Abstract Body (Do not enter title and authors here): The helical motion during the macroscopic contraction of the heart is driven by the twisted arrangement of cardiomyocytes. The cardiac fibers exhibit a distinct chirality characterized by a counterclockwise rotation from the epicardial to the endocardial surface. This unique structure of the cardiac fibers forms the nematic pattern akin to that observed in liquid crystal. Although the nematic pattern of cardiac fibers has been studied in 2D, the absence of 3D characterization has limited our understanding of how the microscopic cell chirality translates into macroscopic contractile motion of the heart.

Analyses of the left ventricular free wall of light-sheet and confocal imaging of cleared mouse hearts and diffusion tensor MRI data from human hearts revealed a 135-degree counterclockwise rotation of cardiomyocytes. This chiral pattern is established during stages E12.5-14.5 concomitant with the development of compact layer in mouse embryo. The formation of the local tissue chirality is independent of systemic Left-Right signal as heterotaxy hearts display the same counterclockwise rotation in mice. A prominent feature of liquid crystals is the formation of topological defects, discontinuities of orientation field with nematic order. Our 3D analyses revealed distinct topological defects in the left apex and in the anterior interventricular septum. Mechanical simulation based on these data showed that the 135-degree counterclockwise fiber rotation is advantageous for the macroscopic contractile function and that the work production is reduced in the topological defect regions.

Together, this first 3D analysis of the muscle fiber orientation in mammalian heart provides a solid basis for how chiral nematic behavior of the cardiomyocytes shapes the architecture and function of the heart. The demonstration of the theoretical foundation for the organ function by cellular topology is of great significance to our understanding of the physiology and pathology of the heart.