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End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test–retest repeatability was assessed using the intraclass correlation coefficient and treatment effect size using Cohen’s d statistic. Intraclass correlation coefficients demonstrated excellent repeatability for MRI, 6 min walk test and log to base 10 N-terminal pro-brain natriuretic peptide (log10NT-proBNP). The treatment effect size for MRI-derived right ventricular ejection fraction was large (Cohen’s d 0.81), whereas the effect size for the 6 min walk test (Cohen’s d 0.22) and log10NT-proBNP (Cohen’s d 0.20) were fair. This study supports further evaluation of MRI as a non-invasive end point for clinical assessment and PAH therapy trials.Trial registration number NCT03841344.

Rationale: Pulmonary arterial hypertension (PAH) is a life-shortening condition. The European Society of Cardiology and European Respiratory Society and the REVEAL (North American Registry to Evaluate Early and Long-Term PAH Disease Management) risk score calculator (REVEAL 2.0) identify thresholds to predict 1-year mortality. Objectives: This study evaluates whether cardiac magnetic resonance imaging (MRI) thresholds can be identified and used to aid risk stratification and facilitate decision-making. Methods: Consecutive patients with PAH (n = 438) undergoing cardiac MRI were identified from the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Center) MRI database. Thresholds were identified from a discovery cohort and evaluated in a test cohort. Measurements and Main Results: A percentage-predicted right ventricular end-systolic volume index threshold of 227% or a left ventricular end-diastolic volume index of 58 ml/m2 identified patients at low (10%) risk of 1-year mortality. These metrics respectively identified 63% and 34% of patients as low risk. Right ventricular ejection fraction >54%, 37–54%, and

Background: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in patients with heritable and idiopathic pulmonary arterial hypertension (PAH). Circulating levels of Interleukin-1 (IL-1) are raised in patients and animal models. Whether interplay between BMP and IL- 1 signalling can explain the local manifestation of PAH in the lung remains unclear. Methods: Cell culture, siRNA and mRNA microarray analysis of RNA isolated from human Pulmonary artery (PASMC) and Aortic (AoSMC) smooth muscle cells were used. R899X+/- BMPR2 transgenic mice fed western diet for six weeks were given daily injections of IL-1s prior to assessment for PAH and tissue collection. Results: PASMC have reduced inflammatory activation in response to IL-1s compared with AoSMCs, however PASMC with reduced BMPR2 demonstrated an exaggerated response. Mice treated with IL-1s had higher white blood cell counts, and significantly raised serum protein levels of IL-6 and OPG plasma levels recapitulating in vitro data. Phenotypically, IL-1s treated mice demonstrated increased pulmonary vascular remodelling. Conclusions: IL-1s induces an exaggerated pulmonary artery specific transcriptomic inflammatory response when BMPR2 signalling is reduced.

Introduction: For clinical trials it is important to know the repeatability and sensitivity to change of study end-points. The aim of this study was to compare non-invasive candidate end-points in patients with pulmonary arterial hypertension (PAH). Methods: We examined 2 field walking tests: the six minute walk test (6MWT) and the incremental shuttle walking test (ISWT) and 2 tests of RV function: NT-proBNP and cardiac magnetic resonance imaging (cMRI). Patients with PAH underwent 6MWT, ISWT, NT-proBNP and cMRI (visit 1). At follow-up at around 6 months the investigations were repeated x2 within 24 hours (visits 2 and 3). Test-retest repeatability (visits 2 vs 3) and change with therapy (visit 2 minus visit 1) were assessed by the intraclass correlation coefficient (ICC) and a paired t-test respectively. Results: Of 44 patients, 40 completed the study; 27 patients underwent initiation or escalation of PAH therapy and 13 were stable on therapy. For all patients the ICC for the ISWT was 0.99, 6MWT 0.99, NT-proBNP 0.72, right ventricular end-systolic volume (RVESV) 0.98 and right ventricular ejection fraction (RVEF) 0.83. Following initiation or escalation of therapy there was an increase in ISWT, mean difference +40m (standard deviation (SD) 79), p=0.02 and 6MWT distance, +35m (SD 79) p=0.04, a reduction in RVESV -20ml (SD 30) p=0.002, and an increase in RVEF, +4% (SD 9), p=0.04 respectively. There was no significant change in NT-proBNP, -206 pg/m (SD 684), p=0.15. Conclusion: ISWT and 6MWT had excellent repeatability and are sensitive to change in PAH. CMRI but not NT-proBNP has excellent repeatability and is sensitive to change.

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity).This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.

