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Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy characterized by extensive pre-capillary arterial remodeling, instigating increased pulmonary vascular resistance and eventual right heart failure. Rare mutations in the SOX17 gene and common variants in the enhancer region are thought to predispose to PAH. Central to the PAH pathobiology is lung immune cell recruitment, orchestrated by the overproduction of chemokines (e.g. CXCL10) via the induction of NF-κB. Emerging evidence from murine models of SOX17 impairment suggests perivascular leukocyte accumulation in the lung, likely due to disordered inflammatory mediator expression. Therefore, in the current study we assessed the role of SOX17 deficiency in human pulmonary artery endothelial cells (HPAECs) on selected inflammatory mediator release. Following a semi-quantitative array of 100 cytokines and chemokines, we identified markedly elevated CXCL10 and CXCL11 mRNA and soluble protein release in SOX17 -silenced HPAECs (versus control siRNA-treated cells), driven by excessive NF-κB p65 activity. Further, we show that plasma CXCL10 levels are raised in a small cohort ( n  = 3) of carriers of pathogenic SOX17 rare variants versus healthy controls. Finally, SOX17 knockdown HPAEC supernatants mediated the in vitro migration of transfectants expressing CXCR3. Therefore, enhanced lymphocyte migration may be a pathomechanism of PAH due to SOX17 loss, driven by a CXCL10/CXCL11/CXCR3 axis.

Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes.

Correspondence to Dr Stephen John Wort, Pulmonary Hypertension Department, Royal Brompton Hospital, London, London, UK; s.wort@imperial.ac.uk Pulmonary hypertension (PH) is a feared complication in patients with any chronic lung disease,1 but those with lung fibrosis have an especially poor mortality and the morbidity burden is very high.2 3 Up to very recently, there has been an almost nihilistic attitude towards these patients, since the lack of treatment options restricted the indication of a definitive diagnosis through right heart catheterisation (RHC) to lung transplant evaluation and enrolment in a clinical trial.4 Although with sound rationale, randomised placebo-controlled trials (RCT) with pulmonary vasodilators, have been negative or at worse detrimental5 (figure 1). Whereas conventional survival analysis provides a non-significant intention-to-treat HR (0.71, 95% CI, 0.46 to 1.10; p=0.1227), the IPCW and RPSFT methods calculated the change in mortality associated with the use of inhaled treprostinil as 0.62 (95% CI, 0.07 to 0.98; p=0.047) and 0.26 (95% CI, 0.39 to 0.99; p=0.048), respectively. [...]the latest European Society of Cardiology/European Respiratory Society PH guidelines state that phosphodiesterase-5 inhibitors may be considered on a case-to-case basis in patients with ILD with severe PH.15 The other issue worth considering is identifying responders to the treatment, as treprostinil may initially be given to patients deemed most likely to benefit. Survival analysis from the INCREASE study in PH-ILD: evaluating the impact of treatment crossover on overall mortality.

