Collaborative Research: Intra- and Extra-Cellular Mechanisms of Right Ventricular Stiffening and their Role on the Organ Scale

The stiffness of the heart’s right ventricle (RV) is a critical determinant of cardiac health. For example, RV stiffness is a strong predictor of disease progression in pulmonary hypertension. It may even be a more reliable indicator of clinical outcomes than traditional measures of RV function, such as contractility. This research addresses the current lack of fundamental understanding of how intra- and extra-cellular mechanisms contribute to the stiffening of the RV. This topic has largely been overlooked in favor of studies focused on the structure and function of the heart’s left ventricle (LV). Given the significant differences in physiology between the RV and LV, this critical gap in knowledge presents a barrier to advancement in the diagnosis and treatment of RV-related conditions. Thus, by filling this gap, this project will provide insight into the mechanobiology of RV stiffening while supporting the development of new diagnostic tools, prognostic markers, and therapeutic strategies. This research is well-aligned with NSF’s mission to advance scientific progress and contribute to public welfare by addressing a significant health challenge. Furthermore, the project will provide educational and training opportunities for underrepresented student populations and enrich open science initiatives through publicly accessible content, such as live-streamed cardiac anatomy lessons. This project aims to delineate and model the intra- and extra-cellular mechanisms contributing to RV myocardial stiffening using a combination of experimental and computational approaches. Experimentally, micro-scale mechanical tests will be conducted on individual cardiomyocytes, followed by mechanical testing of combined cardiomyocyte-extracellular matrix strip assemblies. Primary myocardial samples isolated from the RV of both healthy and diseased sheep with established pulmonary hypertension will be included. Among the many potential biological mechanisms of RV stiffening, investigation will begin on variations in titin isoform expression and phosphorylation states and changes in endomysial collagen composition, density, and cross-linking. Computationally, machine-learning-based surrogate modeling approaches will be used to bring micro-scale models of cardiomyocytes and extracellular matrix up to the organ scale, where ultimately the role of each stiffening mechanism on tissue-scale measures, such as RV diastolic function, will be interrogated. The primary outcome of this work will be a multi-scale model that enhances understanding of RV physiology and diastolic dysfunction, thus contributing both valuable mechanobiological insights into RV remodeling and a set of open-source computational tools for future cardiovascular research. 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.