Table 3:

Recent PAH clinical trials targeting endothelial signaling pathways

EC Phenotype targeted	Therapy	Mechanism of Action	Design	Duration	Identifier(s)
Altered EC metabolism	Dichloroacetate	Inhibits PDK	Phase I	16weeks	NCT01083524
	Metformin	Increases glucose uptake	Phase I	12weeks	NCT03349775
	Ranolazine	Reduces intracellular calcium	Phase I-IV RCTs	12–26weeks	NCT02829034
					NCT01839110
					NCT02133352
	Trimetazidine	Inhibits oxidation of free fatty acids	Phase II/III	12weeks	NCT03273387
Altered EC metabolism, Inflammation	Bardoxolone methyl	Nrf2/NFkB pathway	Phase II/III RCTs	16weeks-5years	NCT02036970
					NCT02657356
					NCT03068130
Inflammation	Anakinra	Inhibits IL-1 receptor	Phase I/II	14days-4weeks	NCT01479010
					NCT03057028
	Tocilizumab	Inhibits IL-6 binding	Phase II	24weeks	NCT02676947
	Ubenimex	Inhibits aminopeptidases	Phase II	24weeks-1year	NCT02736149
					NCT02664558
Vasoconstriction	EPC-induced eNOS gene transfer	eNOS gene transfer	Phase II	24weeks	NCT03001414

Multiple EC signaling pathways are being targeted by therapies that are currently in clinical trials of PAH. Abbreviations: EC, endothelial cell; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; IL, interleukin; NFκB, nuclear factor κB; Nrf, nuclear factor erythroid 2–related factor; PDK, pyruvate dehydrogenase kinase; RCT, randomized controlled trials.