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
Electrophysiologic Properties Of The Ventricular Myocardium Promoting Reentry
Funder
National Health and Medical Research Council
Funding Amount
$272,871.00
Summary
Ventricular tachycardia is a dangerous heart rhythm that usually occurs in people with prior heart attacks. These people often have scarring on their heart and the tachycardia occurs due to electrical activity forming a circuit around the scar. This study will examine the factors that cause ventricular tachycardia to begin by looking at the characteristics of the scarring.
The Effect Of Smoking On The Exacerbation Of Stroke: Oxidative Stress Involvement And Cerebrovascular Response.
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
This grant addresses whether smoking contributes to the severity of stroke outcome. The studies outlined in this proposal will contribute significantly in our understanding of how smoking contributes to the progression of stroke. The understanding of the involvement of smoking in the progression of stroke will be of great benefit in the development of improved stroke patient management.
Platelet And Endothelial Function In Atrial Fibrillation
Funder
National Health and Medical Research Council
Funding Amount
$105,825.00
Summary
Atrial fibrillation is the most common heart rhythm disturbance in the adult population and leads to substantial increased death and disability from stroke. In this research scheme, we will study the contribution of platelet (clot forming cells) and endothelial (lining of blood vessels) dysfunction in atrial fibrillation. The successful outcome of this project will lead to a better understanding of the underlying mechanisms of clot formation and may lead to a better target for future drugs.
Prevention Of Stroke Caused By Carotid Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$200,062.00
Summary
Stroke is a leading cause of death and disability and a huge drain on health resources in Australia and worldwide. Carotid artery atherosclerosis (vascular disease) is an important cause of stroke. Currently surgery (with a significant risk of stroke-death) is commonly performed to prevent carotid stroke. My aim is to show that current best practice medical intervention is superior to surgery and to identify high risk patients for whom additional stroke prevention strategies may be justified.
Efficacy Of Coronary Sinus Ablation For The Treatment Of Atrial Fibrillation: A Randomised Controlled Study.
Funder
National Health and Medical Research Council
Funding Amount
$377,917.00
Summary
Atrial fibrillation is the most common sustained cardiac arrhythmia in the population. Left atrial catheter ablation is rapidly becoming a drug free alternative treatment for drug-resistant atrial fibrillation. The proposed study will examine whether ablation at a unique anatomical site adjacent to the left atrium (the coronary sinus) will increase procedural success compared to the conventional approach.
The Importance Of P38 MAPK Signalling In Aging-Related Ischaemic Intolerance And Failed Cardioprotection
Funder
National Health and Medical Research Council
Funding Amount
$496,302.00
Summary
Ischaemic heart disease is the leading cause of death in Australia, and will rise in coming years with the aging of our population. Our research shows aged hearts become less resistant to damage during ischaemia-heart attack, and insensitive to normally beneficial therapies. This project will identify molecular changes responsible for these changes. By understanding how age impairs the hearts defences, it may be possible to improve therapy of ischaemic heart disease in older patients.
Single-Beat Preload Recruitable Stroke Work Measurement Of Cardiac Contractility In Three Mammalian Models.
Funder
National Health and Medical Research Council
Funding Amount
$241,980.00
Summary
The accurate measurement of the inherent pumping capacity of the heart muscle is difficult because (i) most measurements currently in use cannot accurately discriminate between the contribution of the heart muscle and that of the vascular system to the results obtained, and (ii) the measurements which can discriminate currently require invasive measurements and procedures that frequently restrict their use. The overall purpose of this proposal is to more rigorously validate a promising method we ....The accurate measurement of the inherent pumping capacity of the heart muscle is difficult because (i) most measurements currently in use cannot accurately discriminate between the contribution of the heart muscle and that of the vascular system to the results obtained, and (ii) the measurements which can discriminate currently require invasive measurements and procedures that frequently restrict their use. The overall purpose of this proposal is to more rigorously validate a promising method we have developed that will (i) make accurate assessment possible from a single cardiac beat in both experimental animals and human subjects; (ii) reduce the number of experimental animals required for such measurements by permitting sequential measurements in the same animals; (iii) make it possible to perform such measurements non-invasively in human subjects.Read moreRead less
Coronary artery disease usually presents with chest pain resulting from cardiac muscle being starved of blood and oxygen due to narrowings in the coronary arteries supplying the heart muscle (myocardial ischaemia). The common test to detect this state is the electrocardiogram or ECG which often shows changes known as ST segment shifts. This project follows earlier work and will explain why the ST changes occur and also will determine how to maximize the information from the ECG so that clinician ....Coronary artery disease usually presents with chest pain resulting from cardiac muscle being starved of blood and oxygen due to narrowings in the coronary arteries supplying the heart muscle (myocardial ischaemia). The common test to detect this state is the electrocardiogram or ECG which often shows changes known as ST segment shifts. This project follows earlier work and will explain why the ST changes occur and also will determine how to maximize the information from the ECG so that clinicians are better able to predict the site, size and timing of the ischaemia from the ECG. The proposal will use detailed measurement of the electric field around the ischaemic region to build up the three dimensional electric field from which the explanation as to why the body surface patterns occur will be gleaned by computer modelling. This project will extend the field measurement back into the myocardium using intramyocardial electrodes with a spacing of 2 mm. This project will result in better analysis of the ECG in patients with chest pain, better practice in selecting patients for admission or early treatment and could result in substantial savings to the health system from reduced admissions, more appropriate investigation and treatment. A better diagnosis on one patient daily in Austarlia alone would be expected to save one million dollars in the year.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