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Pulmonary arterial hypertension (PAH) is a rare multifactorial disease with an unfavorable prognosis. Sildenafil therapy can improve functional capacity and pulmonary hemodynamics in PAH patients. Nowadays, it is increasingly recognized that the effects of sildenafil are pleiotropic and may also involve changes of the pro-/antioxidant balance, lipid peroxidation and autonomic control. In present study we aimed to assess the effects of sildenafil on the fatty acids (FAs) status, level of hydroxynonenal (HNE) and heart rate variability (HRV) in PAH patients. Patients with PAH were characterized by an increase in HNE and changes in the FAs composition with elevation of linoleic, oleic, docosahexanoic acids in phospholipids as well as reduced HRV with sympathetic predominance. Sildenafil therapy improved exercise capacity and pulmonary hemodynamics and reduced NT-proBNP level in PAH. Antioxidant and anti-inflammatory effects of sildenafil were noted from the significant lowering of HNE level and reduction of the phopholipid derived oleic, linoleic, docosahexanoic, docosapentanoic FAs. That was also associated with some improvement of HRV on account of the activation of the neurohumoral regulatory component. Incomplete recovery of the functional metabolic disorders in PAH patients may be assumed from the persistent increase in free FAs, reduced HRV with the sympathetic predominance in the spectral structure after treatment comparing to control group. The possibilities to improve PAH treatment efficacy through mild stimulation of free radical reactions and formation of hormetic reaction in the context of improved NO signaling are discussed., Highlights • Sildenafil showed antioxidant and anti-inflammatory effects in pulmonary hypertension. • Sildenafil reduced hydroxynonenal level and improved fatty acid profile in serum. • Improvement of heart rate variability and functional capacity was noted after therapy. • Mild prooxidant activity is suggested as the mechanism to improve sildenafil efficacy.

Summary Background Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. Methods The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II–IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm 5 and a walk distance of 150–450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. Findings Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70–0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). Interpretation In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. Funding Actelion Pharmaceuticals Ltd.

Excessive production of reactive oxygen species, oxidative stress (OS) and metabolic dysfunction are the major contributors for the development and progression of pulmonary arterial hypertension (PAH). Sildenafil was shown to improve pro-/antioxidant balance but its long–term effects on PAH are not well understood. This work was aimed to study the effect of the prolonged use of sildenafil on the metabolic dysfunction associated with redox imbalance in PAH. In the PAH patients treated at least 12 months with sildenafil, who did not show signs of disease progression, the parameters of lipid peroxidation, endocannabinoid system, redox signaling and apoptosis were measured at the follow up visits scheduled three months apart. Our results showed increase in hydroxynonenal, hydroxyhexanal, and malonic dialdehyde together with decrease in phospholipids derived linoleic, arahidonic and docosahexanoic fatty acids after three month of sildenafil therapy. Also lowering in endocannabinoid anandamide and its receptor 2-arachidonoyl glycerol and increased level of NF-kB were noted. Clinically PAH patients did not show any signs of deterioration by 6 minute walk test, functional class, heart rate variability and pulmonary hemodynamics followed by echocardiography during the study. Obtained results demonstrate that prolonged use of sildenafil does not restore metabolic dysfunction associates with PAH. Concurrent target use of antioxidants would beneficially influence the outcome.