Background: There is heterogeneity in right ventricular (RV) remodeling, and the likelihood of progression to RV failure (RVF) in response to pulmonary arterial hypertension (PAH) that is not explained by differences in the degree of afterload. We aimed to characterize alterations in RV metabolism during the development of RVF secondary to PAH in Sprague-Dawley (SD) and Fischer rats that exhibit adaptive and maladaptive RV remodeling, respectively.
Methods/Results: PAH was induced by a subcutaneous injection of the VEGFR antagonist, SU5416 and 3-weeks of hypoxia (SUHx). Fischer rats exhibited 100% mortality by 5-weeks, whereas SD rats showed excellent survival up to 9-weeks (88%;p<0.0001). Proteomics analysis revealed 92 differentially expressed RV proteins in Fischer compared to SD PAH rats (p<0.05), of these 27% were mitochondrial, suggesting a role for mitochondrial energy metabolism as an early determinant for maladaptive RV hypertrophy. At 4 weeks, in vivo oxidative metabolism, assessed by [11C]Acetate clearance (kmono), was significantly elevated in Fischer rats compared to SD (RV/LV ratio:0.82±0.09 vs 1.0±0.11min-1, respectively;p<0.05). Despite higher oxidative metabolism, Fischer rats exhibited a trend towards reduced RV power (p=0.055), and therefore, impaired RV efficiency compared to SD (0.24±0.04 vs. 0.45±0.11J/s×min-1×g, respectively;p<0.001). The potential for elevated oxidative metabolism in Fischer was also confirmed ex vivo by citrate synthase activity in RV homogenates. Activity of this key tricarboxylic acid (TCA) enzyme were markedly elevated in both naïve and SUHx Fischer in comparison to SD rats. In contrast, no baseline differences were observed in oxidative phosphorylation complex activity, measured in permeabilized RV cardiac fibers. Together these data suggests inefficiency in Fischer rats is due to impaired coupling between oxidative metabolism and ATP production.
Conclusion: These data point to impaired efficiency of RV energetics in the development of maladaptive remodeling in Fischer rats, and suggest that strategies to improve RV energetics may reverse this maladaptive phenotype.