healthy heart tissue display substantial mechanical differences. How this 'microscale heterogeneity' affects the mechanical function of bulk myocardium has never been studied, but has far-reaching implications. This project examines the impact of microscale heterogeneity by testing two hypotheses: (1) That it has an appreciable influence on myocardial contraction even in normal hearts, and (2) That increasing microscale heterogeneity beyond normal limits disrupts tissue function. After measuring the nature and scope of microscale heterogeneity, its effects on tissue mechanical behavior will be predicted using a novel multiscale computational model. This model is comprised of a biophysically detailed muscle contraction model embedded in a finite element mesh for simulation of three-dimensional tissue mechanics. The predictions produced by the model can be tested by genetically manipulating cellular heterogeneity in engineered myocardial tissue mimics and measuring their biomechanical characteristics. The aggregate behavior of a network of adjacent but functionally different muscle cells has the potential of displaying new and surprising emergent properties. If proven correct, these hypotheses would shift current opinion on the determinants of myocardial relaxation and tissue homeostasis while shedding light on disease mechanisms.