Clinical Trials Targeting Metabolism in Pulmonary Arterial Hypertension

Abstract

Metabolic derangement is a pathologic feature of pulmonary arterial hypertension (PAH).1 Metabolic abnormalities such as aerobic glycolysis and impaired fatty acid oxidation are consistently observed across different animal models of PAH. Importantly, altered metabolism in human PAH and experimental models is not restricted to the pulmonary vasculature, raising the possibility that PAH is a systemic metabolic disease.2 For example, lipid accumulation is present in the myocardium and skeletal muscle of humans with PAH and the right ventricle exhibits increased glucose uptake compared with matched controls. As a result of these observations, targeting metabolic dysfunction has emerged as an important therapeutic approach for patients with PAH.3 This article will review key aspects of metabolism in PAH, existing metabolic data in humans, and will describe completed and ongoing clinical trials targeting metabolic dysfunction in patients with PAH.

Effects of macitentan and tadalafil monotherapy or their combination on the right ventricle and plasma metabolites in pulmonary hypertensive rats

“…Evidence suggests that changed metabolism plays a key role in PAH pathogenesis 36 and a number of novel pharmacological agents targeting those changes are under investigation for their effects in PAH. 37 In addition, several circulating metabolites determine the adverse outcome of patients with PAH 38 serving as potential biomarkers. Moreover, some circulating metabolites are correlated with the RV parameters in PAH patients.…”

“…Initially, we searched for metabolites, which were significantly altered by disease versus healthy control and we investigated if the agents used were able to recover those changes in both SuHx and PAB rats. Evidence suggests that changed metabolism plays a key role in PAH pathogenesis 36 and a number of novel pharmacological agents targeting those changes are under investigation for their effects in PAH 37 . In addition, several circulating metabolites determine the adverse outcome of patients with PAH 38 serving as potential biomarkers.…”

MicroRNA‑18a‑5p regulates the Warburg effect by targeting hypoxia‑inducible factor 1α in the K562/ADM cell line

“…Targeting the Warburg effect provides potential therapeutic opportunities for leukemia ( 18 ). A clinical trial has been carried out to change the metabolic process in order to enhance drug sensitivity ( 19 ). Hypoxia-inducible factor 1α (HIF-1α) plays a key role in the Warburg effect.…”