Until recently, tests of vascular structure, function and compliance have been used predominantly for assessing the efficacy of treatment – for example, aggressive medical therapy may yield improvements in vascular structure and function with a concomitant decrease in cardiac events. However, the role of abnormal vessel function in the development of atherosclerosis, and the relationship of structural changes in peripheral vessels with coronary disease might suggest that these tests could be used as a screening test for patients with subclinical coronary disease. At present, there is insufficient evidence to support the theory that normal vascular structure and function can rule out significant coronary disease, and indeed, such an association may be confounded by the presence of risk factors that alter these test results in the absence of significant coronary artery disease (CAD). The overall hypothesis of the studies undertaken in this thesis was that utilizing contemporary technology during ultrasonic and tonometric assessment of arterial structure, function and compliance, it is possible to non-invasively characterise both early and advanced arterial dysfunction and identify patients both at risk and with cardiovascular disease. The aim of these studies was to determine whether these tests can be used to guide intervention when arterial dysfunction is diagnosed and whether they are robust enough as a follow-up tool. The thesis initially reviews arterial structure, function and compliance and their relationship to cardiovascular risk and in particular, CAD. This review provides a rationale for the studies undertaken here to resolve clinical and technical issues as well as provide an insight into the tests chosen to assess arterial function. The second chapter discusses the methodology used in these studies to assess arterial structure, function and compliance, diagnose coronary artery disease and determine cardiovascular risk. They range from stress echocardiography for the diagnosis of CAD to tests for arterial structure (carotid intima-media thickness [IMT]), endothelial function (brachial artery reactivity [BAR]), local arterial distensibility (distensibility coefficient [DC]) and systemic or total arterial compliance (TAC). In addition, several methods will be discussed for assessing local arterial elasticity with a novel imaging technique. The rationale for using tests for arterial structure, function and compliance in patients with CAD as well as cardiovascular risk is examined in chapter 3. Chapter 3 examines the use of TAC, IMT and BAR in patients undergoing dobutamine stress echocardiography (DSE) in a group of patients with and without disease. TAC was neither an independent predictor of CAD risk or patients having CAD in this study. BAR was a predictor of risk status but not of patients having CAD. Only IMT was an independent predictor of both patients at risk for CAD and those with CAD. In chapter 3 both pulse pressure and total arterial compliance were only univariate predictors of risk for CAD. Chapter 4 examines three different methods of estimating TAC, all based on the two-element Windkessel model in 320 patients with and without cardiovascular risk. The pulse-pressure method (PPM) is based on a combination of pressure, obtained using applanation tonometry of the radial artery, and an estimate of stroke volume obtained by Doppler echocardiography of the left ventricular outflow and by 2D echocardiographic dimension of the left ventricular outflow tract. The area method (AM) is an integral variation of the Windkessel equations and is based on the derived central pressure waveform. The stroke volume-pulse pressure method (SVPP) is a simple ratio of stoke volume and pulse pressure. We conclude that they correlate well and show similar differences between groups with and without risk. The PPM had the smallest difference from the mean and standard deviation in Bland Altman analysis and we therefore used the PPM for most future studies. Chapter 5 discusses the use of tissue Doppler for the derivation of central pressure and determination of distensibility coefficient, a marker of local arterial elasticity. Tissue Doppler can be used to evaluate the low frequency, high amplitude signals which come from tissue by changing filtering settings on an ultrasound machine. Using off-line software, the tissue velocities can be extracted and with a processing algorithm, vessel wall displacement values over time can be generated. These vessel wall displacement values which are in microns (µm) can then be used to calculated distensibility coefficient which is calculated as 2*((net displacement/minD)/PP). We studied a large group of patients with and without cardiovascular risk and conclude that DC using tissue Doppler correlates highly with DC by B-mode and M-mode imaging and is also very reproducible. In a subgroup, the vessel displacement values were “calibrated” using mean and diastolic pressure and with specialised software and a transfer function, central pressure wave forms were reconstructed. In this study we conclude that the central pressure obtained using tissue Doppler displacement of the carotid artery correlates highly with that obtained using applanation tonometry although there are technical challenges involved. With the known prognostic value of pulse pressure, chapter 6 explores whether there is added benefit to measuring total arterial compliance over pulse pressure alone. Once again patients with and without disease were studied and we conclude that brachial pulse pressure correlates well with TAC in men with normal cardiac function. However, in women and in patients at the low and high extremes of function, and in patients with preclinical and overt cardiovascular disease, there appears to be incremental value in measuring TAC. The role of cardiovascular risk factors in association with TAC is examined in chapter 7. Several studies have shown that TAC is lower in certain groups due to age, height, hypertension, hyperlipidaemia or other factors. We studied 720 patients with and without cardiovascular risk factors and did several multiple linear regression models based on anthropomorphic variables. Age was an independent correlate of TAC in most of the regression models and we conclude that TAC is associated with multiple risk factors, but age is a major determinant. The influence of age and other correlates may dwarf the contribution of individual risk factors and therefore their alteration with therapy. Chapter 8 examines the correlates of preclinical cardiovascular disease in both indigenous and non-indigenous Australians with and without diabetes mellitus (DM). DM is a major health problem in the Indigenous population in Australia and CVD occurs earlier in this group than in caucasians and is responsible for 1/3 of all deaths. We studied a large group of indigenous Australians with and without DM and matched them to a caucasian population. There were no differences in BAR between the groups probably due to large standard deviations in the measurements. In assessing DC, both DM groups had significantly lower DC than the non-DM groups. However, in the IMT analysis both of the indigenous groups had significantly higher IMT than their caucasian counterparts and even after IMT was corrected for age, Indigenous patients even at an early age had significantly higher IMT. We conclude that despite a high incidence of risk factors in indigenous Australians both with and without DM, ethnicity (and various other risk factors for which it is a marker) appears to be an independent predictor of preclinical cardiovascular disease. In chapter 3 we determined that TAC was not an independent correlate of patients either at risk of CAD or with CAD. Chapter 9 discusses the results of a study of patients presenting for stress echocardiography for either detection of CAD or risk stratification. Ischaemia was detected in 25% of cases and TAC was similar in those with and without ischaemia. In multiple linear regression models however, in addition to cardiovascular risk factors TAC was independently associated with both the presence of CAD and the extent of ischaemia at stress echocardiography. Several studies have used vascular function as an outcome measure in intervention trials, either lifestyle or pharmacologic. In chapter 10 we undertook a lifestyle and diet intervention study in a large group of healthy patients with type-II DM. The tests for IMT, BAR and TAC were used in addition to biochemical markers and fitness assessment. At follow-up the intervention group had significant changes in weight and BMI and significantly increased fitness but failed to show any changes in any of the vascular parameters. We conclude that while metabolic and fitness parameters respond to treatment in patients with type-II DM, the early changes seen in vascular structure, function and compliance may not change in the long term. Although TAC has been correlated with hypertension, LVH, myocardial ischaemia and heart failure there are few data existing regarding the relationship of TAC to outcome. In the final chapter of this thesis we sought whether TAC was predictive of outcome in a large, primary prevention group of patients with varying degrees of cardiovascular risk. We followed up 719 patients who were studied between 2001 and 2008 in Brisbane, Australia and examined TAC in relation to mortality and a composite endpoint of death or hospital admission. There were significant differences in groups having low and normal TAC for both death and the composite endpoint and in patients with intermediate and high Framingham 10-year risk TAC was an independent predictor of both death and the composite endpoint. We conclude that TAC correlates with outcome in patients with varying degrees of cardiovascular risk and also adds incremental benefit to Framingham risk alone in patients with intermediate risk.