Effects Of Risk Factor Control On Atherosclerosis, Vasoreactivity And Cardiac Ischemia In Patients On Dialysis
Funder
National Health and Medical Research Council
Funding Amount
$212,126.00
Summary
End-stage renal failure is one of the commonest serious chronic diseases; in Australia, over 10,000 patients are in dialysis programs or have functioning transplants. The commonest cause of death in this patient group is coronary artery disease, and attempts are routinely made to identify patients with this problem, with the intent of controlling this risk by angioplasty or bypass surgery. Unfortunately, these procedures may be less effective than usual, because the process of artery narrowing i ....End-stage renal failure is one of the commonest serious chronic diseases; in Australia, over 10,000 patients are in dialysis programs or have functioning transplants. The commonest cause of death in this patient group is coronary artery disease, and attempts are routinely made to identify patients with this problem, with the intent of controlling this risk by angioplasty or bypass surgery. Unfortunately, these procedures may be less effective than usual, because the process of artery narrowing is more aggressive in patients with renal disease. Moreover, this process may cause patients with negative testing for coronary disease at one point in time to develop coronary problems over follow-up. In this study, we propose to use a standard stress testing protocol to stratify the risk of coronary events in a group of at risk patients on dialysis. Those at highest risk will undergo bypass surgery, while those at intermediate and low risk will be randomized to usual care, or an aggressive treatment of atheroma with cholesterol reduction, folic acid supplementation (aiming to normalize homocysteine), blood pressure and blood sugar control. The effects of this approach will be followed by examination of biochemical markers of atherosclerosis, and imaging of arterial thickness and reactivity (reflecting tests of structure and function of the vasculature). We will also assess of the progression or reduction of abnormal cardiac stress responses, and the occurence of events at follow-up. Finally, follow-up data will be used to compare the predictive value of the 2 stress testing protocols. The results of this study will enhance our understanding of the importance of the atherosclerotic process in renal patients, and move the management approach for coronary disease in renal failure toward active risk factor control and away from revascularization.Read moreRead less
Examining GWAS-identified Loci Of Interest In Predicting Coronary Events In Subjects With Known Coronary Heart Disease: The LIPID Genetic Study
Funder
National Health and Medical Research Council
Funding Amount
$649,940.00
Summary
Can modern genetic analysis identify the genes which predict future heart attacks? We will follow up 4337 patients who have already suffered a heart attack and use the findings from the exciting new technique of GWAS (Gene wide association studies) to study their whole genetic map, select gene markers from thousands of possibilities to identify those at highest risk. This will develop a genetic markers of risk and shed light on previously unsuspected mechanisms of heart disease.
Depression And Risk Of Coronary Heart Disease: A Prospective Study Of Mediating Haemostatic Risk Factors
Funder
National Health and Medical Research Council
Funding Amount
$327,625.00
Summary
Growing evidence suggests that depression, anger and anxiety play a role in causing coronary heart disease (CHD) and complicating the outcome in existing CHD. This may occur by effects of these emotions on promoting blood clotting and the stickiness of platelets - the blood cells responsible for blood clotting. This pilot study will follow a group of people with depression but without CHD and a control group over 8 months to compare how the blood clotting profile changes as depression resolves. ....Growing evidence suggests that depression, anger and anxiety play a role in causing coronary heart disease (CHD) and complicating the outcome in existing CHD. This may occur by effects of these emotions on promoting blood clotting and the stickiness of platelets - the blood cells responsible for blood clotting. This pilot study will follow a group of people with depression but without CHD and a control group over 8 months to compare how the blood clotting profile changes as depression resolves. The potential benefits of this research are a better understanding of the links between the common illnesses of depression and CHD that might improve the prevention and treatment of heart disease.Read moreRead less
Statistical Methods For The Analysis Of Trends In Coronary Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$112,747.00
Summary
