Right heart remodeling in Sugen/hypoxia rat model of severe pulmonary hypertension

Pulmonary hypertension (PH) directly impacts the right heart through pressure overload. Unlike well-characterized remodeling of the left ventricle in systemic hypertension, PH-induced changes in the right heart are less understood. Here, we investigate chamber-specific alterations in the right atrium (RA) and right ventricle (RV) in a rat model of PH. PH was induced in 6-week-old male Wistar rats using Sugen/hypoxia (SuHx) treatment. Right heart pressure overload was confirmed by catheterization. Cardiac remodeling was characterized by using confocal microscopy, micro-CT, optical mapping, and proteomic mass spectrometry. The increase in right-heart mass was predominantly attributable to cardiomyocyte hypertrophy, with concomitant extracellular-matrix remodeling. Hypertrophy was associated with significantly elevated right heart pressures after SuHx treatment, further progressing during the subsequent normoxia. At the end of the PH protocol, electrophysiology analysis showed significant prolongation of the action potential in both the RA and RV. Proteomic analysis revealed pronounced alterations in the RV, with substantial overlap with the RA and LV, and more upregulated than downregulated proteins. GO analysis indicated increased expression of sarcomeric and fibrillar proteins and reduced expression of proteins related to oxidative energy production. In conclusion, myocardial remodeling in PH is based on cardiomyocyte hypertrophy rather than cell proliferation. Electrophysiological changes along with increased pressure in the right atrium might contribute to phenotype progression. Changes in proteome show commonalities and differences in RA and RV pressure-induced pathways that that warrant therapeutic exploration.