Over the past ten years there has been a marked reduction in the number of deaths from heart disease. A major factor contributing to this is the wider use of a group of medicines called statins. Large clinical trials including the Heart Protection Study played a key role in demonstrating the important protective actions of statins for patients with symptoms of heart disease, as well as for those who are likely to develop disease because of high cholesterol levels or other risk factors. However, this study was unable to predict those who had the most active disease and likely to suffer from heart attacks or other vascular events such as stroke. If a simple diagnostic test became available to detect people at highest risk of disease at an early stage, this would allow more intensive medical treatment, as well as diet and lifestyle advice to cut their risk of life-threatening vascular events or sudden death. Endothelin is a vasoconstrictor peptide produced by the endothelium (a single layer of cells that line every blood vessel). Research over the past twenty years has strongly implicated endothelin in the underlying processes leading to heart disease. But measuring endothelin in blood samples is too difficult to provide a reliable means of diagnosis. However, when endothelin is produced in cells it is synthesized as part of a large protein called proendothelin. Because fragments of this protein are also secreted with endothelin it is likely that one of these fragments can provide a reliable indicator of the level of endothelin production, and indirectly the presence of active heart disease. The aims of this project are: (1) to identify the best fragment of proendothelin to use as a new diagnostic test, and (2) to evaluate the usefulness of this test to detect people with heart disease. The diagnostic potential of this new test will be evaluated in a two-step process. Firstly, samples from a well-characterised set of 500 diabetic patients who have undergone detailed screening for heart disease, and progression of disease will be used to assess which is the best method of proendothelin measurement for identifying active heart disease. The second stage of validation will be to apply the best method to measurement of the baseline samples from the 20,536 subjects participating in the Heart Protection Study. These investigations are likely to lead to a new diagnostic test for screening for heart disease.