Cardiovascular research in the Clinical School is based in the School’s Departments of Medicine (Divisions of Cardiovascular Medicine, Respiratory Medicine, Clinical Pharmacology), Public Health and Primary Care, Clinical Biochemistry, Clinical Neurosciences, and Haematology. There are close links with the Biological School’s Departments of Biochemistry, Pharmacology and Physiology. Cardiovascular research also comprises defined work streams in several MRC Centres (Stem Cells, Translational Research in Obesity and related metabolic disorders (MRC CTROM), and MRC Units (Epidemiology, Biostatistics), the Gurdon Institute, and the Wellcome Trust Sanger Institute (WTSI). Clinical cardiovascular research involves collaborations with Addenbrooke’s and Papworth Hospitals with links to the integrative physiology and genomics themes. Research focuses on both the vasculature and the heart, ranging from the molecular and cellular levels, through studies of genetically modified (GM) mice to clinical studies of patients, with emphasis on defining mechanisms of major cardiovascular diseases and identifying and exploiting potential new therapeutic agents.
Within the Clinical School a major area of interest is the pathogenesis of atherosclerosis with particular emphasis on vascular smooth muscle apoptosis and cell senescence and the role of immune cells and macrophages in both atherogenesis and plaque stability (http://www.med.cam.ac.uk/html/div/cardio.html)). These studies also extend to cerebrovascular disease and novel imaging studies of vascular inflammation (http://www.neurology.cam.ac.uk/stroke/about/index.html), and to the use of both imaging and biomarkers to identify vulnerable plaques in patients and the consequences of coronary artery disease on myocardial blood flow. The mechanisms underlying cardiac hypertrophy and heart failure, and in particular myocyte apoptosis are being determined at both cellular and whole organism level. Pulmonary hypertension is another major focus with programmes in molecular pathogenesis and experimental medicine (http://www.med.cam.ac.uk/html/div/respmed.html). The role of transforming growth factor-beta in vascular remodelling is being intensely studied in the context of systemic and pulmonary vascular disease. Experimental medicine studies in patients with pulmonary hypertension underway at Papworth Hospital, the largest referral centre for this condition in the UK. Metabolic and imaging studies of left and right heart failure and myocardial ischaemia are exploring the role of these approaches in myocardial revascularisation and the potential of cardiac preconditioning. Animal models of disease coupled with genomic studies and state-of-the-art imaging modalities (e.g. PET and CT) are providing insights into new pathways for disease pathogenesis and targets for therapy. A variety of genetically modified mouse models for cardiovascular and pulmonary vascular disease have been generated and phenotyped using a systems biology approach involving gene expression, proteomic and metabolomic profiles and the techniques of integrative physiology.
At the population level studies are focussed on the identification of gene-lifestyle interactions to determine risk factors for disease and to facilitate the development of individual and population-level interventions (http://www.phpc.cam.ac.uk). Areas of research include coronary heart disease and type 2 diabetes. These studies have established major national and international collaborations involving large numbers of incident cases and controls (http://www.iph.cam.ac.uk).
Discovery approaches focus on genome-wide association studies and other comprehensive “omics” approaches (e.g. proteomics, metabolomics) to identify the functional elements in genetic regions associated with metabolic and cardiovascular traits. Functional characterisation of associated loci is undertaken in human cell lines and in parallel studies of model organisms (e.g. zebrafish). A major example of this approach is the work on platelet biology and atherothrombosis (http://www.haem.cam.ac.uk). In the thrombotic stage of atherosclerosis and other vascular pathologies, platelets interact with exposed collagen in the subendothelium and basement membrane of the blood vessels to initiate thrombus formation. This interaction is studied at the molecular and cellular levels and in mouse models. One example is the development of inhibitors of thrombosis
The link between cardiovascular disease and obesity is being determined using a functional genomics approach, with a focus on insulin resistance (http://www.mrl.ims.cam.ac.uk). This involves high throughput genetic analysis in humans, advanced physiological phenotyping protocols in man and rodent models, and ex vivo/in vitro studies of mechanism in cell biology experiments. State-of-the-art transcriptomic, proteomic and lipidomic profiling technologies combined with advanced bioinformatics are being used to determine tissue-specific pathological metabolic networks relevant to systemic insulin resistance and associated cardiovascular complications. This will provide the basis for a long-term programme to identify individuals with a high genetic risk of coronary artery disease.
Cardiovascular Research in Cambridge also a focuses on the pathogenesis of hypertension, arterial stiffness, genetics of sodium handling and action on the circulation of G-protein coupled receptors (http://www.med.cam.ac.uk/html/div/clinpharm.html). The genetics of hypertension is being studied partly as member of the Medical Research Council British genetics of hypertension (“BRIGHT) collaboration, and partly in a select cohort of local patients with salt-dependent hypertension at a young age. The work involves clinical studies on patients with hypertension or arterial stiffness, in vitro pharmacology and in vivo imaging using positron emission tomography and CT in collaboration with the Wolfson Brain Imaging Centre (http://www.wbic.cam.ac.uk/). Major areas of interest are the regulation of blood pressure, the molecular genetics of essential hypertension and pre-eclampsia the pressor peptides endothelin-1 and urotensin as well as novel ‘orphan’ GPCRs, identified within the human genome.
Cardiovascular research at the Clinical School has close links with research performed in the Biological School’s Departments of Biochemistry, Pharmacology and Physiology. For example, the developmental programming of cardiovascular disease and particularly the role of perinatal hypoxia and intrauterine growth retardation are being investigated using in vivo fetal physiology and rodent models (http://www.pdn.cam.ac.uk). Early cardiovascular patterning is being pursued employing the zebrafish and both mouse and human embryonic stem cells are used to study cardiovascular development and the factors determining cardiac and smooth muscle cell differentiation (http://www.iscb.cam.ac.uk). The role of angiogenesis in a number of diseases such as cancer, diabetes mellitus, rheumatoid arthritis and cardiovascular disease is being studied using a variety of cellular and molecular techniques including gene arrays to identify, localize and quantify genes that control angiogenesis. The function of these genes is explored using 2D and 3D cell culture systems with real-time multicolour imaging (http://www.path.cam.ac.uk). At the molecular and cellular level, endothelial regulation of vascular smooth muscle and vasodilator mechanisms are being studied, focusing on the cardiovascular pharmacology of the cannabinoids, which act through a variety of mechanisms to relax the blood vessels, and calcium signalling in smooth muscle (http://www.phar.cam.ac.uk). Studies of the electrophysiology of endothelial cells in situ are showing how drugs affect their membrane potential, which modulates vascular smooth muscle tone. Mouse models are also being used to investigate the pathophysiology of cardiac arrhythmias (http://www.bioc.cam.ac.uk/index.html). The mice have deleted or mutated ion channels in the heart that result in cardiac arrhythmias that model the corresponding arrhythmias in patients. Additional work is being done with the Sanger Institute to identify genetic variations associated with arrhythmias using high throughput sequencing of DNA samples from large numbers of affected families in Europe and China.
Additional principal investigators: