OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. RESULTS: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]). CONCLUSION: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.

• MeSH
• analýza dat * MeSH
• bezpečnost MeSH
• časové faktory MeSH
• chronická nemoc MeSH
• lidé středního věku MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• plicní embolie komplikace   farmakoterapie   MeSH
• plicní hypertenze farmakoterapie   etiologie   MeSH
• prospektivní studie MeSH
• pyrazoly škodlivé účinky   terapeutické užití   MeSH
• pyrimidiny škodlivé účinky   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• recidiva MeSH
• registrace * MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.

• MeSH
• amidy aplikace a dávkování   MeSH
• arteria pulmonalis patologie   patofyziologie   MeSH
• dospělí MeSH
• hypoxie krev   etiologie   patologie   MeSH
• intravenózní infuze MeSH
• Kaplanův-Meierův odhad MeSH
• kinázy asociované s rho antagonisté a inhibitory   metabolismus   MeSH
• kohortové studie MeSH
• krysa rodu rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• peroxidasa aplikace a dávkování   krev   metabolismus   MeSH
• plíce patologie   MeSH
• plicní hypertenze krev   mortalita   patologie   patofyziologie   MeSH
• potkani Sprague-Dawley MeSH
• pyridiny aplikace a dávkování   MeSH
• rekombinantní proteiny aplikace a dávkování   krev   metabolismus   MeSH
• remodelace cév účinky léků   fyziologie   MeSH
• vazokonstrikce účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• krysa rodu rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH