Medicine (Austin & Northern Health) - Theses
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ItemMeasures of vascular reactivity and plasma biomarkers as indicators of coronary artery disease with special reference to the retinal circulation( 2013)Coronary heart disease accounts for greater morbidity in Australia than any other single disease and is the cause of nearly one fifth of all deaths. Dysfunction of the vascular endothelium occurs early in the development of atherosclerosis and progresses silently through a preclinical stage, until it manifests clinically. Genetic and systemic risk factors such as dyslipidaemia, diabetes mellitus, smoking, and hypertension contribute to its development. A simple non-invasive endothelial function test is warranted which might identify presymptomatic subjects at risk of developing complications of atherosclerosis. In humans, in vivo, endothelial function assessment has always been difficult and the dominant methods involve assessment of vasodilator function. This assessment may add value to the widely used Framingham risk score to predict risk of future cardiovascular events and potentially overcome some of its limitations. The retinal circulation is unique as it allows a non-invasive window to the health of the circulation in vivo in humans and is controlled by autoregulatory mechanisms. The general aim of this thesis is to determine whether changes in retinal vascular calibre and dynamic function correlate with markers of systemic and coronary endothelial function, and predict underlying coronary artery disease in patients with risk factors of atherosclerosis. Three groups of patients were prospectively recruited; a group with documented coronary artery disease (CAD) defined as coronary angiographic stenosis of >50% (n = 78), a group without CAD but with at least two traditional risk factors of atherosclerosis (n = 119), and a final group of patients with acute coronary syndromes (n = 61). Retinal arteriolar and venular dilatation in response to diffuse luminance flicker light (FI-RAD and FI-RVD) were measured in both eyes after pupil dilatation using the Dynamic Vessel Analyzer and expressed as percentage increase over baseline diameter. A fundus camera was used to acquire static retinal photographs and a computer-based standardised protocol was used to assess the changes in retinal artery and vein diameter and expressed as central retinal artery and vein equivalent (CRAE and CRVE). High resolution vascular ultrasound was used to assess brachial artery flow mediated dilatation, reactive hyperaemia velocity and shear rate in response to a 5 minute brachial artery occlusion. Augmentation index (AI) and reactive hyperaemia index (RHI) were assessed utilising digital peripheral arterial tonometry. Forearm blood flow was measured at baseline and during reactive hyperaemia, achieved by brachial artery occlusion for 5 minutes, utilizing venous occlusion plethysmography. The index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured using a coronary pressure guidewire in a subset of patients. In this group, coronary flow mediated dilatation (cFMD) defined as percentage increase in coronary artery diameter during hyperaemia was assessed by quantitative coronary angiography (QCA). Blood samples were collected from all patients and plasma vascular biomarkers including high sensitivity C-reactive protein (hs-CRP), endothelin, adrenomedullin, urotensin-II, cyclic guanosine 3', 5'-monophosphate (cGMP), C-type natriuretic peptide (CNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were measured. All statistical analyses were performed using SPSS version 18 for Windows (SPSS Inc., Chicago, IL, USA). As shown in Chapter 3, flicker-light induced retinal vascular response was attenuated in patients with diabetic retinopathy independent of risk factors of atherosclerosis. Correlation between right and left eyes was moderate and accordingly we recommend that examining both eyes would be more reliable. In Chapter 4, it was shown that advanced age and elevated glucose levels were associated with reduced flicker-light induced retinal arteriolar dilatation, independent of other risk factors of atherosclerosis while flicker-light induced retinal venular dilatation was attenuated in patients with elevated glucose and creatinine levels. Increased HDL was found to be associated with smaller central retinal vein equivalent (CRVE) while increased triglyceride level was associated with larger CRVE. Fractal dimension was associated with advanced age and elevated systolic blood pressure. Elevated endothelin-1 was associated with generalised smaller retinal vessels, focal arteriolar narrowing, diabetic retinopathy and attenuated flicker-light retinal arteriolar response. CRP was elevated in patients with diabetic retinopathy (DR). It