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
The Role Of Mechanoelectric Feedback In Cardiac Arrhythmogenesis
Funder
National Health and Medical Research Council
Funding Amount
$307,550.00
Summary
Arrhythmias are disruptions of the normal electrical rhythm of the heart, and can vary from asymptomatic to fatal. It used to be thought that the electrical and mechanical functions of the heart muscle were essentially separate: the electrical activity triggered contraction something like pulling the trigger of a gun- once events were in motion, the electrical events played no further role. However, in recent years it has become apparent that this is an over-simplification of the real situation. ....Arrhythmias are disruptions of the normal electrical rhythm of the heart, and can vary from asymptomatic to fatal. It used to be thought that the electrical and mechanical functions of the heart muscle were essentially separate: the electrical activity triggered contraction something like pulling the trigger of a gun- once events were in motion, the electrical events played no further role. However, in recent years it has become apparent that this is an over-simplification of the real situation. In fact, the electrical activity of the heart is influenced strongly by the degree and timing of stretch to which the heart muscle is subjected, a process called Mechano-electric feedback. Since it can be demonstrated in isolated tissues, mechano-electric feedback must be an intrinsic property of the heart muscle. It has been shown in isolated heart preparations that passive stretch produces electrical disturbances in the normal action potential shape and propagation and that these electrical disturbances can be powerful enough to generate severe arrhythmias. There are paralells in human diseases. For example, atrial arrhythmias are common in older people, and it seems that these may be due to chronic stretch of the atria, as a consequence of high blood pressure. In addition, in those patients recovering from a heart attack, it seems likely that the damaged part of the heart muscle subjects the surrounding tissue to unusual mechanical stresses, and may trigger arrhythmias. This project aims to investigate the mechanisms underlying this mechano-electric feedback, in an attempt to understand some types of arrhythmias. Using molecular biology techniques, we will look at the gene expression of a novel type of stretch-activated potassium channel in both healthy and diseased animal hearts, with the aim of seeing if changes in the level of expression of these channels is correlated with changes in the response of the heart to stretch.Read moreRead less
Remodelling In Cardiac Hypertrophy: Implications For Arrhythmogenesis
Funder
National Health and Medical Research Council
Funding Amount
$48,361.00
Summary
High blood pressure (HBP) affects 1 in 3 adults. Cardiac hypertrophy (thickened heart muscles) is a common condition seen in HBP. This research seeks to study the underlying changes in electrical, structural and molecular properties of the heart that may contribute to the increased sudden death and atrial fibrillation (irregular heart rhythm) associated with both HBP and cardiac hypertrophy. The new understanding may identify new treatment targets to reduce these life-threatening conditions.
Roles Of Interleukins, Chemokines And Circulating Cells In Cardiac Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$434,134.00
Summary
Cardiac fibrosis is a disease of the heart in which large amounts of collagen are deposited within the heart tissue. This leads to poor heart function and may also lead to sudden death due to arrhythmias (abnormal electrical pulses). This study sets out to define the role of substances called interleukins and special circulating cells called lymphocytes, macrophages and progenitor cells in the development of cardiac fibrosis.
Molecular Mechanisms Of Cardiac Function And Disease
Funder
National Health and Medical Research Council
Funding Amount
$10,053,131.00
Summary
Adult-onset heart disease remains the leading cause of death and disability in our society, with almost 2 million Australians affected. Furthermore, structural heart malformations are the most common type of abnormality at birth and the leading cause of deaths in infants dying from non-infectious causes. Many of these problems are due to defects in the development, repair and-or function of heart muscle cells or cardiomyocytes. Thus, we propose to understand, in fine detail, cardiomyocyte as wel ....Adult-onset heart disease remains the leading cause of death and disability in our society, with almost 2 million Australians affected. Furthermore, structural heart malformations are the most common type of abnormality at birth and the leading cause of deaths in infants dying from non-infectious causes. Many of these problems are due to defects in the development, repair and-or function of heart muscle cells or cardiomyocytes. Thus, we propose to understand, in fine detail, cardiomyocyte as well as integrated heart development, biology, physiology and function as a prerequisite for the development of major advances in the prevention and treatment of these disorders.Read moreRead less
The Cellular Origin And Nuclear Signaling Mechanisms Of Cardiac Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$383,893.00
Summary
Stem cells have special characteristics; they are able to be grown quickly and they have the potential to turn into different types of cell. These two characteristics indicate the potential to use these cells to repair diseased organs. Heart disease is an ideal area to investigate the use of such cell-based therapy options. This is because a weakened heart muscle is very common (especially as we age) and because without assistance, the body is not able to repair a weakened heart.
