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Pulmonary hypertension is a condition with limited effective treatment options. Chronic thromboembolic pulmonary hypertension (CTEPH) is a notable exception, with pulmonary endarterectomy (PEA) often proving curative. This study investigated the plasma metabolome of CTEPH patients, estimated reversibility to an effective treatment and explored the source of metabolic perturbations.We performed untargeted analysis of plasma metabolites in CTEPH patients compared to healthy controls and disease comparators. Changes in metabolic profile were evaluated in response to PEA. A subset of patients were sampled at three anatomical locations and plasma metabolite gradients calculated.We defined and validated altered plasma metabolite profiles in patients with CTEPH. 12 metabolites were confirmed by receiver operating characteristic analysis to distinguish CTEPH and both healthy (area under the curve (AUC) 0.64-0.94, all p<2×10 -5 ) and disease controls (AUC 0.58-0.77, all p<0.05). Many of the metabolic changes were notably similar to those observed in idiopathic pulmonary arterial hypertension (IPAH). Only five metabolites (5-methylthioadenosine, N1-methyladenosine, N1-methylinosine, 7-methylguanine, N-formylmethionine) distinguished CTEPH from chronic thromboembolic disease or IPAH. Significant corrections (15-100% of perturbation) in response to PEA were observed in some, but not all metabolites. Anatomical sampling identified 188 plasma metabolites, with significant gradients in tryptophan, sphingomyelin, methionine and Krebs cycle metabolites. In addition, metabolites associated with CTEPH and gradients showed significant associations with clinical measures of disease severity.We identified a specific metabolic profile that distinguishes CTEPH from controls and disease comparators, despite the observation that most metabolic changes were common to both CTEPH and IPAH patients. Plasma metabolite gradients implicate cardiopulmonary tissue metabolism of metabolites associated with pulmonary hypertension and metabolites that respond to PEA surgery could be a suitable noninvasive marker for evaluating future targeted therapeutic interventions., Competing Interests: Conflict of interest: E.M. Swietlik reports grants from British Heart Foundation, during the conduct of the study; personal fees from Actelion, outside the submitted work. Conflict of interest: P. Ghataorhe is an employee of GSK. Conflict of interest: K.I. Zalewska reports grants from Actelion, during the conduct of the study. Conflict of interest: J. Wharton has nothing to disclose. Conflict of interest: L.S. Howard reports grants, personal fees for lectures, steering committee and advisory board work, and non-financial support for meeting attendance from Actelion, personal fees for lectures and advisory board work from Bayer and MSD, personal fees for advisory board work from GSK, outside the submitted work. Conflict of interest: D. Taboada reports speaker honoraria and education/travel grants from Actelion, Bayer, GlaxoSmithKline, Lilly, MDS and Pfizer, outside the submitted work. Conflict of interest: J.E. Cannon reports grants from Actelion, during the conduct of the study; non-financial support for meeting attendance from Actelion, outside the submitted work. Conflict of interest: N.W. Morrell has nothing to disclose. Conflict of interest: M.R. Wilkins has nothing to disclose. Conflict of interest: M. Toshner reports grants and personal fees from Bayer and Actelion, personal fees from MSD, GSK and MorphogenIX, outside the submitted work. Conflict of interest: J. Pepke-Zaba has received speaker fees and honoraria for consultations from Actelion and MSD, and educational grants (paid to institution) from Actelion and Merck. Conflict of interest: C.J. Rhodes reports personal fees from Actelion and United Therapeutics, outside the submitted work., (Copyright ©ERS 2021.)

Rationale: Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disorder in which inflammation and immunity have emerged as critical early pathogenic elements. Although proinflammatory processes in PH and pulmonary arterial hypertension (PAH) are the focus of extensive investigation, the initiating mechanisms remain elusive. Objectives: We tested whether activation of the complement cascade is critical in regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and can serve as a prognostic biomarker of outcome in human PAH. Methods: We used immunostaining of lung tissues from experimental PH models and patients with PAH, analyses of genetic murine models lacking specific complement components or circulating immunoglobulins, cultured human pulmonary adventitial fibroblasts, and network medicine analysis of a biomarker risk panel from plasma of patients with PAH. Measurements and Main Results: Pulmonary perivascular-specific activation of the complement cascade was identified as a consistent critical determinant of PH and PAH in experimental animal models and humans. In experimental hypoxic PH, proinflammatory and pro-proliferative responses were dependent on complement (alternative pathway and component 5), and immunoglobulins, particularly IgG, were critical for activation of the complement cascade. We identified Csf2/GM-CSF as a primary complement-dependent inflammatory mediator. Furthermore, using network medicine analysis of a biomarker risk panel from plasma of patients with PAH, we demonstrated that complement signaling can serve as a prognostic factor for clinical outcome in PAH. Conclusions: This study establishes immunoglobulin-driven dysregulated complement activation as a critical pathobiological mechanism regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and demonstrates complement signaling as a critical determinant of clinical outcome in PAH.

Aims: We sought to identify metabolic pathways associated with right ventricular (RV) adaptation to pulmonary hypertension (PH). We evaluated candidate metabolites, previously associated with survival in pulmonary arterial hypertension, and used automated image segmentation and parametric mapping to model their relationship to adverse patterns of remodelling and wall stress., Methods and Results: In 312 PH subjects (47.1% female, mean age 60.8 ± 15.9 years), of which 182 (50.5% female, mean age 58.6 ± 16.8 years) had metabolomics, we modelled the relationship between the RV phenotype, haemodynamic state, and metabolite levels. Atlas-based segmentation and co-registration of cardiac magnetic resonance imaging was used to create a quantitative 3D model of RV geometry and function-including maps of regional wall stress. Increasing mean pulmonary artery pressure was associated with hypertrophy of the basal free wall (β = 0.29) and reduced relative wall thickness (β = -0.38), indicative of eccentric remodelling. Wall stress was an independent predictor of all-cause mortality (hazard ratio = 1.27, P = 0.04). Six metabolites were significantly associated with elevated wall stress (β = 0.28-0.34) including increased levels of tRNA-specific modified nucleosides and fatty acid acylcarnitines, and decreased levels (β = -0.40) of sulfated androgen., Conclusion: Using computational image phenotyping, we identify metabolic profiles, reporting on energy metabolism and cellular stress-response, which are associated with adaptive RV mechanisms to PH., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency., (Copyright © 2016. Published by Elsevier Inc.)

High-penetrance autosomal dominant cancer susceptibility genes such as BRCA2 and MEN1 result in specific patterns of cancers in individuals who inherit germline mutations. Their incidence in the population is relatively low, however, and it is highly unusual to identify individuals with two or more inherited cancer gene mutations. We describe a family with multiple cases of MEN1-associated cancers as well as pancreatic adenocarcinoma, ovarian cancer, and male breast cancer, in which we identified germline mutations in both MEN1 and BRCA2. To our knowledge, this is the first report of a patient with both MEN1 and BRCA2 mutations and with a personal history of hyperparathyroidism and pancreatic neuroendocrine tumors.