02. Cardiovascular - Recent Highlights

Papworth Hospital is a nationally designated centre for the diagnosis and treatment of patients with severe pulmonary arterial hypertension (PAH) and is the only centre designated to undertake pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension (CTEPH). The BRC funding allocated to the Pulmonary Vascular Diseases Unit (PVDU) at Papworth supports two research nurses who are central to the success of our translational programme. Significant added value has come from the reallocation of internal funds to support two clinical research fellows within the Unit.

As evidence of successful training of fellows provided by the BRC, one recent fellow is now an MRC clinical training fellow and another has been awarded a Clinical Lecturer position within the Translational Medicine and Therapeutics programme to undertake translational research in pulmonary hypertension.

The research outputs from the PVDU have doubled since the introduction of BRC funding. BRC support has enabled closer collaborative links between the basic science laboratories within CUH and the PVDU at Papworth, leading to high impact publications and the identification of new biomarkers. Research highlights over the past year have been the publication of a Phase II proof-of-concept and safety study supporting the use of an entirely novel class of therapy in this condition, tyrosine kinase inhibition, and the identification of levels of inflammatory cytokines as strong predictors of survival in PAH9.

The BRC has supported complex interventional studies of cardioprotection during PCI by both providing some of the required infrastructure and fostering a change in culture regarding clinical academic activity. The studies form a central aspect of the academic activity of one of the clinical lecturers supported by the BRC, who is now seeking to secure an intermediate fellowship to continue the studies after completion of his training.

The BRC also supports a research fellow investigating whether more detailed patient selection enhances the response to Cardiac Resynchronisation therapy (CRT ' biventricular pacing). The study recruited 210 patients attending the Wellcome Trust Clinical Research Facility before device implantation, and is a collaboration between Papworth and CUH. An interim analysis was used to inform changes in the routine care of this group of patients including adoption of more extensive pre-implantation imaging and selection of the site of left ventricular pacing, optimisation of the device immediately following implantation, and the establishment of a clinic to optimise the device using non-invasive cardiac output measurements (which have been demonstrated to be equivalent to, and much easier to perform, than detailed echocardiography). The changes in the CRT clinic evolved directly through the research programme which itself was carefully developed after a pilot study of 50 patients who assisted in the design of the larger study reported above. A measure of success is the almost complete follow-up that has been achieved at the 6-month assessment.

The framework of the BRC (including the biochemical laboratory to analyse peptides and other metabolic hormones) has also enabled experimental medicine studies to assess the utility of GLP-1 to protect the heart against stunning and ischaemic LV dysfunction. These were initially supported by an experimental medicine grant from the BHF and MRC, and after encouraging results a further recent award has been made by the MRC to continue these studies. The clinical fellow undertaking this work has collaborated closely both within the BRC cardiovascular group, and with interventional colleagues to extend the studies of cardioprotection during PCI.

The cardiovascular PET programme examines non-invasive measurement of inflammation, hypoxia and other markers of high-risk atherosclerotic plaque disease. The BRC has funded a trainee vascular surgeon who is supervising 2 ongoing translational research studies. One prospective study is investigating the determinants of aortic aneurysm expansion over a 3-year period, hypothesising that inflammation, hypoxia or neovascularisation detected by PET/CT or MRI at baseline is predictive of future aneurysm expansion.

A second trial is examining the mechanism of the increased risk of cardiovascular death in patients with rheumatoid arthritis, using PET/CT to detect changes in arterial inflammation in patients on anti-TNF therapy. We have shown that rheumatoid patients have increased aortic inflammation on FDG PET/CT imaging, which is reduced by anti-TNF therapy. Further studies are investigating the effect of anti TNF therapy on aortic and carotid plaque inflammation. We have also shown that supplementation with BH4 improves endothelial function but not aortic stiffness in rheumatoid patients, proving that reduced NO bioavailability is not responsible for increased stiffness. It is likely that these two ongoing studies will yield high-impact papers, and BRC funding for personnel and equipment was key to generating pilot data to allow subsequent substantive grant funding (from the British Heart Foundation (BHF) in both cases).

There are also fruitful collaborations with industry. One study, just completed, was the first multicentre FDG PET/CT vascular imaging study in the world. The BRC-funded PET/CT machine was the hub of this study, with London and Oxford also providing imaging services. 99 subjects with atherosclerosis were recruited and imaged to determine whether a novel anti-atherosclerosis drug was efficacious at lowering baseline inflammation. The study was carried out with GSK, and the results will be presented in late November 2010 at the American Heart Association meeting. BRC funding has also allowed 'discipline hopping' studies, such as the collaborations with Prof Morrell and Dr Pepke-Zaba at Papworth, where PET/CT is being used to investigate pulmonary artery inflammation in subjects with pulmonary hypertension.