Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake

Abstract

In severe pulmonary hypertension (SPH), prior studies have shown an increase in right ventricle (RV) uptake of glucose, but it is unclear whether there is a change in the relative utilization of fatty acids. We hypothesized that in the RV in SPH, as in left ventricular (LV) failure, there is altered substrate utilization, with increased glucose uptake and decreased fatty acid uptake. SPH was induced in rats by treatment with the VEGF receptor inhibitor SU5416 and 3 wk of hypoxia (10% FiO2 ), followed by an additional 4 wk of normoxia (SU-Hx group). Control rats were treated with carboxymethylcellulose vehicle and 7 wk of normoxia (CMC-Nx group). The rodents then underwent positron emission tomography with sequential administration of two radiotracers, 2-deoxy-2-[(18)F]fluoroglucose ((18)F-FDG) and 14-(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)F-FTHA), analogs of glucose and fatty acid, respectively. Five CMC-Nx and 3 SU-Hx rats completed the entire experimental protocol. In the RV, there was a mild increase in (18)F-FDG uptake (1.35-fold, P = 0.085) and a significant decrease in (18)F-FTHA uptake (-2.1-fold, P< 0.05) in the SU-Hx rats relative to the CMC-Nx rats. In the LV, SU-Hx rats had less uptake of both radiotracers compared with CMC-Nx rats. Less RV fatty acid uptake in SPH was corroborated by decreased fatty acid transporters and enzymes in the RV tissue, and specifically a decrease in lipoprotein lipase. In the RV in rats with SPH, there is a major shift in metabolic substrate preference, largely due to decreased fatty acid uptake.

Platelets from pulmonary hypertension patients show increased mitochondrial reserve capacity

“…These observations in platelets are consistent with prior studies linking FAO to increased reserve capacity in cardiomyocytes (7,14). Our data also mirror prior studies in other tissues in PH demonstrating a decreased reliance on glucose oxidation (15) and increased FAO enzyme activity (13). The observed trend toward decreased PDH activity and increased CPT1 enzyme activity observed in the PH platelets provides an enzymatic basis for substrate switching.…”

“…Notably, mitochondrial and metabolic aberrations are not confined to the pulmonary vasculature. Cardiac tissue and cells from animal models of PH have shown altered mitochondrial ETC enzyme expression, as well as changes in substrate utilization (12)(13)(14)(15)(16)(17), and increased expression of glycolytic enzymes has also been reported in the skeletal muscle of PH patients (18). Consistent with a central role for this glycolytic shift in PH pathogenesis, pharmacologic therapy that suppresses glycolysis while enhancing oxidative phosphorylation attenuates PH progression (10,15).…”

Assessment of right ventricular metabolism: An emerging tool for monitoring pulmonary artery hypertension

“…27 A recent study investigating RV metabolism in the Sugen5416/Hypoxia rat model found a significant decrease in RV FTHA uptake and an increase in RV FDG uptake at 8 weeks. 13 In comparison with these findings, the current study by Drozd et al showed a twofold increase in FTHA uptake at 5 weeks, which was slightly lower but still elevated at 8 weeks. Interestingly, in the current study, the increased FTHA uptake was not affected by macitentan therapy at this 8-week time point.…”

“…There is growing evidence from both animal studies 12,13 and clinical observations 14-16 that PAH is associated with increased RV FDG uptake compared to controls. In small cohorts of PAH patients, the left ventricle (LV) to RV FDG uptake ratio was shown to correlate well with pulmonary artery pressures 17 and RV ejection fraction.…”

Update on novel targets and potential treatment avenues in pulmonary hypertension

“…203,229). In the SuHx model of PH, severe RV dysfunction was associated with a shift in metabolic substrate utilization, measured via imaging for 2-deoxy-2-[ 18 F]fluoroglucose (glucose analog) and 14-(R,S)-[ 18 F]fluoro-6-thia-heptadecanoic acid (fatty acid analog), demonstrating increased glucose, and reduced fatty acid, uptake (96). These results were consistent with data in patients indicating increased RV glucose uptake that correlated with RV dysfunction (33,150,275).…”