What triggers RV Fiber Re-Orientation in response to RV pressure overload, and what is its Consequence on Inter-Ventricular Decoupling?

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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 left ventricle (LV) in RV function is almost completely discounted, but previous research from the 90’s has suggested that the LV is more important for RV function than the contracting RV free wall. Our preliminary data shows that LV torsion rate is reduced in children with PH and in mice after pulmonary arterial banding (PAB), which is correlated with reduced RV ejection fraction in both species. However, when we induced LV pressure overload in the PAB mice (by partial aortic constriction), we improved their LV torsion rate and RV systolic function. This was further validated with in silico studies of the bi-ventricular heart, which showed that targeting LV torsion rate could improve RV systolic function, but it depends on RV free wall fiber orientation. Therefore, these results left us with the following questions: (1) What new orientation do the fibers adopt in response to pressure overload (our preliminary results are not consistent with others), and does this new orientation improve or worsen RV function? (2) How does RV fiber re-orientation impact LV-to-RV mechanical assistance during systole? (3) How does the transient fiber re-orientation and stiffening impact mechanical stress/strain within the tissue, and how does that impact -or is driven by- gene expression? 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 expose how they trigger their downstream remodeling pathways. The questions being answered in this project will lead to a better understanding of how RV structural remodeling, in response to pressure overload, impacts RV function and interventricular coupling, and identify target genes governing this process for future studies.