Rationale: Accumulating evidence implicates inflammation in pulmonary arterial hypertension (PAH) and therapies targeting immunity are under investigation, although it remains unknown if distinct immune phenotypes exist. Objective: Identify PAH immune phenotypes based on unsupervised analysis of blood proteomic profiles. Methods and Results: In a prospective observational study of group 1 PAH patients evaluated at Stanford University (discovery cohort; n=281) and University of Sheffield (validation cohort; n=104) between 2008 and 2014, we measured a circulating proteomic panel of 48 cytokines, chemokines, and factors using multiplex immunoassay. Unsupervised machine learning (consensus clustering) was applied in both cohorts independently to classify patients into proteomic immune clusters, without guidance from clinical features. To identify central proteins in each cluster, we performed partial correlation network analysis. Clinical characteristics and outcomes were subsequently compared across clusters. Four PAH clusters with distinct proteomic immune profiles were identified in the discovery cohort. Cluster 2 (n=109) had low cytokine levels similar to controls. Other clusters had unique sets of upregulated proteins central to immune networks—cluster 1 (n=58; TRAIL [tumor necrosis factor-related apoptosis-inducing ligand], CCL5 [C-C motif chemokine ligand 5], CCL7, CCL4, MIF [macrophage migration inhibitory factor]), cluster 3 (n=77; IL [interleukin]-12, IL-17, IL-10, IL-7, VEGF [vascular endothelial growth factor]), and cluster 4 (n=37; IL-8, IL-4, PDGF-β [platelet-derived growth factor beta], IL-6, CCL11). Demographics, PAH clinical subtypes, comorbidities, and medications were similar across clusters. Noninvasive and hemodynamic surrogates of clinical risk identified cluster 1 as high-risk and cluster 3 as low-risk groups. Five-year transplant-free survival rates were unfavorable for cluster 1 (47.6%; 95% CI, 35.4%–64.1%) and favorable for cluster 3 (82.4%; 95% CI, 72.0%–94.3%; across-cluster P Conclusions: Blood cytokine profiles distinguish PAH immune phenotypes with differing clinical risk that are independent of World Health Organization group 1 subtypes. These phenotypes could inform mechanistic studies of disease pathobiology and provide a framework to examine patient responses to emerging therapies targeting immunity.

Pulmonary hypertension due to left heart disease (PH-LHD) is the most common type of pulmonary hypertension, although an accurate prevalence is challenging. PH-LHD includes PH due to systolic or diastolic left ventricular dysfunction, mitral or aortic valve disease and congenital left heart disease. In recent years a new and distinct phenotype of "combined post-capillary and pre-capillary PH," based on diastolic pulmonary gradient and pulmonary vascular resistance, has been recognized. The roles of right ventricular dysfunction and pulmonary vascular compliance in PH-LHD have also been elucidated recently and they appear to have significant clinical implications. Echocardiography continues to play a seminal role in diagnosis of PH-LHD and heart failure with preserved LV ejection fraction, as it can identify valve disease and help to distinguish PH-LHD from pre-capillary PH. Right, and occasionally left heart catheterization, remains the gold-standard for diagnosis and phenotyping of PH-LHD, although Cardiac Magnetic Resonance Imaging is emerging as a useful alternative tool in non-invasive diagnostic and prognostic assessment of PH-LHD. In this review, the latest evidence for more recent advances will be discussed, including the role of fluid challenge and exercise during cardiac catheterization to unravel occult post-capillary and the role of vasoreactivity testing. The use of many or all of these diagnostic techniques will undoubtedly provide key information about sub-groups of patients with PH-LHD that might benefit from medical therapy previously considered to be only suitable for pulmonary arterial hypertension.

A patient with severe worsening of pre-existing PAH following treatment with bosutinib improved on cessation http://ow.ly/gJy7302uXL7

This study set out to explore whether a teaching programme developed and delivered by medical students yielded an improvement of attendees' examination performance or their experience of preparing for the target assessment.Over 4 years all students were invited to consent to use of their official examination data. Students were ranked for baseline performance and again for performance in the target assessment. Change in rank was compared for attendees and non-attenders. Additionally, a questionnaire was distributed to students before and after the peer-led programme. Attendees' responses were compared to those of non-attenders.No statistically significant difference in change in rank was observed between the two groups on evaluation of quantitative performance data. The majority of students (81.0%) scored the programme four or five in terms of perceived usefulness on a five-point Likert scale. Attendees reported statistically significant increases in preparedness for the examination (p=0.001) and in familiarity with the style of examination questions (p=0.004) compared to students who did not attend.This study suggests that teaching from peers may improve students' perception of their preparedness for official assessments. However, such interventions may be limited in their ability to produce a demonstrable benefit in terms of examination performance.