IntroductionPulmonary hypertension (PH) is a rare pathophysiological disorder associated with many other medical conditions. Diagnosis of PH can be particularly complex when these associated conditions include rare infections such as Whipple’s disease. Here, we present the case of a woman initially diagnosed with sarcoidosis, who later developed severe PH and was subsequently found to have Whipple’s disease.1 2CaseA 43-year-old woman presented with anaemia and generalised lymphadenopathy. A lymph node biopsy revealed non-necrotising granulomatous inflammation which led to an initial diagnosis of sarcoidosis. Treatment with corticosteroids was commenced. During routine cardiac evaluation, echocardiography showed severe pulmonary hypertension (pulmonary artery systolic pressure (PASP) 80 mmHg with right ventricular dysfunction). Right heart catheterisation confirmed pre-capillary PH with a mean pulmonary artery pressure (mPAP) of 29 mmHg and normal wedge pressure. She was diagnosed as having PH associated with sarcoidosis and started on sildenafil. However, the patient developed persistent diarrhoea, a known side effect of sildenafil, which prompted a switch to tadalafil. Despite this, gastrointestinal symptoms persisted. Extensive investigations, including endoscopy and duodenal biopsy, unexpectedly led to the diagnosis of Whipple’s disease. She was treated with intravenous ceftriaxone for two weeks, followed by 12 months of co-trimoxazole therapy. Following the initiation of antibiotic therapy, the patient’s gastrointestinal symptoms improved significantly. Her diarrhoea resolved, and weight gain was noted. After 12 months of co-trimoxazole, a repeat echocardiogram demonstrated a reduction in PASP to 42 mmHg, with normal function of the right ventricle. This clinical improvement supported the hypothesis that the resolution of PH was, at least partly, related to the effective treatment of Whipple’s disease.3 4DiscussionWhipple’s disease is a rare systemic infection caused by Tropheryma whipplei, with the gastrointestinal system being most affected, patients presenting with diarrhoea, malabsorption, and weight loss. Though Whipple’s disease is primarily a gastrointestinal disease, it can involve multiple organs, including the cardiovascular system. Whipple’s disease has been rarely reported as a cause of PH.5 The exact mechanisms linking Whipple’s disease to PH remain unclear. One theory posits that the accumulation of periodic acid-Schiff (PAS)-positive macrophages within the pulmonary vasculature may increase pulmonary vascular resistance, thus contributing to the development of PH (figure 1). Moreover, the reversibility of PH upon appropriate antibiotic treatment lends support to a direct association between the two conditions.6 7 The diagnosis of PH in this patient was initially confounded by the suspicion of sarcoidosis, another cause of PH, and the side effects of sildenafil. This case demonstrates the diagnostic complexity of PH complicating many systemic diseases and the importance of considering rare infectious causes such as Whipple’s disease when gastrointestinal symptoms remain unexplained. A further learning point is that PH associated with Whipple’s disease can improve with antibiotic therapy, reinforcing the need for early correct diagnosis and treatment.Abstract 7-043 Figure 1Periodic Acid-Schiff (PAS) positive staining in macrophages[Figure omitted. See PDF]ReferencesMcGinnis SW, Simms JR. Pulmonary hypertension associated with sarcoidosis: Clinical implications and management strategies. Chest. 2018;153(3):630–639. doi: 10.1016/j.chest.2017.11.050.Smoot JM, Alvarado LR. The role of pulmonary hypertension in systemic diseases: Review of mechanisms and management. J Clin Med. 2020;9(3):775. doi: 10.3390/jcm9030775.Dostal CL, Kollef MH. Tadalafil and ambrisentan for the treatment of pulmonary hypertension. Am J Respir Crit Care Med. 2018;198(9):1157–1168. doi: 10.1164/rccm.201804-0715OC.Soler M, González J, Díaz M, et al. Resolution of pulmonary hypertension with antibiotic therapy in Whipple's disease: A case series. Eur Respir J. 2017;50(6):1700876. doi: 10.1183/13993003.00876-2017.Desnues B, Al Moussawi K, Fenollar F. New insights into Whipple's disease and Tropheryma whipplei infections. Microbes Infect. 2010 Dec;12(14–15):1102–10. doi: 10.1016/j.micinf.2010.08.001.Villanueva R, et al. Pulmonary involvement in Whipple’s disease: Case report and review of the literature. Chest. 2015;148(4):968–974. doi: 10.1378/chest.15-0866.Cacoub P, et al. The pathophysiology of pulmonary hypertension in chronic inflammatory diseases. Curr Opin Pulm Med. 2017;23(4):305–312. doi: 10.1097/MCP.0000000000000389.

Background: The impact of the new “borderline” hemodynamic class for pulmonary hypertension (PH) (mean pulmonary artery pressure [mPAP], 21–24 mm Hg and pulmonary vascular resistance, [PVR], ≥3 wood units, [WU]) in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is unclear. Objectives: The aim of this study was to assess the effect of borderline PH (BLPH) on survival in COPD and ILD patients. Method: Survival was analyzed from retrospective data from 317 patients in 12 centers (Italy, Spain, UK) comparing four hemodynamic groups: the absence of PH (NoPH; mPAP <21 mm Hg or 21–24 mm Hg and PVR <3 WU), BLPH (mPAP 21–24 mm Hg and PVR ≥3 WU), mild-moderate PH (MPH; mPAP 25–35 mm Hg and cardiac index [CI] ≥2 L/min/m 2 ), and severe PH (SPH; mPAP ≥35 mm Hg or mPAP ≥25 mm Hg and CI <2 L/min/m 2 ). Results: BLPH affected 14% of patients; hemodynamic severity did not predict survival when COPD and ILD patients were analyzed together. However, survival in the ILD cohort for any PH level was worse than in NoPH (3-year survival: NoPH 58%, BLPH 32%, MPH 28%, SPH 33%, p = 0.002). In the COPD cohort, only SPH had reduced survival compared to the other groups (3-year survival: NoPH 82%, BLPH 86%, MPH 87%, SPH 57%, p = 0.005). The mortality risk correlated significantly with mPAP in ILD (hazard ratio [HR]: 2.776, 95% CI: 2.057–3.748, p < 0.001) and notably less in COPD patients (HR: 1.015, 95% CI: 1.003–1.027, p = 0.0146). Conclusions: In ILD, any level of PH portends worse survival, while in COPD, only SPH presents a worse outcome.

IntroductionSkeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target.MethodsGDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo.ResultsCirculating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=−0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of <564 pg/L predicted those with preserved muscle strength with a sensitivity and specificity of ≥80%. In vitro GDF-15 stimulated an increase in phosphorylation of TGFβ-activated kinase 1 (TAK1). Antagonising TAK1, with 5(Z)-7-oxozeaenol, in vitro and in vivo led to an increase in fibre diameter and a reduction in mRNA expression of atrogin-1 in both C2C12 cells and in the TA of animals who continued to grow. Circulating GDF-15 levels were also reduced in those animals which responded to treatment.ConclusionsCirculating GDF-15 is a biomarker of muscle loss in PAH that is responsive to treatment. TAK1 inhibition shows promise as a method by which muscle atrophy may be directly prevented in PAH.Trial registration numberNCT01847716; Results.

Objectives To investigate survival in patients with Eisenmenger syndrome based on a systematic review of the literature and reanalysis of data. We specifically tested the hypothesis that previous publications have been subject to immortal time bias, confounding survival analyses. Methods A systematic review of the literature was performed to evaluate survival in treatment naïve patients with Eisenmenger syndrome and standardised mortality ratios were calculated. Furthermore, we used a contemporary cohort of 219 treatment naïve patients with Eisenmenger syndrome from the own institution as a comparison group. Results Overall, 12 studies (published 1971–2013) were identified, including a total of 1131 patients. Only one study seemed to deal appropriately with immortal time bias in this setting. All other studies did not account for this effect, thus overestimating survival prospects of patients with Eisenmenger syndrome by up to 20 years. After accounting for this effect we found high standardised mortality ratios, a 10-year mortality rate approaching 30–40% and no evidence of superior survival prospects of current era patients compared with those seen in the 1970s, 1980s and 1990s. Only, a historical Eisenmenger-cohort from the 1950s/1960s had worse survival. Conclusions The current analysis challenges the traditional view of benign survival prospects of patients with Eisenmenger syndrome. In addition, survival prospects do not seem to have considerably improved over the last decades in untreated patients. These results support a proactive treatment strategy including a more aggressive approach trying to avoid the development of the condition.

Treatment of acute emergencies in patients with pulmonary arterial hypertension (PAH) can be challenging. In the UK and Ireland, management of adult patients with PAH is centred in eight nationally designated pulmonary hypertension (PH) centres. However, many patients live far from these centres and physicians in local hospitals are often required to manage PAH emergencies. A committee of physicians from nationally designated PH centres identified the ‘most common’ emergency clinical scenarios encountered in patients with PAH. Thereafter, a review of the literature was performed centred on these specified topics and a management approach was developed based on best available evidence and expert consensus. Management protocols were developed on the following PAH emergencies: chest pain (including myocardial ischaemia), right ventricular failure, arrhythmias, sepsis, haemoptysis (‘CRASH'), as well as considerations relevant to surgery, anaesthesia and pregnancy. Emergencies are not uncommon in PAH. While expertise in PAH management is essential, all physicians involved in acute care should be aware of the principles of acute management of PAH emergencies. A multidisciplinary approach is necessary, with physicians from tertiary PH centres supporting care locally and planning safe transfer of patients to PH centres when appropriate.

Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. The Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor ( BMPR2 ), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17 , and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2 , encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention. Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2 , ATP13A3 , AQP1 and SOX17 .