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
NOVEL CGMP-BASED THERAPIES PREVENT LEFT VENTRICULAR REMODELLING
Funder
National Health and Medical Research Council
Funding Amount
$533,433.00
Summary
Over 300,000 Australians are affected by heart failure. Current drugs for cardiac remodelling (the decline in heart pumping function and changed structure that precede heart failure) slow but not reverse disease progression. We have identified a new, nitrovasodilator-based therapy superior to those currently available. We propose it represents a more effective treatment for reversing abnormalities in both structure and function in the remodelled heart, preventing or delaying heart failure.
Does Maladaptive Remodelling Of The Heart And Vasculature In Response To Preterm Birth Lead To Long-term Cardiovascular Risk?
Funder
National Health and Medical Research Council
Funding Amount
$535,086.00
Summary
Being born prematurely is linked to the development of high blood pressure (a major risk factor for cardiovascular disease) later in life. In this project we will examine whether injury to the cells lining the cardiovascular system and/or structural changes in the wall of the arteries and the heart, as a result of being born early, lead to an elevation in blood pressure and heart dysfunction in adulthood.
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
TARGETING ROS-INDUCED DAMAGE RESCUES THE DIABETIC HEART
Funder
National Health and Medical Research Council
Funding Amount
$487,669.00
Summary
Over 1 million Australians have diabetes. Many of these patients die from cardiovascular disease. We have identified free radicals as a major cause of decreased pumping function and impaired recovery from each heartbeat in the diabetic heart. Stronger antioxidant approaches and-or activation of protective protein pathways is a more effective treatment for reversing impaired function in the diabetic heart, preventing or delaying heart failure in patients with diabetes.
The Role Of Na-Ca Exchange Current In Cardiac Pacemaker Cells
Funder
National Health and Medical Research Council
Funding Amount
$263,100.00
Summary
The heart rate is controlled by a small group of pacemaker cells within the heart. The pacemaker cells fire spontaneously and this intrinsic rate is modified by the sympathetic and parasympathetic nerves of the autonomic nervous system. We are studying a new current in the pacemaker cells which helps to control the firing rate. This new current is controlled by the intracellular calcium inside the cells so we are also studying the way in which intracellular calcium changes when the autonomic ner ....The heart rate is controlled by a small group of pacemaker cells within the heart. The pacemaker cells fire spontaneously and this intrinsic rate is modified by the sympathetic and parasympathetic nerves of the autonomic nervous system. We are studying a new current in the pacemaker cells which helps to control the firing rate. This new current is controlled by the intracellular calcium inside the cells so we are also studying the way in which intracellular calcium changes when the autonomic nervous system is active. This project will provide new insights into the function of this small group of critical cells and may allow treatment of some cardiac arrhythmias without the expense and surgery involved in the use of artificial pacemakers.Read moreRead less
Macrophage Migration Inhibitory Factor (MIF): Pathological And Therapeutic Significance In Post- Infarct Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$547,577.00
Summary
Ischemic heart injury mediated by the inflammatory response has a significant impact on the prognosis. MIF is a central factor mediating and amplifying the inflammatory response but its role in heart disease remains largely untested. This project will study, for the first time, the crucial role of MIF in ischemic heart disease and will establish important experimental evidence for developing new anti-inflammation therapeutic strategies against ischemic heart injury.
Exertional Dyspnoea With Increased Filling Pressure - Mechanisms And Treatment Strategies
Funder
National Health and Medical Research Council
Funding Amount
$387,793.00
Summary
Patients with early heart disease often present with shortness of breath with exercise, as myocardial reserve at that stage is usually sufficient to maintain normal function at rest . Indeed, much myocardial dysfunction may originate from the modern lifestyle, including inactivity, obesity, the metabolic syndrome and type II diabetes. The potential benefits of making a definitive early diagnosis are large, because it seems more likely that an impact can be made on the disease process (and theref ....Patients with early heart disease often present with shortness of breath with exercise, as myocardial reserve at that stage is usually sufficient to maintain normal function at rest . Indeed, much myocardial dysfunction may originate from the modern lifestyle, including inactivity, obesity, the metabolic syndrome and type II diabetes. The potential benefits of making a definitive early diagnosis are large, because it seems more likely that an impact can be made on the disease process (and therefore, outcome) than with late stage disease. Current treatment strategies are expensive and because they are directed at end-organ damage (heart failure, heart attacks etc), rather ineffective. This multispecialty, multidisciplinary group will undertake a series of unique studies aimed at identifying early cardiovascular disease. The strategy will involve detection of abnormal filling behaviour at stress echocardiography, with randomization into longterm and short-term trials to examine various therapeutic strategies. Sensitive new cardiovascular imaging techniques will be used to detect preclinical abnormalities in the structure and function of the heart and vasculature, facilitating a mechanistic understanding of the process of increasing filling pressure with exercise.Read moreRead less
Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which w ....Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which we have shown to operate in various smooth muscles. This mechanism, termed store-based pacemaking, is entirely different to the currently held cardiac model but could readily achieve the same outcome. We will investigate the hypotheses that this pacemaker mechanism is also fundamental to mammalian heart pacemaking and conduction. Positive support for our hypotheses, as indicated by our findings on amphibian hearts and from pilot findings, may severely challenge the present model for cardiac pacemaking. Such an outcome will have major ramifications on present interpretation of cardiac function in health and disease and will be particularly important to interpretation of disorders associated with cardiac arrhythmias and heart conduction.Read moreRead less
The Effect Of CPAP On Erectile And Endothelial Dysfunction In Impotent Men With Obstructive Sleep Apnea
Funder
National Health and Medical Research Council
Funding Amount
$609,559.00
Summary
Erectile dysfunction is common in men with obstructive sleep apnea, due to vascular damage, which leads to heart attack. CPAP is the preferred treatment for patients with OSA because of its well-proven ability to decrease sleepiness and improve blood pressure control. This study will establish if CPAP can also improve erectile and vascular endothelial dysfunction. These results will shed light on the mechanisms that underpin the relationship between OSA and Erectile Dysfunction.