CAREER: How Does the Heart Contract? A Microstructure-Based Approach to Understand Cardiac Function and Dysfunction

The University Of Central Florida Board Of Trustees, Orlando FL

Investigators

Abstract

This Faculty Early Career Development (CAREER) grant supports research that will link cellular and tissue level mechanics to heart function in health and disease. At the microscale, cardiac tissue consists of a network of continuously branching and merging cardiomyocytes. These heart muscle cells form a complex microstructure with preferential orientations and sheetlet planes. Driven by an electrical signal, the cardiomyocytes shorten and lengthen leading to sheetlets, tissue, and ventricular motion. To investigate function and dysfunction across scales, this project will develop a multiscale and multiphysics model capable of relating observable macroscopic motion to its causes at the cellular and tissue levels. The resulting approach will be applied to investigate localized and diffuse abnormalities and how they contribute to cardiac dysfunction across scales. The microstructure-based understanding of cardiac function can advance the diagnosis and therapy for patients affected by cardiac diseases. The multiscale models will connect changes at the cellular and microstructural levels to tissue and ventricle scale deformation measures, which may lead to new diagnostic markers. Simultaneously, the microscale mechanisms leading to abnormal cardiac motion can suggest targets for therapy planning. To accelerate the dissemination and adoption of the results obtained in this research, the constructed modeling framework and deformation measures will be shared with the imaging community, integrated into the education of graduate and undergraduate students, and included in outreach activities with middle and high school students. This project will develop a microstructure-based understanding of cardiac motion and function. The computational framework will model: (i) the continuous network of the cardiomyocytes; (ii) the complex mesoscale structure; and (iii) cardiomyocytes’ mechanics and electrophysiology. Accounting for these discrete components will uncover how deformation of cells and cell aggregates lead to observed cardiac motion, e.g., longitudinal shortening, wall thickening, and twist during ventricular contraction. The identified deformation modes will be leveraged to formulate microstructure-based markers of cardiac deformation, which will be computed and tested using preclinical voxelwise experimental data. The framework and deformation measures will then be applied to understand the kinematics and mechanics of cardiac dysfunction in the presence of localized scar tissue or diffuse fibrosis and cardiomyocyte function impairment. Micro and mesoscale changes will be accounted for without a priori hypotheses on their effect, enabling the discovery of how cellular and mesoscale abnormalities are connected to macroscopic tissue and ventricular dysfunction. 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.