Collaborative Research: Multiscale Cardiomyocyte Mechano-Adaptation

During every heartbeat, the cells stretch and move as the heart contracts and fills. In disease or following surgery, the way the heart deforms can change, which causes the cells to adapt. Ideally, this adaptation will lead to more efficient heart function, but in some cases, adaptation exacerbates dysfunction, leading to heart failure. The central goal of this project is to mathematically characterize how cardiomyocytes (the primary functional cells in the heart) adapt to changes in their mechanical environment. This research will experimentally measure the cell structure and contractile function of cardiomyocytes exposed to short- and long-term stretching. This will be done using the conditions of both a healthy heart and one whose deformation is perturbed by disease or surgery. Concurrently, we will develop computational models that will provide insight into how perturbed deformations affect the key contractile proteins within the cardiomyocyte. Finally, the experimental and computational results will be combined to create models that can be used to predict cellular adaptation due to any change in deformation. These studies represent a first step toward a computational approach that could be used to guide surgeries or design interventions that optimize cardiac adaptation in heart disease patients. In parallel with these studies, the CardioStart outreach program developed at the University of California-Irvine, will be extended to reach high school students in the vicinity of the University of Minnesota-Twin Cities. Additionally, the program will be expanded with modules that introduce students to cardiac mechano-adaptation.There is a lack of fundamental understanding of how cardiac cells respond to complex mechanical loads. Elucidating the functional adaptation response of cardiac tissues would provide an opportunity to guide surgeries, 3D tissue engineered hearts or patches, and construction of in vitro heart disease models for testing of interventions. Currently, most of the methods are based on qualitative design approaches. For a more quantitative approach, it is necessary to build the fundamental understanding of the mechano-adaptive response of cardiomyocytes, which could be packaged in a model for a predictive design-build framework applicable to a wide variety of challenges. Therefore, our goals are to: 1) Elucidate the acute mechano-adaptive response of cardiomyocytes exposed to complex loads. We hypothesize that the deformation of the cells, caused by the complex loads, changes the dynamics of the actin-myosin motors in the sarcomere leading to changes in efficiency of contraction. 2) Elucidate the long-term mechano-adaptive response of cardiomyocytes exposed to complex loads. We hypothesize that the loss of efficiency in contraction leads to remodeling of the cardiomyocytes to minimize the free energy of the system. Through the combination of experimental measurements and multi-scale models, this project will elucidate both the acute functional and long-term remodeling response of the cardiomyocytes to complex loads.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.