Title: The emergence of mechanical form and function in the cardiac myocyte
Description: The heart actively remodels architecture in response to various physiological and pathological conditions. Gross structural change of the heart is directly reflected at the cellular level by altering the form and function of individual cardiomyocytes. Thus, cardiomyocyte structure and contractility may be associated with cellular morphology. Here we describe new techniques to engineer cardiomyocyte form with micro-scale control. Combing our techniques with traditional traction force assays, we demonstrate that the characteristic morphology of cardiomyocytes observed in a variety of pathophysiological states is correlated with distinct structure and mechanical function. We found that cardiomyocyte contractility is optimized at the cell length to width ratio observed in normal hearts, and decreases in cardiomyocytes with morphologies resembling those isolated from failing hearts. Quantitative analysis of sarcomeric architecture revealed that the change of contractility may arise from alteration of myofibrillar registry. We further demonstrate that the spatial arrangement of the sarcomeric architecture may be understood as a result of the mechanical interaction between the contractile apparatus and the extracellular matrix.

We develop a theoretical model that quantitatively recapitulates the cytoskeletal geometry and contractile characteristics of in vitro cardiomyocytes with defined morphologies. Numerical results reveal that the cooperative behaviors amongst the cell adhesions and contractile apparatus are critical in determining the spatial layout of cardiomyocyte architecture. Our data indicate that cardiomyocyte shape, cytoskeletal architecture, and contractility are tightly coupled, and specifically highlight the importance of extracellular geometric cues in directing the mechanical form and function of the cell. We suggest that the pumping performance of the ventricular wall may be in part determined by the individual myocyte morphology. Exploring the associated mechanisms underlying this link should provide considerable opportunity for treatment of a variety of heart diseases.