The Sheffield Teaching Hospitals Observational Study of Patients with Pulmonary Hypertension, Cardiovascular and other Respiratory Diseases (STH-ObS)

The objective of this study is to collect detailed longitudinal clinical phenotypic information linked to bio-samples from patients with pulmonary hypertension, cardiovascular disease, and other lung / respiratory diseases including COVID-19 and compare with appropriate control groups including healthy volunteers.

We aim to better understand the effect of current treatments and monitoring treatment response and better understand the molecular mechanisms of disease to increase our understanding of the causes, presentations and management of these conditions. This cohort is important part of a national projects examining the genetic and molecular architecture of pulmonary hypertension with major awards from the Medical Research Council and British Heart Foundation.

During the 2020 coronavirus pandemic we amended our protocol to allow the collection of samples and data from patients with coronavirus, and healthcare workers to enable us to conduct research into any long-term effects on lung, pulmonary and cardiovascular health.

We have worked with a number of academic and industry collaborators and are registered with the UK Tissue Directory and Coordination Centre, and have contributed samples to the NIHR BRIDGE study and National Cohort of Idiopathic and Heritable Pulmonary Arterial Hypertension.

Current research projects

Investigation into OPG and related biomarkers in incident cases of pulmonary hypertension

We have discovered that the protein osteoprotegerin (OPG) is involved in the disease process and is easily measurable in patient blood samples. The aim of this study is measure OPG in the blood of patients with Pulmonary Hypertension and related conditions to determine whether it can be used as a biomarker to assess disease progression.

Identifying proteomic biomarkers to detect pulmonary arterial hypertension in patients with systemic sclerosis

We are investigating a proteomic approach (MYRIAD RBM) to discover a protein biomarkers signature using machine learning approaches to help screen for the development of pulmonary arterial hypertension in an at-risk population of patients with systemic sclerosis.

Identifying miRNA signatures for Pulmonary Hypertension

We are investigating the use of miRNA’s found in plasma to discover a disease signature using machine learning approaches to help screen for the development of pulmonary hypertension.

Integration of real-world mobile activity and heart rate/rhythm data to detect cardiopulmonary disease and identify ‘signatures’ of treatment response and 1-year risk scores in PAH.

Working with Euan Ashley and Steve Hershman (Stanford) we are linking data captured by iOS Health and the MyHeart Counts App to address a number of aims and projects.

1. Improve screening to identifying patients at risk of pulmonary hypertension.

2. Assess treatment response and disease progression to test and compare the prognostic accuracy of real-world activity/cardiac function data from MyHeart Counts with standard in-hospital clinical assessments, 1-year risk assessment, biomarkers and patient outcome.

3. Capture real-world activity data from family members of patients with heritable PAH (UK Cohort Study) to identify ‘signals’ of early disease development.

4. Capture real-world activity of patients and healthcare workers at risk or, or recovering from COVID-19.

Recent research papers

1. Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JHR, Simeoni I, Rivers E , Maimaris J et al (2020) Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature. View this article in WRRO 
2. Rhodes CJ, Otero-Núñez P, Wharton J, Swietlik EM, Kariotis S, Harbaum L, Dunning MJ, Elinoff JM, Errington N, Thomson AAR , Iremonger J et al (2020) Whole blood RNA profiles associated with pulmonary arterial hypertension and clinical outcome. American Journal of Respiratory and Critical Care Medicine. View this article in WRRO 
3. Hodgson J, Swietlik EM, Salmon RM, Hadinnapola C, Nikolic I, Wharton J, Guo J, Liley J, Haimel M, Bleda M , Southgate L et al (2020) Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine, 201(5), 575-585. 
4. Wei W, Tuna S, Keogh MJ, Smith KR, Aitman TJ, Beales PL, Bennett DL, Gale DP, Bitner-Glindzicz MAK, Black GC , Brennan P et al (2019) Germline selection shapes human mitochondrial DNA diversity. Science, 364(6442), eaau6520-eaau6520. 
5. Gorman KM, Meyer E, Grozeva D, Spinelli E, McTague A, Sanchis-Juan A, Carss KJ, Bryant E, Reich A, Schneider AL , Pressler RM et al (2019) Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia. The American Journal of Human Genetics, 104(5), 948-956. 
6. Sweatt AJ, Hedlin HK, Balasubramanian V, Hsi A, Blum LK, Robinson WH, Haddad F, Hickey PM, Condliffe RA, Lawrie A , Nicolls MR et al (2019) Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension.. Circulation Research, 124(6), 904-919. View this article in WRRO 
7. Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Aman J, Girerd B , Arora A et al (2019) Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis. The Lancet Respiratory Medicine, 7(3), 227-238. View this article in WRRO 
8. Bohnen MS, Ma L, Zhu N, Qi H, McClenaghan C, Gonzaga-Jauregui C, Dewey FE, Overton JD, Reid JG, Shuldiner AR , Baras A et al (2018) Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension. Circulation. Genomic and precision medicine, 11(10). View this article in WRRO 
9. Chen K-H, Dasgupta A, Lin J, Potus F, Bonnet S, Iremonger J, Fu J, Mewburn J, Wu D, Dunham-Snary K , Theilmann AL et al (2018) Epigenetic Dysregulation of the Drp1 Binding Partners MiD49 and MiD51 Increases Mitotic Mitochondrial Fission and Promotes Pulmonary Arterial Hypertension: Mechanistic and Therapeutic Implications.. Circulation, 138(3), 287-304. View this article in WRRO
10. Gräf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W, Hodgson J, Liu B, Salmon RM, Southwood M , Machado RD et al (2018) Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nature Communications, 9(1). View this article in WRRO 
11. Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift AJ, Dorfmüller P, Preston SD, Southwood M, Hernandez-Sanchez J, Martin J , Treacy C et al (2017) Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension.. Circulation, 136(21), 2022-2033. View this article in WRRO
12. hodes CJ, Wharton J, Ghataorhe P, Watson G, Girerd B, Howard LS, Gibbs JSR, Condliffe R, Elliot CA, Kiely DG , Simonneau G et al (2017) Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study. The Lancet Respiratory Medicine, 5(9), 717-726. View this article in WRRO
13. Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA , Howard LS et al (2017) Plasma Metabolomics Implicate Modified Transfer RNAs and Altered Bioenergetics in the Outcome of Pulmonary Arterial Hypertension.. Circulation, 135, 460-475. View this article in WRRO
14. Rothman AM, Arnold N, Pickworth J, Iremonger J, Ciuclan L, Allan R, Guth-Gundel S, Southwood M, Morrell N, Thomas M , Francis S et al (2016) MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. Journal of Clinical Investigation, 126(7), 2495-2508. View this article in WRRO
15. Pérez de Ciriza C, Lawrie A & Varo N (2014) Influence of pre-analytical and analytical factors on osteoprotegerin measurements.. Clin Biochem, 47(13-14), 1279-1285
16. Rhodes CJ, Wharton J, Boon RA, Roexe T, Tsang H, Wojciak-Stothard B, Chakrabarti A, Howard LS, Gibbs JSR, Lawrie A , Condliffe R et al (2013) Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension.. Am J Respir Crit Care Med, 187(3), 294-302
17. Condliffe R, Pickworth JA, Hopkinson K, Walker SJ, Hameed AG, Suntharaligam J, Soon E, Treacy C, Pepke-Zaba J, Francis SE , Crossman DC et al (2012) Serum osteoprotegerin is increased and predicts survival in idiopathic pulmonary arterial hypertension