A Multi-omic and Multi-Species Analysis of Right Ventricular Failure

Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved RV-targeted treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified changes in multiple metabolic pathways in the RV of PAB pigs, and pathway alterations that were conserved between species. However, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs. When compared to humans, the pig PAB molecular signature was more similar to patients with RVF than rodents. These data suggest there are divergent molecular responses of RVF across species, and pigs more accurately recapitulate the metabolic molecular signature of human RVF. RNA from bulk RV free wall tissue from control pigs and pulmonary artery banded pigs