Sheffield has a long and proud history in pulmonary hypertension dating back over 60 years. In the 1950s, Donald Heath working within the Sheffield Regional Cardiovascular Centre based in the City General Hospital, now the Northern General Hospital, put forward the first description of the pathology of “hypertensive pulmonary vascular disease”, highlighting distinct muscularisation of small pulmonary arteries and severe intimal fibrosis that almost totally occluded the vessels. At that time, the prognosis for patients with pulmonary arterial hypertension was very poor and there were few treatment options. Remarkable advances in the pharmacological management of pulmonary hypertension have been achieved in the past 20 years but the search continues for treatments to reverse the relentless pulmonary vascular remodelling that characterises the disease.
Now located at the Royal Hallamshire Hospital, the Sheffield Pulmonary Vascular Disease Unit (SPVDU) led by Prof David Kiely is the UKs largest specialist centre, and one of the largest worldwide diagnosing and actively following up patients with pulmonary hypertension. SPVDU manages all major forms of adult pulmonary hypertension including large numbers of idiopathic and associated-PAH, pulmonary hypertension associated with lung disease and chonic thromboembolic pulmonary hypertension (CTEPH).
A significant strength of SPVDU is the detailed clinical phenotyping performed with data available as metadata to corresponding biological samples. A further strength is the cardiopulmonary MR-based imaging and computational physiological modelling that was developed in Sheffield (Prof Jim Wild). This expertise was recently recognised by an MRC-BHF capital infrastructure award of £7.5M for pulmonary imaging (POLARIS). Typical phenotyping to diagnose PH includes perfusion lung scanning, high resolution CT, CT pulmonary angiography, MR cardiac function, MR angiography with gadolinium and late enhancement studies, hyperpolarised gas lung MRI for assessment of associated respiratory disease, right heart catheterisation (RHC), ECG, echocardiography, spirometry and an incremental shuttle walking test. With over 700 RHC and MRI studies performed annually this provides world-class phenotyping data on one of the worlds largest cohorts of treatment-naïve patients. Building on this, the Sheffield Pulmonary Hypertension Biobank was initiated via funding from the Sheffield NIHR Cardiovascular Biomedical Research Unit in June 2009 with the ambition of building a large, world-class bioresource from incident cases of all major forms of adult PH, with longitudinal follow up. The PH biobank is led by Dr Allan Lawrie and is linked through an integrated clinical research database (PHArQ) via collaboration with the Clinical Research Systems Team (CReST) within the Sheffield Teaching Hospitals Foundation Trust (STHFT) led by Dr Steven Wood. This enables PHArQ to be linked with the clinical phenotype metadata described above and to the PH pharmacy database for accurate assignment of treatment metadata. Biological sample storage is managed via a HTA approved Tissue Bank and linked into PHArQ. With further BHF funding in 2012 the biobank has continued to grow into a world class resource.
With these expanding research tools, large datasets and systems biology approaches we are now able to 'dig deep’ to identify novel pathways and genes that are commonly, and uniquely active, at different stages of disease progression and treatment. Finding drugable targets among these pathways that translate from pre-clinical models of disease to human treatments has been challenging. However, through detailed assessments using imaging and biomarkers, a better understanding of different clinical phenotypes and risk will develop, and should allow stratification of patients into cohorts that may respond to specific therapeutics.