is a new culprit gene for IPAH ranking second to BMPR2. The rare deleterious mutations in BMP9, which lead to the reduction in BMP9 secretion and impairment in BMP9 function, account for 6.7% of IPAH cases.

Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through HPLC-MS, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase (SMS) were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase (SMS) in the pathological process. Inhibition of SMS in vitro suppressed platelet-derived growth factor-BB–mediated proliferation of PASMCs, and in vivo attenuated monocrotaline-mediated pulmonary hypertension in rats.Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.

BackgroundPulmonary arterial hypertension (PAH) is a rare systemic disorder associated with considerable metabolic dysfunction. Although enormous metabolomic studies on PAH have been emerging, research remains lacking on metabolic reprogramming in experimental PAH models. We aim to evaluate the metabolic changes in PAH and provide new insight into endogenous metabolic disorders of PAH.MethodA single subcutaneous injection of monocrotaline (MCT) (60 mg kg− 1) was used for rats to establish PAH model. Hemodynamics and right ventricular hypertrophy were adopted to evaluate the successful establishment of PAH model. Plasma samples were assessed through targeted metabolomic profiling platform to quantify 126 endogenous metabolites. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to discriminate between MCT-treated model and control groups. Metabolite Set Enrichment Analysis was adapted to exploit the most disturbed metabolic pathways.ResultsEndogenous metabolites of MCT treated PAH model and control group were well profiled using this platform. A total of 13 plasma metabolites were significantly altered between the two groups. Metabolite Set Enrichment Analysis highlighted that a disruption in the urea cycle pathway may contribute to PAH onset. Moreover, five novel potential biomarkers in the urea cycle, adenosine monophosphate, urea, 4-hydroxy-proline, ornithine, N-acetylornithine, and two candidate biomarkers, namely, O-acetylcarnitine and betaine, were found to be highly correlated with PAH.ConclusionThe present study suggests a new role of urea cycle disruption in the pathogenesis of PAH. We also found five urea cycle related biomarkers and another two candidate biomarkers to facilitate early diagnosis of PAH in metabolomic profile.

DNA methylation plays critical roles in vascular pathology of pulmonary hypertension (PH). The underlying mechanism, however, remains undetermined. Here, we demonstrate that global DNA methylation was elevated in the lungs of PH rat models after monocrotaline administration or hypobaric hypoxia exposure. We showed that DNA methyltransferase 3B (DNMT3B) was up-regulated in both PH patients and rodent models. Furthermore, Dnmt3b−/− rats exhibited more severe pulmonary vascular remodeling. Consistently, inhibition of DNMT3B promoted proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in response to platelet-derived growth factor–BB (PDGF-BB). In contrast, overexpressing DNMT3B in PASMCs attenuated PDGF-BB–induced proliferation/migration and ameliorated hypoxia-mediated PH and right ventricular hypertrophy in mice. We also showed that DNMT3B transcriptionally regulated inflammatory pathways. Our results reveal that DNMT3B is a previously undefined mediator in the pathogenesis of PH, which couples epigenetic regulations with vascular remodeling and represents a therapeutic target to tackle PH.

Despite advances in treatments and improved survival, patients with pulmonary hypertension still experience poor exercise and functional capacity, which has a significant detrimental impact on their quality of life. The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine 3′,5′-monophosphate (cGMP) pathway has been shown to play an important role in cardiovascular physiology, especially in vasodilation and pulmonary vascular tone. The oral sGC stimulator riociguat has a dual mode of action on the NO–sGC–cGMP pathway: direct stimulation of sGC independent of NO and indirect simulation via sensitization of sGC to endogenous NO. Riociguat is now licensed in >50 countries worldwide, including in Europe, the USA, Canada, and Japan. Approval for the treatment of pulmonary arterial hypertension (PAH) was based on Phase III data from the PATENT studies, in which riociguat significantly improved exercise capacity, pulmonary vascular resistance, a range of secondary end points, and hemodynamic parameters in patients with symptomatic PAH. In the Phase III CHEST studies, riociguat consistently improved exercise capacity in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy and is now the only drug to be approved for this indication. Riociguat was well tolerated in long-term studies of PAH and CTEPH. This review describes the role of the NO–sGC–cGMP pathway in the pathophysiology of pulmonary hypertension, and reviews the clinical efficacy and safety of riociguat in patients with PAH and inoperable or persistent/recurrent CTEPH. Based on its demonstrated efficacy and established safety profile, riociguat is a promising treatment option for patients with PAH and CTEPH.