This project studies the mechanisms involved in rejection of skin and heart grafts using a novel model to track the behaviour of individual graft-reactive white blood cells. We will test two promising new techniques to limit graft rejection: using drugs to inhibit the entry of graft-reactive cells into the graft, and administering cells with the ability to suppress the function of graft-reactive cells. This work will help us to design new therapies to prevent heart graft rejection.
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.
A Randomised Double Blinded Placebo Controlled Trial Of Adrenaline In Cardiac Arrest.
Funder
National Health and Medical Research Council
Funding Amount
$200,500.00
Summary
It is estimated that in excess of 30,000 Australians per year suffer a cardiac arrest, mostly occurring outside of hospital. This sudden and often unpredictable event commonly occurs as a result of acute heart disease, injury, drug overdose and many other illnesses which affect both males and females of all ages. Unfortunately, the survival of those suffering a cardiac arrest remains poor. Best evidence to date suggests overall survival from cardiac arrest to be in the order of about 5%. While t ....It is estimated that in excess of 30,000 Australians per year suffer a cardiac arrest, mostly occurring outside of hospital. This sudden and often unpredictable event commonly occurs as a result of acute heart disease, injury, drug overdose and many other illnesses which affect both males and females of all ages. Unfortunately, the survival of those suffering a cardiac arrest remains poor. Best evidence to date suggests overall survival from cardiac arrest to be in the order of about 5%. While the survival for those suffering cardiac arrest remains poor, the rapid initiation of cardiopulmonary resuscitation (CPR) and defibrillation has been clearly shown to improve outcome. While defibrillation and CPR have been shown to be beneficial, the use of vasoactive drugs such adrenaline has not been proven to improve survival in cardiac arrest. This is despite adrenaline being internationally recommended as first line drug therapy in the advanced life support (ALS) management of cardiac arrest. It is now well acknowledged that clinical trials need to be undertaken to determine the clinical effects of adrenaline when used for cardiac arrest. The purpose of this study is to randomise patients suffering a cardiac arrest to receive either adrenaline (according to standard ALS guidelines) or a placebo. All other care for both groups will be the same and in accordance with current ALS guidelines. In this way we will be able to determine the effects of adrenaline on outcome, particularly survival, following cardiac arrest. The study will run for three years and involve all cardiac arrests attended by the Ambulance Service in Perth.Read moreRead less
How Does Oxygen Regulate Ca2+ Channel Function In Cardiac Myocytes?
Funder
National Health and Medical Research Council
Funding Amount
$475,517.00
Summary
Oxygen occupies a key role in cellular metabolism and function. Oxygen delivery to cells is critical and lack of oxygen such as occurs during a heart attack can be lethal. Death occurs commonly by induction of arrhythmia or a disturbance in the heart beat. The abnormal heart beat cannot enable the heart to pump blood efficiently and vital organs are then deprived.Exactly how arrhythmia is induced is not understood. The normal heart beat occurs as a result of propogation of electrical signals thr ....Oxygen occupies a key role in cellular metabolism and function. Oxygen delivery to cells is critical and lack of oxygen such as occurs during a heart attack can be lethal. Death occurs commonly by induction of arrhythmia or a disturbance in the heart beat. The abnormal heart beat cannot enable the heart to pump blood efficiently and vital organs are then deprived.Exactly how arrhythmia is induced is not understood. The normal heart beat occurs as a result of propogation of electrical signals through heart muscle cells. The electrical activity is generated and sustained by movement of salts or ions through membrane proteins known as ion channels. One of these channels, the L-type calcium channel plays a vital role in cardiac excitation and contraction. A reduction in oxygen alters the function of the L-type calcium channel. However, the exact mechanism for this is uncertain. An oxygen sensing mechanism in the cell is responsible for the regulation of channel function during hypoxia. The exact identity of the oxygen sensor is currently the centre of debate. Four hypotheses have been proposed. This proposal aims to examine in detail the four hypotheses of oxygen sensing to definitively determine the identity of the oxygen sensor. This information should increase our understanding of how calcium channels function during stressful conditions such as during a heart attack.Read moreRead less