Interaction of vascular structure and function with myocardial ischaemia and survival

Fathi, Robert B. (2003). Interaction of vascular structure and function with myocardial ischaemia and survival PhD Thesis, School of Medicine, The University of Queensland.

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Author Fathi, Robert B.
Thesis Title Interaction of vascular structure and function with myocardial ischaemia and survival
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2003
Thesis type PhD Thesis
Supervisor Thomas H. Marwick
Total pages 321
Collection year 2003
Language eng
Subjects L
321003 Cardiology (incl. Cardiovascular Diseases)
730106 Cardiovascular system and diseases
Formatted abstract
Though conduit vessel stenosis can directly influence downstream ischaemia, other contributors of ischaemia exist. This thesis examines the input of the structure and function of the supplying vessels to the development of ischaemia. Vascular structure is assessed using carotid intima-media thickness (IMT), a non-invasive technique which marks atherosclerotic burden. Vascular function is a reflection of the health of the endothelium and its integrity. The endothelium normally controls vascular tone and function through the secretion of paracrine substances such as the vasodilator nitric oxide. Endothelial function is under the influence of various cardiovascular risk factors and the general vascular milieu. Modifications of, and improvements in these risk factors can have a beneficial effect on vascular function and also myocardial ischaemia. A non-invasive method of assessment of endothelial function is brachial artery reactivity (BAR) in which flow mediated dilatation (FMD) of the brachial artery is used as a marker of vessel function. This technique shows moderate correlation with coronary artery reactivity and thus has been used as a surrogate marker of coronary endothelial function. A graphical depiction of vascular dysfunction and the studies described in this thesis with the eventual role in assessing cardiovascular outcome is displayed in Figure 0-1.

This thesis initially reviews the literature regarding the causes and consequences of vascular dysfunction along with the methodology for BAR. The following chapters describe the importance of vascular structure and atherosclerotic burden. The technique and the measurement of carotid IMT is described along with its clinical significance.

The goal of examining the determinants of ischaemia requires a specific marker of ischaemia (as opposed to angiographic coronary artery disease or detection of hyperaemia). The role of dobutamine stress echocardiography (DbE) as a marker of myocardial ischaemia, as well as quantitative measures of myocardial function are assessed in Chapter 3. This chapter summarizes two aspects of stress echocardiography methodology that were important for the design of subsequent studies as initially we had planned for the candidate to interpret all studies. Firstly the use of a computer based teaching program in which accuracy of novice readers to detect significant ischaemia increased from 84% to 88% {P=0.01). The second section looks at a quantitative method of incorporating sonographer gathered myocardial Doppler velocity (MDV) information into the segmental scoring of novice readers. Although overall accuracy increased from 68% to 77% {P<0.05) for novice readers, this study was important in the decision to select an independent expert reader for some of the subsequent studies in the work.

The fourth chapter is a description of the other methodologies used for this thesis. It includes the segmental arterial supply, echocardiographic measurement of left ventricular (LV) volume, mass and diastolic parameters, quantitative coronary angiography and assessment of lesion morphology, degree of jeopardized myocardium. This is followed by biochemical analyses and assessment of quality of life.

The basis for the subsequent studies is Chapter 5, which assesses the contribution of complex coronary plaque morphology on the extent of DbE induced ischaemia. In a study of 196 patients undergoing these investigations, patients with complex disease were older with more extensive coronary disease and extent of jeopardized myocardium. However complex plaque morphology remained an independent predictor of the extent of ischaemia. This led to the question of the mechanism of this effect - especially the implications of complex plaque morphology on downstream vascular function.

The influence of vascular function in relation to ischaemia, lesion complexity, vascular inflammation and acuity is addressed in Chapter 6. Seventy-eight patients with stable and unstable angina pectoris (UAP) underwent BAR, high sensitivity C-reactive protein (CRP) assessment and coronary angiography and lesion assessment. Vascular function was not related to inflammation, clinical presentation or lesion morphology.

In order to investigate the contribution of vascular function to ischaemia, Chapter 7 addresses the role of aggressive lipid lowering using atorvastatin (80mg/day) versus usual care of lipids in a group of 60 randomized patients with symptomatic coronary disease not amenable to revascularization. After 3 months of therapy, patients with aggressive lipid lowering had fewer ischaemic segments (P=0.04), greater FMD (P =0.001) and improved quality of life scores.

The results of Chapter 7 may have reflected an effect from decreased low-density lipoprotein cholesterol (LDL) or decreased oxidized-LDL. We therefore sought to describe the effect of antioxidant therapy with Vitamin E and lipoic acid on BAR and ischaemic burden in 20 patients with coronary disease (CAD) in Chapter 8. After 6 months of therapy no significant difference in BAR or ischaemic burden was found between the control and active therapy groups.

The contribution of long term lipid lowering to vascular structure and function in patients with CAD and chronic kidney disease (CKD) is presented in Chapter 9. After 2 years of therapy with atorvastatin 80 mg/day patients with ischaemic heart disease (IHD) had decreased carotid IMT whereas no change was shown in patients with CKD. The change in carotid IMT was correlated with reduced myocardial ischaemia, suggesting the vascular milieu of patients with CKD is an independent contributor of their accelerated atherosclerosis.

Patients with CKD have multiple atherosclerotic risk factors and endothelial dysfunction. We proposed that these patients would be a good model for exploring the interaction between endothelial dysfunction and risk factors. The influence of endothelial function on subclinical LV dysfunction is portrayed in Chapter 10. Patients with CKD were investigated due to the common occurrence of both endothelial dysfunction and LV dysfunction in this group. Sixty-eight patients with no evidence for CAD were compared with age and risk matched controls. While increasing risk number was associated with subclinical LV dysfunction, this association did not exist for BAR, suggesting that endothelial dysfunction is not a significant contributor to subclinical renal cardiomyopathy.

Finally Chapter 11 investigates the prognostic value of baseline BAR in 444 patients at risk of cardiac events who were followed up for a median period of 24 months. Patients in the lowest fertile of FMD had significantly more cardiovascular events then the combined group of middle and highest levels of FMD. A strong relationship between tertiles of carotid IMT and survival was also demonstrated.

In summary a complex interplay exists between extent of myocardial ischaemia and vascular structure and function. Improvement in both vascular structure and function, which is intimately associated with the vascular milieu, may influence the presence and extent of ischaemia.
Keyword Coronary heart disease
Vascular endothelium -- Pathophysiology

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
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Created: Fri, 24 Aug 2007, 18:23:07 EST