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Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z ( CTSZ , cg04917472 ) , Conserved oligomeric Golgi complex 6 ( COG6 , cg27396197 ) , and Zinc Finger Protein 678 ( ZNF678 , cg03144189 ) , reached epigenome-wide significance ( p  < 10 −7 ) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity ( p  < 10 −4 ). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ , encoding protease cathepsin Z. Pulmonary arterial hypertension is a complex disease characterised by high morbidity and mortality. Here, the authors report methylation profiling of patients, finding disease associations in genes CTSZ , COG6 and ZNF678 .

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG , and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH. Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.

Patients with acute pulmonary embolism (PE) exhibit a wide spectrum of clinical and laboratory features when presenting to hospital and pathophysiologic mechanisms differentiating low-risk and high-risk PE are poorly understood. To investigate the prognostic value of clinical, laboratory and radiological information that is available within routine tests undertaken for patients with acute PE. Electronic patient records (EPR) of patients who underwent Computed Tomography Pulmonary Angiogram (CTPA) scan for the investigation of acute PE during 6-month period (01.01.2016-30.06.2016) were examined. Data was gathered from EPR for patients that met inclusion criteria and all CTPA scans were re-evaluated. Biochemical thresholds of low-grade and high-grade inflammation, serum CRP >10mg/L and >150mg/L and serum albumin concentrations <35g/L and <25 g/L, were combined in the Glasgow Prognostic Score (GPS) and peri-operative Glasgow Prognostic Score (poGPS) respectively. Neutrophil Lymphocyte ratio (NLR) was also calculated. Pulmonary Embolus Severity Index score was calculated. Of the total CTPA reports (n = 2129) examined, 245 patients were eligible for inclusion. Of these, 20 (8%) patients had died at 28-days and 43 (18%) at 6-months. Of the 197 non-cancer related presentations, 28-day and 6-month mortality were 3% and 8% respectively. Of the 48 cancer related presentations, 28-day and 6-month mortality were 29% and 58% respectively. On univariate analysis, age ≥65 years (p<0.01), PESI score ≥100(p = <0.001), NLR ≥3(p<0.001) and Coronary Artery Calcification (CAC) score ≥ 6 (p<0.001) were associated with higher 28-day and 6-month mortality. PESI score ≥100 (OR 5.2, 95% CI: 1.1, 24.2, P <0.05), poGPS ≥1 (OR 2.5, 95% CI: 1.2-5.0, P = 0.01) and NLR ≥3 (OR 3.7, 95% CI: 1.0-3.4, P <0.05) remained independently associated with 28-day mortality. On multivariate binary logistic regression analysis of factors associated with 6-month mortality, PESI score ≥100 (OR 6.2, 95% CI: 2.3-17.0, p<0.001) and coronary artery calcification score ≥6 (OR 2.3, 95% CI: 1.1-4.8, p = 0.030) remained independently associated with death at 6-months. When patients who had an underlying cancer diagnosis were excluded from the analysis only GPS≥1 remained independently associated with 6-month mortality (OR 5.0, 95% CI 1.2-22.0, p<0.05). PESI score >100, poGPS≥1, NLR ≥3 and CAC score ≥6 were associated with 28-day and 6-month mortality. PESI score ≥100, poGPS≥1 and NLR ≥3 remained independently associated with 28-day mortality. PESI score ≥100 and CAC score ≥6 remained independently associated with 6-month mortality. When patients with underlying cancer were excluded from the analysis, GPS≥1 remained independently associated with 6-month mortality. The role of the systemic inflammatory response (SIR) in determining treatment and prognosis requires further study. Routine reporting of CAC scores in CTPA scans for acute PE may have a role in aiding clinical decision-making regarding treatment and prognosis.

Patients with pulmonary hypertension (PH) are happy to perform simple exercise capacity tests at home and believe this is feasible. A proportion of patients are able to use an electronic form to complete quality of life questionnaires. These findings are being used to build a telemedicine strategy for PH patients.

