Fatty acid oxidation inhibition as a potential novel treatment strategy in pulmonary artery hypertension and right heart failure

BackgroundPulmonary arterial hypertension (PAH) leads to right ventricular (RV) failure and compromised energetics characterized by impaired glucose oxidation (GO) and augmented glycolysis. In this study, we hypothesized that fatty acid oxidation inhibition improved overall myocardial oxidative metabolism and attenuated PAH severity.MethodsA PAH model of Sugen-Hypoxia was generated in Sprague Dawley rats. A malonyl CoA decarboxylase inhibitor (MCDI) was given orally (100 mg/kg/day) to inhibit mitochondrial transfer of free fatty acids. PAH rats were randomly allocated to 3 separate groups: baseline (assessed after PAH generation), treatment (MCDI for 3wks) and control (vehicle for 3wks). PAH severity was assessed by measuring pulmonary arterial acceleration time (PAAT) using echocardiography, and with Millar catheterization for RV systolic pressure (RVSP). Single-photon emission computed tomography (SPECT) was performed to assess RV ejection fraction (RVEF) using technetium-99m pertechnetate. The positron emission tomography (PET) was applied using tracers [18F]fluoro-2-deoxy-glucose (FDG) and 14(R,S)-[18F]fluoro-6-thia-hepadecanoic acid (FTHA) to measure the standardized uptake values (SUV) of glucose and fatty acids, respectively. Total myocardial oxidative metabolism was also measured by the [11C]-acetate (C11) PET tracer that enters the tricarboxylic acid cycle and is cleared by mitochondrial oxidation. After sacrifice, cardiac tissues were collected for ATP quantification using luciferase driven bioluminescence normalized to healthy rats.ResultsA reduction in PAH severity was seen in MCDI-treated rats, as indicated by an increase in PAAT (20.6±1.0 ms (treatment) versus 15.6±0.6 ms (control) and 15.7±0.6 ms (baseline); p≤0.006), and a decrease in RVSP (65.3±3 mmHg (treatment) versus 114±5 mmHg (control) and 87±3 mmHg (baseline); p=0.001). RVEF was also improved in the MCDI treatment group (67.6±1.9%) compared to control (61.3±5.8%) and baseline (63.6±2.4%) groups. The RV/LV FTHA SUV ratio was decreased in the treatment group (46±15%) compared to control (85±10%) and baseline (83±11%). Although the FDG SUV was equivalent between groups, overall oxidative metabolism was greater in MCDI treatment as indicated by increased C11 clearance constant in MCDI-treated rats (0.067±0.010 1/min) compared to control (0.052±0.006 1/min) and baseline (0.054±0.008 1/min). The RV normalized ATP level of MCDI-treated rats was increased compared to vehicle-treated rats (1.01±0.07 versus 0.80±0.01; p=0.04).ConclusionMCDI treatment was associated with a reduction in PAH severity (increased PAAT, decreased RVSP and improved RVEF). Increased ATP content and C11 clearance rate, reduced FTHA uptake and maintained FDG uptake suggest an increased GO and/or reduced glycolysis. This metabolic modulation therapy may represent a means to treat or prevent RV dysfunction. Further studies are required. BackgroundPulmonary arterial hypertension (PAH) leads to right ventricular (RV) failure and compromised energetics characterized by impaired glucose oxidation (GO) and augmented glycolysis. In this study, we hypothesized that fatty acid oxidation inhibition improved overall myocardial oxidative metabolism and attenuated PAH severity. Pulmonary arterial hypertension (PAH) leads to right ventricular (RV) failure and compromised energetics characterized by impaired glucose oxidation (GO) and augmented glycolysis. In this study, we hypothesized that fatty acid oxidation inhibition improved overall myocardial oxidative metabolism and attenuated PAH severity. MethodsA PAH model of Sugen-Hypoxia was generated in Sprague Dawley rats. A malonyl CoA decarboxylase inhibitor (MCDI) was given orally (100 mg/kg/day) to inhibit mitochondrial transfer of free fatty acids. PAH rats were randomly allocated to 3 separate groups: baseline (assessed after PAH generation), treatment (MCDI for 3wks) and control (vehicle for 3wks). PAH severity was assessed by measuring pulmonary arterial acceleration time (PAAT) using echocardiography, and with Millar catheterization for RV systolic pressure (RVSP). Single-photon emission computed tomography (SPECT) was performed to assess RV ejection fraction (RVEF) using technetium-99m pertechnetate. The positron emission tomography (PET) was applied using tracers [18F]fluoro-2-deoxy-glucose (FDG) and 14(R,S)-[18F]fluoro-6-thia-hepadecanoic acid (FTHA) to measure the standardized uptake values (SUV) of glucose and fatty acids, respectively. Total myocardial oxidative metabolism was also measured by the [11C]-acetate (C11) PET tracer that enters the tricarboxylic acid cycle and is cleared by mitochondrial oxidation. After sacrifice, cardiac tissues were collected for ATP quantification using luciferase driven bioluminescence normalized to healthy rats. A PAH model of Sugen-Hypoxia was generated in Sprague Dawley rats. A malonyl CoA decarboxylase inhibitor (MCDI) was given orally (100 mg/kg/day) to inhibit mitochondrial transfer of free fatty acids. PAH rats were randomly allocated to 3 separate groups: baseline (assessed after PAH generation), treatment (MCDI for 3wks) and control (vehicle for 3wks). PAH severity was assessed by measuring pulmonary arterial acceleration time (PAAT) using echocardiography, and with Millar catheterization for RV systolic pressure (RVSP). Single-photon emission computed tomography (SPECT) was performed to assess RV ejection fraction (RVEF) using technetium-99m pertechnetate. The positron emission tomography (PET) was applied using tracers [18F]fluoro-2-deoxy-glucose (FDG) and 14(R,S)-[18F]fluoro-6-thia-hepadecanoic acid (FTHA) to measure the standardized uptake values (SUV) of glucose and fatty acids, respectively. Total myocardial oxidative metabolism was also measured by the [11C]-acetate (C11) PET tracer that enters the tricarboxylic acid cycle and is cleared by mitochondrial oxidation. After sacrifice, cardiac tissues were collected for ATP quantification using luciferase driven bioluminescence normalized to healthy rats. ResultsA reduction in PAH severity was seen in MCDI-treated rats, as indicated by an increase in PAAT (20.6±1.0 ms (treatment) versus 15.6±0.6 ms (control) and 15.7±0.6 ms (baseline); p≤0.006), and a decrease in RVSP (65.3±3 mmHg (treatment) versus 114±5 mmHg (control) and 87±3 mmHg (baseline); p=0.001). RVEF was also improved in the MCDI treatment group (67.6±1.9%) compared to control (61.3±5.8%) and baseline (63.6±2.4%) groups. The RV/LV FTHA SUV ratio was decreased in the treatment group (46±15%) compared to control (85±10%) and baseline (83±11%). Although the FDG SUV was equivalent between groups, overall oxidative metabolism was greater in MCDI treatment as indicated by increased C11 clearance constant in MCDI-treated rats (0.067±0.010 1/min) compared to control (0.052±0.006 1/min) and baseline (0.054±0.008 1/min). The RV normalized ATP level of MCDI-treated rats was increased compared to vehicle-treated rats (1.01±0.07 versus 0.80±0.01; p=0.04). A reduction in PAH severity was seen in MCDI-treated rats, as indicated by an increase in PAAT (20.6±1.0 ms (treatment) versus 15.6±0.6 ms (control) and 15.7±0.6 ms (baseline); p≤0.006), and a decrease in RVSP (65.3±3 mmHg (treatment) versus 114±5 mmHg (control) and 87±3 mmHg (baseline); p=0.001). RVEF was also improved in the MCDI treatment group (67.6±1.9%) compared to control (61.3±5.8%) and baseline (63.6±2.4%) groups. The RV/LV FTHA SUV ratio was decreased in the treatment group (46±15%) compared to control (85±10%) and baseline (83±11%). Although the FDG SUV was equivalent between groups, overall oxidative metabolism was greater in MCDI treatment as indicated by increased C11 clearance constant in MCDI-treated rats (0.067±0.010 1/min) compared to control (0.052±0.006 1/min) and baseline (0.054±0.008 1/min). The RV normalized ATP level of MCDI-treated rats was increased compared to vehicle-treated rats (1.01±0.07 versus 0.80±0.01; p=0.04). ConclusionMCDI treatment was associated with a reduction in PAH severity (increased PAAT, decreased RVSP and improved RVEF). Increased ATP content and C11 clearance rate, reduced FTHA uptake and maintained FDG uptake suggest an increased GO and/or reduced glycolysis. This metabolic modulation therapy may represent a means to treat or prevent RV dysfunction. Further studies are required. MCDI treatment was associated with a reduction in PAH severity (increased PAAT, decreased RVSP and improved RVEF). Increased ATP content and C11 clearance rate, reduced FTHA uptake and maintained FDG uptake suggest an increased GO and/or reduced glycolysis. This metabolic modulation therapy may represent a means to treat or prevent RV dysfunction. Further studies are required.