The prevalence and distribution of congenital thrombophilia is still unclear in patients with pulmonary embolism (PE). We aimed to determine the prevalence and clinical characteristics of congenital thrombophilia in PE patients and their subsequent outcomes. A prospective observational study was conducted from May 2013 to June 2018. A total of 436 consecutive patients with PE were enrolled. All patients were tested for protein C, protein S, antithrombin III (ATIII), factor V Leiden, and prothrombin G20210A mutations. The median follow-up duration was ∼800 days (range, 11-1872 days). Congenital thrombophilia was diagnosed in 31 of 436 (7.1%) patients; 12 patients had protein C deficiency (2.8%), 13 had protein S deficiency (3.0%), 5 had ATIII deficiency (1.1%), and 1 had (0.2%) factor V Leiden. Age ≤50 years at the first episode (odds ratio [OR], 5.43; 95% confidence interval [CI], 2.35-13.52; P < .001) and male sex (OR, 2.67; 95% CI, 1.15-6.78; P = .03) were 2 independent predictors of congenital thrombophilia in PE patients. There was no statistically significant difference in the prevalence of congenital thrombophilia between PE patients with and without risk factors (P = .58). We also found no significant difference in the risk of having a composite outcome of death or recurrent venous thromboembolism between patients with and without congenital thrombophilia (hazard ratio, 0.18; 95% CI, 0.02-5.69; P = .08). These results suggest that age and male sex are independently associated with the occurrence of congenital thrombophilia in PE patients but that congenital thrombophilia is not associated with the risk of recurrence or death with anticoagulation therapy.

BACKGROUND: The pathological mechanism of chronic thromboembolic pulmonary hypertension (CTEPH) is not fully understood, and inflammation has been reported to be one of its etiological factors. IgG regulates systemic inflammatory homeostasis, primarily through its N -glycans. Little is known about IgG N -glycosylation in CTEPH. We aimed to map the IgG N -glycome of chronic thromboembolic pulmonary hypertension to provide new insights into its pathogenesis and discover novel markers and therapies. METHODS: We characterized the plasma IgG N -glycome of patients with chronic thromboembolic pulmonary hypertension in a discovery cohort and validated our results in an independent validation cohort using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Thereafter, we correlated IgG N -glycans with clinical parameters and circulating inflammatory cytokines in patients with CTEPH. Furthermore, we determined IgG N -glycan quantitative trait loci in chronic thromboembolic pulmonary hypertension to reveal partial mechanisms underlying glycan changes. RESULTS: Decreased IgG galactosylation representing a proinflammatory phenotype was found in CTEPH. The distribution of IgG galactosylation showed a strong association with NT-proBNP (N-terminal pro-B-type natriuretic peptide) in CTEPH. In line with the glycomic findings, IgG pro-/anti-inflammatory N -glycans correlated well with a series of inflammatory markers and gene loci that have been reported to be involved in the regulation of these glycans or inflammatory immune responses. CONCLUSIONS: This is the first study to reveal the full signature of the IgG N -glycome of a proinflammatory phenotype and the genes involved in its regulation in CTEPH. Plasma IgG galactosylation may be useful for evaluating the inflammatory state in patients with CTEPH; however, this requires further validation. This study improves our understanding of the mechanisms underlying chronic thromboembolic pulmonary hypertension inflammation from the perspective of glycomics.

Background: Right ventricle (RV) function is among the most important prognostic factors for pulmonary arterial hypertension (PAH) patients. Inhaled iloprost, an inhaled member of the prostacyclin family, is effective for the treatment of severe PAH and acute RV failure. However, the acute effects of iloprost on RV physiology have not been thoroughly explored in the past.Materials and Methods: This prospective study involved 69 incident PAH patients, including 23 idiopathic PAH (IPAH) patients, 26 patients with PAH associated with connective tissue disease (CTD-PAH) and 20 with PAH associated with congenital heart disease (CHD-PAH). All patients underwent both right heart catheterization and cardiac magnetic resonance imaging at baseline and 20 min after 5 μg iloprost inhalation.Results: Acute iloprost inhalation reduced PVR from 13 ± 7 to 10 ± 6 Wood U (P < 0.001), increased RV ejection fraction (RVEF) from 31 ± 11 to 35 ± 12 % (P < 0.001), increased RV stroke volume from 53 ± 21 to 57 ± 22 ml (P < 0.001) and decreased RV end-diastolic volume from 179 ± 67 to 172 ± 69 ml (P < 0.001). Acute iloprost inhalation-induced RVEF improvement was correlated with the degree of PVR reduction (P < 0.001) in IPAH patients, but not in CTD-PAH or CHD-PAH patients.Conclusion: Acute iloprost inhalation improved RVEF, RV stroke volume and decreased RV volume in IPAH and CTD-PAH patients. Iloprost-induced RVEF increase was proportional to PVR reduction in IPAH patients, but not in CTD-PAH or CHD-PAH patients.