Pulmonary arterial hypertension (PAH) severity is associated with alterations in the heart’s metabolism, but a recent study showed that Opsumit (macitentan) can reduce these metabolic changes, lessening PAH severity and easing strain on the heart’s right ventricle.
The study, “Effects of an endothelin receptor antagonist, Macitentan, on right ventricular substrate utilization and function in a Sugen 5416/hypoxia rat model of severe pulmonary arterial hypertension,” was reported in the Journal of Nuclear Cardiology, a publication of the American Society of Nuclear Cardiology.
Progressive right ventricular (RV) dysfunction and, eventually, right heart failure is a consequence of PAH. But despite its severity, there are no therapies that directly and selectively target the heart’s RV in PAH patients. Instead, treatment is centered on improved pulmonary vascular remodeling.
One therapeutic treatment is Opsumit, an endothelin receptor antagonist with demonstrated and significant benefits to PAH patients. Endothelins are proteins that constrict blood vessels and raise blood pressure, both key pathogenic mediators of PAH. The disease has also been shown to alter the metabolism of the heart’s muscle (myocardium). Targeting such changes in myocardial metabolism is a potential new therapeutic strategy for PAH.
To investigate the effects of Opsumit, researchers monitored the metabolism (glucose and fatty acid) in a live rat model of PAH.
PAH was induced in the male Sprague-Dawley rats. After five weeks, the animals were randomly assigned to receive Opsumit (30 mg/kg daily) treatment or no treatment. The use of glucose and fatty acids was determined by positron emission tomography (PET) scanning, a functional imaging technique used to observe metabolic processes in the body by tracing a radioactive drug. Researchers injected radioactive glucose and fatty acid molecules to assess metabolic changes throughout the progression of PAH, and how these changes correlate with RV function.
They detected serial changes in both glucose and fatty acid metabolism with PAH. Specifically, glucose uptake was shown to increase linearly with disease severity. Fatty acid metabolism only increased early in the disease, with no sustained changes detected as PAH progressed.
Rats treated with Opsumit showed improvements in PAH severity and RV function, in agreement with previously published studies. Additionally, the animals had significantly longer pulmonary artery acceleration time, corresponding to less severe pulmonary hypertension and an improved RV ejection fraction.
Overall, the study showed that PAH is associated with changes in RV metabolism, characterized by increased fatty acid and glucose uptake in the RV. Treatment with Opsumit reduced PAH severity and was associated with a decrease in glucose utilization, which improved RV function.