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

该学院早期职业发展（CAREER）资助支持将细胞和组织水平力学与健康和疾病中的心脏功能联系起来的研究。在微观尺度上，心脏组织由连续分支和合并的心肌细胞网络组成。这些心肌细胞形成具有优先取向和片状平面的复杂微结构。在电信号的驱动下，心肌细胞缩短和延长，导致小片、组织和心室运动。为了研究跨尺度的功能和功能障碍，该项目将开发一个多尺度和多物理模型，能够将可观察到的宏观运动与其在细胞和组织水平上的原因联系起来。由此产生的方法将被应用于调查局部和弥漫性异常，以及它们如何有助于跨尺度的心功能障碍。基于心脏微结构的心功能研究有助于心脏疾病的诊断和治疗。多尺度模型将细胞和微观结构水平的变化与组织和心室尺度变形措施联系起来，这可能会导致新的诊断标记。同时，导致异常心脏运动的微观机制可以为治疗计划提供目标。为了加速本研究成果的传播和应用，我们将把构建的模型框架和变形测量方法与影像学界共享，并将其纳入研究生和本科生的教育中，同时将其纳入与初中和高中学生的外联活动中。本项目将发展基于微观结构的心脏运动和功能理解。计算框架将建模：（i）心肌细胞的连续网络;（ii）复杂的中尺度结构;（iii）心肌细胞的力学和电生理学。考虑这些离散分量将揭示细胞和细胞聚集体的变形如何导致观察到的心脏运动，例如，纵向缩短、室壁增厚和心室收缩时的扭曲。将利用所识别的变形模式来制定基于微结构的心脏变形标记，将使用临床前体素实验数据对其进行计算和测试。然后，将应用框架和变形措施来了解局部瘢痕组织或弥漫性纤维化和心肌细胞功能障碍存在下的心脏功能障碍的运动学和力学。微观和中尺度的变化将在没有先验假设的情况下解释其影响，从而发现细胞和中尺度异常如何与宏观组织和心室功能障碍联系在一起。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.