Introduction: We hypothesized that metabolic modulation by inhibiting fatty acid oxidation improves right ventricular (RV) failure in rat models of pulmonary arterial hypertension (PAH).Methods: Two rat models of PAH (Sugen_Hypoxia (SugHx)) and (pulmonary artery banding (PAB)) were treated by a malonyl CoA decarboxylase inhibitor (MCDI), an inhibitor of fatty acid transfer into the mitochondria (100 mg/kg/day PO; for 3wks). The controls received the drug vehicle. PAB rats had sham controls for MCDI and vehicle groups. Single-photon emission computed tomography (SPECT) for RV ejection fraction (RVEF) and positron emission tomography (PET) for metabolism were performed after 3wks of treatment. [F]fluoro-2-deoxy-glucose (FDG), 14(R,S)-[F]fluoro-6-thia-hepadecanoic acid (FTHA) and [C]-acetate were used to estimate RV glucose utilization, fatty acid uptake and oxidative metabolism rate using standard uptake values (SUVs) for FDG and FTHA and monoexponential clearance rate for [C]-acetate. The ATP content in excised RVs was measured by a bioluminescence kit and normalized to normal rats.Results: In vehicle-treated rats, the RVEFs were 59.6±4.2% (SugHx) and 64.0±0.6% (PAB) which were increased by MCDI treatment to 67.6±1.9% (p=0.08) and 70.6±0.9% (p=0.003), respectively. RVEF in vehicle and MCDI-treated sham rats did not differ (78.7±0.3 vs 80.0±2.0%). FTHA SUVs were higher in vehicle-treated (SugHx: 4.2±0.8; PAB: 3.7±0.2) vs MCDI-treated (SugHx: 2.0±0.4, p=0.03; PAB: 1.8±0.2, p=0.003) rats. In the sham groups, FTHA SUVs were equivalent regardless of treatment. MCDI treatment was not associated with FDG SUV changes in either PAH model. PAB rats (MCDI and vehicle) had 85±17% higher FDG SUVs than their sham controls (p<0.001). In vehicle-treated rats, [C] clearance rates were 0.066±0.004 (SugHx) and 0.082±0.004 (PAB) 1/min which were increased by the MCDI treatment to 0.199±0.020 (p<0.001) and 0.136±0.006 (p<0.001) 1/min, respectively. The RV ATP content in vehicle-treated rats was lower than MCDI group (0.80±0.01 vs 1.01±0.07, p=0.04).Conclusions: MCDI decreased FA uptake and led to increased RVEF, ATP and oxidative metabolism in PAH rats. This metabolic modulation is a novel approach to treat PAH-induced RV failure.