Cardiovascular science and medicine
Cardiovascular research is carried out in a number of departments and affiliated institutes and involves collaborations with Addenbrooke's and Papworth Hospitals and colleagues in the Schools of the Physical Sciences and Technology. 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 an emphasis on defining mechanisms of major cardiovascular diseases and identifying and exploiting potential new therapeutic agents.
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 macrophages in plaque stability. These studies also extend to cerebrovascular disease and novel imaging studies of vascular inflammation, 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. 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 are 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.
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. 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. 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). An example of this approach is the work on platelet biology and atherothrombosis. This has allowed the development of inhibitors of thrombosis using novel antagonists or human antibodies to block the platelet-collagen interaction.
The link between cardiovascular disease and obesity is being determined using a functional genomics approach, with a focus on insulin resistance. 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. 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.
Angiogenesis is the development of new blood vessels from an existing vascular bed. Normal vascular proliferation only occurs during embryonic development, the female reproductive cycle and wound healing. It is also important in a number of diseases such as cancer, diabetes mellitus, rheumatoid arthritis and cardiovascular disease. The approach is to understand the cellular, molecular and genetic factors which regulate blood vessel structure and function. A variety of cellular and molecular techniques are employed 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.
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. Studies of the electrophysiology of endothelial cells in situ are showing how drugs affect their membrane potential, which modulates vascular smooth muscle tone. There is also a focus on the role of G-protein-coupled receptors (GPCRs, targets for about 50% of current drugs) together with their transmitters in human disease. This involves both in vitro pharmacology and in vivo imaging using PET. The vascular pharmacology of these receptors and putative antagonists are explored directly using measures of human vascular function.
Mouse models are also being used to investigate the pathophysiology of cardiac arrhythmias. The mice have deleted or mutated ion channels in the heart that result in cardiac arrhythmias that model the corresponding arrhythmias in patients. An important technique is fractionation, for following the dispersion of the cardiac electrogram through the heart. Abnormalities in the fractionation profile in the mice closely resemble those observed in patients with the same genetic mutations. This technique has led to substantial improvement in the diagnosis of patients at risk of cardiac arrhythmias and will significantly improve their management. Additional work is being done to identify genetic variations associated with arrhythmias using high throughput sequencing of DNA samples from large numbers of affected families in Europe and China.