Cause and effect of transient changes in stress, gene expression, and RV fiber orientation during RV remodeling, and its impact on RV function and inter-ventricular coupling in pulmonary hypertension

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PROJECT SUMMARY Pulmonary hypertension (PH) is a cardiopulmonary disease that ultimately leads to right ventricular (RV) failure. Currently there are no approved therapies targeting the RV and most research is focused on reducing fibrosis, although it is unclear if this will ultimately improve RV pumping function. However, the orientation of collagen and cardiomyocyte fibers likely have a major influence on RV function and are largely overlooked in ongoing research and clinical practice. Furthermore, the role of the LV in RV function is almost completely discounted, but previous research from the 90’s has suggested that the left ventricle (LV) is more important for RV function than the contracting RV free wall. Our previous data has shown that the mechanics of LV contraction is drastically different in children with PH and in mice after pulmonary arterial banding (PAB). Furthermore, mathematical simulations of the heart in our lab have shown that the mechanical burden of the remodeling and pressure-overloaded RV can result in the mechanistic problems we see in both ventricles in children with PH. However, two critical questions remain unanswered: how do changes in RV structure impact RV and LV contractile mechanics, and how do these changes in LV contractile mechanics impact RV function? In this study, we will combine the PAB mouse model with in silico simulations to investigate how changes in RV fiber orientation and stiffening, in the RV free wall, impact RV pumping function. Then, we will combine PAB with aortic constriction to study how RV remodeling interferes with LV torsion and if this interrupts LV-to-RV mechanical assistance during systole. Finally, by collecting a time course dataset of imaging and gene expression, we will identify genes that are directly impacted by changes in mechanical stress and how they trigger their downstream remodeling pathways. By bridging the gap between gene expression, structure, function, and inter-ventricular contractile mechanics, this project could lead to a better understanding of adaptive vs. maladaptive remodeling pathways. Furthermore, our research is focused on identifying those remodeling characteristics with the biggest influence on function and could expose gene expression pathways that will serve as drug targets in future studies.