Cardiac Tissue Organization and Contractility

Abstract

From the sarcomere to the myocardium, the heart is intricately organized on a wide range of length-scales. Multiple types of heart diseases are associated with remodeling of myofibrils and their sarcomeres - the basic force producing unit of the heart. However, it is not fully understood how organization of cardiac tissues affects the contractility properties. Disorganized tissues were found to be significantly weaker than predicted based on measurements from organized tissues. However, the prediction is based on a simplified net-force model, which has never been proven to accurately represent cardiac tissues because organizational variations are associated with downstream effects such as changes in gene expression levels that can further affect function. We hypothesized that these downstream effects could be muted if the cells were directed to organize locally (∼250 micron scale), while keeping the global organization varied (∼2 mm scale). The relationship between global organization and force production was modeled using a metric describing structure and developed contraction stress, and the locally organized, parquet, tissues were made with a range of global organizations. All of these tissues were then tested using the “heart-on-a-chip” device to measure the global stress production. We have shown that with muted downstream effects, which are normally driven by local tissue organization, the global organization of the myofibrils is related to the net stress developed by a cardiac tissue through a single parameter analytical model. We have also shown that disorganized tissues tend to spontaneously form organized patches that are ∼120 microns in scale, which can now be tested in conjunction with the force-organization model. These results will lead to a better understanding of the normal and pathological hearts.