Coronary heart disease is a leading cause of mortality, morbidity and medical costs in Australia. During the 1950's and 1960's, rates of coronary disease increased rapidly, then in the late 1960's they started to decline. This decrease has continued steadily for 30 years. While some other westernised countries have had this same experience, in Eastern Europe and in many developing countries coronary disease is increasing. There is a huge amount of evidence from experimental studies in animal and ....Coronary heart disease is a leading cause of mortality, morbidity and medical costs in Australia. During the 1950's and 1960's, rates of coronary disease increased rapidly, then in the late 1960's they started to decline. This decrease has continued steadily for 30 years. While some other westernised countries have had this same experience, in Eastern Europe and in many developing countries coronary disease is increasing. There is a huge amount of evidence from experimental studies in animal and human subjects and population studies in many countries that the major determinants of coronary disease are high blood pressure, cigarette smoking and high cholesterol (and other lipids) as well as dietary factors, obesity and physical inactivity. Recently several large multicentre studies have found unexpectedly weaker associations between heart risk factors and disease rates. It is hypothesised that this is due to inappropriate analyses in which data from populations at different stages of the coronary epidemic have been combined. The aim of this study is to develop improved statistical methodology to help understand recent findings from large scale studies, such as the World Health Organization's MONICA Project, the US ARIC study and the Seven Countries study. It will provide new theoretical results and statistical software for their implementation. From a public health perspective the most important outcome will be clarification of recent apparently anomalous findings about the importance of established risk factors and effective treatments in reducing coronary disease at the population level.Read moreRead less
Intracellular Cholesteryl Ester Hydroperoxides And Hydroxides- Their Metabolism And Their Modulation Of Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$182,029.00
Summary
Atherosclerosis is the disease which causes narrowings in arteries underlying such serious medical conditions as heart attack and stroke. A key component in the formation of atherosclerotic narrowings is the accumulation of fat-filled cells called foam cell macrophages in artery walls. Our study investigates the nature of the fats that macrophages accumulate, and how mild modification of these fats changes the metabolism of the macrophage. Cholesterol circulates in the blood stream as specialise ....Atherosclerosis is the disease which causes narrowings in arteries underlying such serious medical conditions as heart attack and stroke. A key component in the formation of atherosclerotic narrowings is the accumulation of fat-filled cells called foam cell macrophages in artery walls. Our study investigates the nature of the fats that macrophages accumulate, and how mild modification of these fats changes the metabolism of the macrophage. Cholesterol circulates in the blood stream as specialised particles called lipoproteins. The lipoprotein containing most of the cholesterol is low density lipoprotein (LDL), so-called bad cholesterol. LDL is the main source of fat that accumulates in the artery wall in atherosclerosis. When in the artery wall, it is taken up by macrophages which develop a foamy appearance. The accumulation of LDL fats within macrophages is greatly enhanced by the prior modification of LDL. The most well known of these modifications is oxidation- a chemical process of fat spoilage as occurs with rancid butter. Mild oxidation of LDL is well known to occur in human atherosclerosis. However, the ability of macrophages to accumulate the products of mild oxidation has never been established. We have recently discovered that the lipid products of mild oxidation of LDL can build up in macrophages. We achieved this by developing a new system of feeding oxidised LDL to macrophages. Surprisingly, not only could these lipid oxidation products be internalised by the cells, but they progressively accumulated over time, and caused major disturbances in the ability of macrophages to clear ordinary fats inside the cell. This means that mild oxidation of LDL can cause secondary damage inside the macrophage, which is far greater than had previously been realised. This project investigates precisely how the oxidised LDL is metabolised by macrophages and how it disturbs other cell functions.Read moreRead less
Formation, Structure And Metabolism Of High Density Lipoproteins Containing Both ApoAI And ApoAII On The Same Particle
Funder
National Health and Medical Research Council
Funding Amount
$296,884.00
Summary
It is well known that high levels of cholesterol in blood cause coronary heart disease. It is also known that not all of the cholesterol in blood is bad. Whereas the cholesterol carried in particles called low density lipoproteins (LDLs) causes heart disease, other cholesterol carriers in blood known as high density lipoproteins (HDLs) actually protect against the development of heart disease. However, HDLs include several different populations of particles, only some of which are protective. On ....It is well known that high levels of cholesterol in blood cause coronary heart disease. It is also known that not all of the cholesterol in blood is bad. Whereas the cholesterol carried in particles called low density lipoproteins (LDLs) causes heart disease, other cholesterol carriers in blood known as high density lipoproteins (HDLs) actually protect against the development of heart disease. However, HDLs include several different populations of particles, only some of which are protective. One determinant of the ability of HDLs to protect against coronary heart disease is their protein composition. This project investigates how the protein composition of HDL populations influences their structure, function and metabolism. It is also concerned with understanding what regulates the relative concentrations of the different HDL populations. The studies of HDL structure, function and metabolism will allow us to understand why the different HDL populations differ in their abilities to protect against heart disease. The regulation studies will tell us how to go about designing therapies to increase the levels of those HDL populations that do protect.Read moreRead less
