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 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), underlie most heritable forms of PAH. Since the missing heritability likely involves genetic variation confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 PAHnegative control subjects. Case-control analyses revealed significant overrepresentation of rare variants in novel genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We provide evidence for familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, led to reduced secretion from transfected cells. In addition, we identified pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings provide new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

These data show differences between venous and capillary gene expression both at baseline, and post vaccination, which may impact on the conclusions regarding immunological mechanisms drawn from studies using these different sampling methodologies.

ObjectiveTo investigate the association between troponin positivity in patients hospitalised with COVID-19 and increased mortality in the short term.SettingHomerton University Hospital, an inner-city district general hospital in East London.DesignA single-centre retrospective observational study.ParticipantsAll adults admitted with swab-proven RT-PCR COVID-19 to Homerton University Hospital from 4 February 2020 to 30 April 2020 (n=402).Outcome measuresWe analysed demographic and biochemical data collected from the patient record according to the primary outcome of death at 28 days during hospital admission.MethodsTroponin positivity was defined above the upper limit of normal according to our local laboratory assay (>15.5 ng/L for females, >34 ng/L for males). Univariate and multivariate logistical regression analyses were performed to evaluate the link between troponin positivity and death.ResultsMean age was 65.3 years for men compared with 63.8 years for women. A χ2 test showed survival of patients with COVID-19 was significantly higher in those with a negative troponin (p=3.23×10−10) compared with those with a positive troponin. In the multivariate logistical regression, lung disease, age, troponin positivity and continuous positive airway pressure were all significantly associated with death, with an area under the curve of 0.889, sensitivity of 0.886 and specificity of 0.629 for the model. Within this model, troponin positivity was independently associated with short-term mortality (OR 2.97, 95% CI 1.34 to 6.61, p=0.008).ConclusionsWe demonstrated an independent association between troponin positivity and increased short-term mortality in COVID-19 in a London district general hospital.

Current NICE guidance recommends CT coronary angiography (CTCA) as first line for investigation of new onset stable chest pain, however; CTCA is not yet readily available in all UK centres. DSE remains recommended in current ESC guidance and provides a readily available, low cost alternative (1). Indeed, a negative test has been demonstrated to have an excellent negative predictive value in the region of >98% (2). Aim We sought to evaluate the rate of cardiac events within two years of a negative DSE. Methods We performed a retrospective data interrogation of all DSE's performed in the Mater Hospital Cardiac Investigations Department between 2017 and 2019. MACE was evaluated at two years. Data were extracted using local electronic healthcare records. Statistical analysis performed using SPSS software.Results 302 DSE's were performed during the study period. The mean age was 64.1±10.4years with 41.7% male. Of the population, 16.2% had a prior history of IHD with 19.2% being diabetic. All tests were requested by the Cardiology team on an outpatient. 15 patients had a positive test. At two years the negative predictive value of a negative DSE was 98.3%. A positive test had a sensitivity for predicting coronary artery disease of 86.7% with a false positive rate of approximately of 13.3%. The overall complication rate was low at 0.7%. Using a combined endpoint of time to ACS or revascularisation; there was a significant difference (p<0.001) in event free survival between groups (figure 1).Conclusion DSE is a safe test with a high sensitivity for detecting coronary artery disease. Furthermore, compared to a positive test, a negative test has a strong negative predictive value for cardiac events at two years.