seems that poorly controlled diabetes has a major effect on retinal vessel in addition to advanced age, renal impairment and hypertension. As discussed in Chapter 5, there was no correlation found between retinal vascular flicker light response and brachial artery FMD, hyperaemic forearm blood flow and coronary FMD. Retinal flicker light response was positively correlated with augmentation index, which is a marker of arterial stiffness, which may indicate that flicker light response reflects arterial stiffness as well as microcirculatory vasomotor function. Smaller retinal arterioles and venules were associated with larger baseline brachial artery diameter and reduced shear rate while larger retinal venules were associated with decreased fractional flow reserve, reduced peripheral vascular resistance, and increased forearm blood flow at baseline and during reactive hyperaemia. Diabetic retinopathy was associated with increased peripheral and coronary microvascular resistance, decreased forearm blood volume repaid at 1 minute, increased AI, larger baseline brachial artery diameter and decreased coronary flow mediated dilatation. The main finding of Chapter 6 was that flicker light induced retinal arteriolar dilatation (FI-RAD) is attenuated in patients with CAD compared to patients without CAD. This finding suggests that retinal endothelial microvascular dysfunction is linked to the presence of CAD. FI-RAD was superior to a Framingham based CVD risk score and all other retinal structural changes in predicting underlying coronary artery disease and was independent of traditional risk factors of atherosclerosis. In Chapter 7, the relationship between systemic and coronary vascular markers was examined. Brachial artery FMD had no association with coronary FMD, hyperaemic forearm blood flow or RHI in this cohort of patients with risk factors of atherosclerosis. Larger brachial artery diameter and decreased baseline velocity were found to be associated with increased minimum peripheral vascular resistance, and reduced brachial artery FMD, shear rate and reactive hyperaemia velocity. Increased shear rate was associated with increased FMD. The relationship of peripheral and coronary vascular reactivity measures with risk factors of atherosclerosis was examined in Chapter 8. Augmentation index was a predictor of underlying coronary artery disease. AI was increased with advanced age, hypertension and in current smokers. Brachial artery FMD was decreased with increased creatinine, while shear rate was reduced with advanced age, male gender and dyslipidaemia. Hyperaemic forearm blood flow was decreased with advanced age and increased creatinine while peripheral vascular resistance was increased with increased systolic blood pressure. Index of microcirculatory resistance (IMR) was elevated in patients with diabetes. In this chapter the relationship of peripheral and coronary vascular markers with plasma vascular biomarkers were examined. Elevated plasma ET-1 was associated with increased peripheral and coronary microcirculatory resistance, decreased RHV, decreased GTN-induced vasodilatation, decreased RH-FBF and decreased blood volume repaid at 1 and 5 minutes. Elevated plasma ADM level was associated with increased CFR and coronary FMD. This relationship might be due to direct vasoconstrictor effect or through its inhibitory effects on nitric oxide production. Whether long term treatment with endothelin receptor blockers reduces coronary microcirculatory resistance is unknown. Finally, the relationship between plasma vascular biomarkers and atherosclerosis risk factors was examined in Chapter 9. Hs-CRP and NT-proBNP were significantly elevated in the ACS group compared with stable CAD and non-CAD groups. Smoking was associated with increased ET-1 and reduced ADM levels, while increased ET-1 was associated with advanced age, elevated blood pressure and reduced glomerular filtration rate. All of these factors are associated with increased cardiovascular risk which might be due to an imbalance between NO and ET-1 levels in the endothelium resulting in increased vascular tone. In general, no association was found between retinal vascular changes and traditional markers of endothelial function such as flow mediated dilatation in the peripheral and coronary circulations. The lack of association could be due to differences in vascular control mechanisms between different segments of the circulation in the myocardium, skeletal muscle and retinal circulatory beds. The data presented in this thesis show an association between retinal vascular structure and function and underlying coronary artery disease. In this regard, retinal vascular assessment could be used as a risk marker for vascular disease, but further study will be required to establish the technique in clinical practice.