To evaluate current digital inclusion in the Scottish pulmonary hypertension population, a paper questionnaire was offered to the entirety of patients with pulmonary arterial hypertension in Scotland. The Scottish Index of Multiple Deprivation was used to stratify patients into deprivation deciles. 464 patients returned questionnaires (86%). 91% had reliable internet access. 89% had access to an internet‐enabled device. 71% used the internet daily. The most common barriers to increased internet usage were confidence with technology (19%) and lack of perceived personal benefit (7%). 54% would like virtual healthcare to complement in person review and 58% would like to monitor their health digitally. Older patients were less likely to use the internet and had less desire for virtual healthcare. Rural living did not negatively impact access to the internet. Younger, more rural, and less deprived patients currently use and desire more online exercise. Deprived patients were less likely to have internet access or internet enabled devices, more likely to have no device or a mobile without internet, and had less desire for virtual healthcare or digital health monitoring. Most patients have the means of accessing the internet and support virtual healthcare in addition to direct clinician contact. However, digital engagement was lower in older and more deprived patients. The high response rate supports paper over online survey methodology for future digital inclusion research. Future digital healthcare strategies need to integrate this knowledge to minimize age‐ and deprivation‐related inequity.

Cardiac magnetic resonance-derived ventricular variables are predictive of mortality in pulmonary arterial hypertension. Rodent models which emphasize ventricular function, allowing serial monitoring, are needed to identify pathophysiological features and novel therapies for pulmonary arterial hypertension. We investigated longitudinal changes in the Sugen–hypoxia model during disease progression. Sprague Dawley rats (n = 32) were divided into two groups. (1) Sugen–hypoxia: a dose of subcutaneous Sugen-5416 and placed in hypobaric hypoxia for two weeks followed by normoxia for three weeks. (2) Normoxia: maintained at normal pressure for five weeks. Rats were examined at five or eight weeks with right-heart catheter, cardiac magnetic resonance, and autopsy. Compared to normoxic controls (23.9 ± 4.1 mmHg), right ventricular systolic pressure was elevated in Sugen–hypoxia rats at five and eight weeks (40.9 ± 15.5 mmHg, p = 0.026; 48.9 ± 9.6 mmHg, p = 0.002). Right ventricular end-systolic volume index was increased in eight weeks Sugen–hypoxia (0.28 ± 0.04 µlcm–2, p = 0.003) compared to normoxic controls (0.18 ±0.03 mlcm–2). There was progressive dilatation of the right ventricular at eight weeks Sugen–hypoxia compared to normoxic controls (0.75 ± 0.13 µlcm–2 vs 0.56 ± 0.1 µlcm–2 p = 0.02). Ventricle mass index by cardiac magnetic resonance at five weeks (0.34 ± 0.06, p = 0.003) and eight weeks Sugen–hypoxia (0.34 ± 0.06, p = 0.002) were higher than normoxic controls (0.21 ± 0.04). Stroke volume, right ventricular ejection fraction, and left ventricular variables were preserved in Sugen–hypoxia. Ventricular changes during the course of illness in a pulmonary arterial hypertension rodent model can be examined by cardiac magnetic resonance. These changes including right ventricular hypertrophy and subsequent dilatation are similar to those seen in pulmonary arterial hypertension patients. Despite the persisting pulmonary hypertension, there are features of adaptive cardiac remodeling through the study duration.

Risk stratification models in pulmonary arterial hypertension (PAH) rely on World Health Organisation Functional Class (WHO FC). A high proportion of patients are classified as WHO FC III, a heterogenous group which limits the stratification abilities of risk models. The Medical Research Council (MRC) Dyspnoea Scale may allow a more precise assessment of functional status and improve current risk models. We investigated the ability of the MRC Dyspnoea Scale to assess survival in PAH and compared performance to WHO FC and the COMPERA 2.0 models. Patients with Idiopathic, Hereditary or Drug‐induced PAH who were diagnosed between 2010 and 2021 were included. The MRC Dyspnoea Scale was retrospectively applied as derived from a combination of patient notes, 6MWD tests results and WHO functional status using a purpose‐designed algorithm. Survival was assessed using Kaplan–Meier analyses, log rank testing and Cox proportional hazard ratios. Model performance was compared with Harrell's C Statistic. Data from 216 patients were retrospectively analyzed. At baseline, of 120 patients classified as WHO FC III, 8% were MRC Dyspnoea Scale 2, 12% Scale 3, 71% Scale 4 and 10% Scale 5. The MRC Dyspnoea Scale performed well compared to the WHO FC and COMPERA models at follow up (respectively, C‐statistic 0.74 vs. 0.69 vs. 0.75). It was possible to use the MRC Dyspnoea Scale to subdivide patients in WHO FC III into groups which had distinct survival estimates. We conclude that at follow‐up, the MRC Dyspnoea Scale may be a valid tool for the assessment of risk stratification in pulmonary arterial hypertension.