The Coronary Vascular Bed, Shear Stress, Endothelial Signalling And Myocyte Electrophysiology
Funder
National Health and Medical Research Council
Funding Amount
$133,774.00
Summary
Physiologic control muscle performance includes a little understood signal from the walls of blood vessels stimulated by pressure and flow which effect muscle function. How this signal operates is controversial. We have developed a model which enables the evaluation of such signalling where changes in flow in the circumflex coronary artery induce easily measured local changes in electrophysiology which are confined to the territory of the circumflex coronary artery and which can be compared with ....Physiologic control muscle performance includes a little understood signal from the walls of blood vessels stimulated by pressure and flow which effect muscle function. How this signal operates is controversial. We have developed a model which enables the evaluation of such signalling where changes in flow in the circumflex coronary artery induce easily measured local changes in electrophysiology which are confined to the territory of the circumflex coronary artery and which can be compared with control values from the left anterior descending coronary artery territory. We propose to use this stable model to evaluate the origin, the transmission agent and the mechanism by which it alters the action potential duration.Read moreRead less
Increasing Cardiovascular Risk Assessment In First Degree Relatives Of Patients With Premature Heart Disease: An RCT
Funder
National Health and Medical Research Council
Funding Amount
$113,972.00
Summary
Family history is a risk factor for ischaemic heart disease (IHD), especially if the history includes early onset disease. Families share both genetic and environmental risk factors, many of which can be modified to reduce the risk of heart disease. The aim of this project is to trial an intervention to promote heart disese risk assessment among the relatives of patients with premature heart disease. This is a first step toward prevention of heart disease in these families.
Does Oxidation Of Lipoproteins By Thiocyanate-derived Oxidants Produced By Myeloperoxidase Contribute To Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$357,930.00
Summary
Considerable evidence links the heme enzyme myeloperoxidase with atherosclerosis (hardening of the arteries), a disease that kills approximately 40% of Australians, and particularly people who smoke. The reasons for the elevated risk in smokers is not fully understood, though it is known that they have elevated thiocyanate levels - a major substrate for myeloperoxidase. The role of myeloperoxidase and thiocyanate in lipoprotein damage in atherosclerosis will be addressed in this project.
Targetting The NADPHoxidase Source Of Reactive Oxygen Species In Vascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$552,250.00
Summary
In Australia, coronary heart disease (CHD) leading to heart attacks or strokes is the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, appears to be an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the cells that make up the artery wall. Using novel DNA-type molecules we have recently discovered that a protein called Nox4 is ....In Australia, coronary heart disease (CHD) leading to heart attacks or strokes is the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, appears to be an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the cells that make up the artery wall. Using novel DNA-type molecules we have recently discovered that a protein called Nox4 is crucial for the production of oxygen free radicals by blood vessels. Furthermore, we have identified a class of drugs that selectively block the activity of Nox4 in blood vessels. We now wish to directly test whether inhibiting Nox4, either with DNA-type molecules, various drugs known to block Nox4, or by complete elimination of the Nox4 gene in mice, prevents the development of CHD in animal models. This work will not only advance our understanding of the origin of vascular oxidative damage but will also allow us to identify novel therapeutic targets in the treatment of cardiovascular diseases that are associated with increased oxidative stress. The same drugs and molecules might also prove useful for improving recovery from heart attacks and strokes, for Nox4 may be turned on in the heart and brain in these conditions. Information obtained in our study will be useful in directing future prescription practices in clinical management of CHD and stroke, and for designing new therapeutic compounds for CHD.Read moreRead less