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

ABSTRACT: Pulmonary arterial hypertension is a severe respiratory disease characterized by pulmonary artery remodeling. RV dysfunction and dysregulated circulating metabolomics are associated with adverse outcomes in pulmonary arterial hypertension. We investigated effects of tadalafil and macitentan alone or in combination on the RV and plasma metabolomics in SuHx and PAB models. For SuHx model, rats were injected with SU5416 and exposed to hypoxia for three weeks and then were returned to normoxia and treated with either tadalafil (10?mg/kg in chow) or macitentan (10?mg/kg in chow) or their combination (both 10?mg/kg in chow) for two weeks. For PAB model, rats were subjected to either sham or PAB surgery for three weeks and treated with above-mentioned drugs from week 1 to week 3. Following terminal echocardiographic and hemodynamic measurements, tissue samples were collected for metabolomic, histological and gene expression analysis. Both SuHx and PAB rats developed RV remodeling/dysfunction with severe and mild plasma metabolomic alterations, respectively. In SuHx rats, tadalafil and macitentan alone or in combination improved RV remodeling/function with the effects of macitentan and combination therapy being superior to tadalafil. All therapies similarly attenuated SuHx-induced changes in plasma metabolomics. In PAB rats, only macitentan improved RV remodeling/function, while only tadalafil attenuated PAB-induced changes in plasma metabolomics.

SUBMITTER: Mamazhakypov A

PROVIDER: S-EPMC7672745 | biostudies-literature | 2020 Oct-Dec

REPOSITORIES: biostudies-literature

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

Mamazhakypov Argen A Weiß Astrid A Zukunft Sven S Sydykov Akylbek A Kojonazarov Baktybek B Wilhelm Jochen J Vroom Christina C Petrovic Aleksandar A Kosanovic Djuro D Weissmann Norbert N Seeger Werner W Fleming Ingrid I Iglarz Marc M Grimminger Friedrich F Ghofrani Hossein A HA Pullamsetti Soni S SS Schermuly Ralph T RT

Pulmonary circulation 20201001 4

Pulmonary arterial hypertension is a severe respiratory disease characterized by pulmonary artery remodeling. RV dysfunction and dysregulated circulating metabolomics are associated with adverse outcomes in pulmonary arterial hypertension. We investigated effects of tadalafil and macitentan alone or in combination on the RV and plasma metabolomics in SuHx and PAB models. For SuHx model, rats were injected with SU5416 and exposed to hypoxia for three weeks and then were returned to normoxia and t ...[more]

PMID: 33240483

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Project description:BackgroundThe evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.MethodsAmong consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.ResultsTwenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.ConclusionTriple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.

Dataset Information

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

Publications

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

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