Remote exercise tests for patients with pulmonary hypertension (PH) would improve the telemedicine strategies in this disease. The PHRET study assessed the validity and feasibility of four remote exercise tests performed by PH patients at home. Participants undergoing diagnostic assessment for PH were included. At baseline, patients completed a 6MWT followed by a range of study tests including a Timed Up and Go (TUG) test, a Sit‐to‐Stand (STS), a Step Test (ST), and a tele‐6MWT (T6MWT) performed outside using a GPS‐enabled smartphone. Patients performed these tests at home following discharge and at first follow‐up. Analysis focused on comparing the results of study tests to the standard 6MWT. The discontinuation rate was 15%. Ninety‐seven percent of patients were able to complete a TUG, 92% a STS, 73% a ST, and 49% a T6MWT. At baseline, correlation between the standard 6MWT and study tests, respectively, was T6MWT 0.93, ST 0.78, STS 0.71, and TUG −0.76 (p < 0.001). Direction of change in the study test agreed with the standard 6MWT in 68% of the follow‐up ST, 68% of the STS, 71% of the TUG, and 79% of the T6MWT. Patients were able to complete the tests at home, there were no adverse incidents and ≥92% of patients were happy to continue performing home tests. Remote exercise testing is feasible. The T6MWT was a valid remote measure of exercise capacity, but could only be performed by a limited number of patients. The high discontinuation rate may impact the utility of remote tests.

ObjectiveGroup II pulmonary hypertension (PH) can be challenging to distinguish from Group I PH without proceeding to right heart catheterisation (RHC). The diagnostic accuracy of the H2FPEF and OPTICS scores was investigated in Scotland.MethodsPatients were included in the study if they were referred to the Scottish Pulmonary Vascular Unit between 2016 and 2020 and subsequently diagnosed with Group II PH or Group I PH which was either idiopathic, heritable or pulmonary veno-occlusive disease. The established cut offs for the H2FPEF and for the OPTICS scores were applied retrospectively to predict the presence of Group II PH. The diagnosis from the scores were compared with the MDT consensus diagnosis following RHC.Results107 patients with Group I PH and 86 patients with Group II PH were included. Retrospective application of the OPTICS score demonstrated that pretest scoring would detect 28% of cases with Group II PH yet at the cost of misdiagnosing 4% of patients with Group I as Group II PH (specificity 0.96). The H2FPEF score had a far greater sensitivity (0.70) yet reduced specificity (0.91), leading to misdiagnosis of 9% of Group I PH cases.ConclusionWhile the specificity of these scores was high, the lack of perfect specificity limits their utility as it results in missed patients with Group I PH. As a consequence, they cannot replace RHC as the means of diagnosing the aetiology of PH in their current form. The scores may still be used to support clinical judgement or to indicate the advisability for further provocative testing at RHC.

Our aim is to assess the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab. Inflammation and autoimmunity are established as important in PAH pathophysiology. One of the most robust observations across multiple cohorts in PAH has been an increase in IL6, both in the lung and systemically. Tocilizumab is an IL-6 receptor antagonist established as safe and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma. In case reports where the underlying cause of PAH is an inflammatory process such as systemic lupus erythematosus, mixed connective tissue disease (MCTD), and Castleman’s disease, there have been case reports of regression of PAH with tocilizumab. TRANSFORM-UK is an open-label study of intravenous (IV) tocilizumab in patients with group 1 PAH. The co-primary outcome measures will be safety and the change in resting pulmonary vascular resistance (PVR). Clinically relevant secondary outcome measurements include 6-minute walk distance, WHO functional class, quality of life score, and N-terminal pro-brain natriuretic peptide (NT-proBNP). If the data support a potentially useful therapeutic effect with an acceptable risk profile, the study will be used to power a Phase III study to properly address efficacy.