Effects And Mechanisms Of Direct Cardiac Compression In Interruption Of Myocardial Remodelling In Chronic Heart Failure.
Funder
National Health and Medical Research Council
Funding Amount
$392,250.00
Summary
Heart failure (HF) is a disease where the heart pumping function is insufficient to provide adequate blood supply to the rest of the body. It is a highly debilitating disease affecting nearly 10 million people worldwide and has a <50% one-year survival in severe cases. Despite significant advances in pharmacotherapy, heart transplant is the only alternative for severe HF but is restricted by lack of donor organs to only ~ 5% of those requiring it. Research has shown that progression of HF is ....Heart failure (HF) is a disease where the heart pumping function is insufficient to provide adequate blood supply to the rest of the body. It is a highly debilitating disease affecting nearly 10 million people worldwide and has a <50% one-year survival in severe cases. Despite significant advances in pharmacotherapy, heart transplant is the only alternative for severe HF but is restricted by lack of donor organs to only ~ 5% of those requiring it. Research has shown that progression of HF is related to many subsequent changes after an initial insult. In addition to pumping failure, HF is associated with deranged compensatory responses such as neurohumoral over-activation, heart chamber enlargement, loss of functional cells, increase of inflammatory mediators and changes in cardiac skeleton (extracellular matrix). The changes in the heart are collectively known as remodelling. Mechanical heart assist is now considered a potential destination therapy for severe HF, superior to pharmacotherapy alone. Improvement of cardiac pumping function and even successful weaning from devices has been reported, along with observations of reverse remodelling. The success of this approach has been limited however, particularly with HF due to coronary disease, the most prevalent form. We developed a novel HeartPatch mechanical assist device to compress the heart from its outer surface. It gives support to both main chambers and avoids blood contact, a feature of currently available devices associated with complications such as blood clotting and infection. Our device has proved effective in animals with acute HF and even with cardiac arrest. We propose to study the effects of our device on the process of remodelling in HF with coronary disease in a controlled manner. The project will enhance understanding of the mechanisms involved in reverse remodelling and further the development of a device which may potentially benefit many severe HF patients.Read moreRead less
Function Of The S100A1 Ca2+-binding Protein Under Physiological And Pathological Conditions
Funder
National Health and Medical Research Council
Funding Amount
$452,545.00
Summary
The S100A1 protein is one of the most abundant proteins in human heart muscle cells. It binds calcium ions and may play a role in the regulation of heart function. S100A1 levels are reduced in human heart failure, but it is unclear whether this reduction contributes to worsening of the disease. To study this, we have generated a genetically modified mouse strain that cannot make the S100A1 protein. We will use these mice to study how important the protein is for heart function under normal condi ....The S100A1 protein is one of the most abundant proteins in human heart muscle cells. It binds calcium ions and may play a role in the regulation of heart function. S100A1 levels are reduced in human heart failure, but it is unclear whether this reduction contributes to worsening of the disease. To study this, we have generated a genetically modified mouse strain that cannot make the S100A1 protein. We will use these mice to study how important the protein is for heart function under normal conditions, and how it contributes to the development of heart failure. Preliminary data indicate that adult mice with reduced S100A1 protein levels develop a form of heart disease that significantly reduces the efficiency of the pump function of the heart.Read moreRead less
Differences Between Physiological And Pathological Cardiac Hypertrophy Offer New Strategies For Treating Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$335,473.00
Summary
The heart becomes large both in athletes as well as in patients with heart disease and failure. In the first instance, the large (hypertrophied) heart has normal or even increased pumping ability (function) whereas in the patient with heart disease the function is depressed and the heart may fail. My studies are directed towards finding out what is the difference in these 2 situations and what mechanisms are responsible for making one big heart pump well and the other big heart pump poorly. Spec ....The heart becomes large both in athletes as well as in patients with heart disease and failure. In the first instance, the large (hypertrophied) heart has normal or even increased pumping ability (function) whereas in the patient with heart disease the function is depressed and the heart may fail. My studies are directed towards finding out what is the difference in these 2 situations and what mechanisms are responsible for making one big heart pump well and the other big heart pump poorly. Specifically my project hopes to identify the genes and proteins responsible for the differences. I have already identified one such gene and I now plan to manipulate this gene by overexpressing it in animals (transgenic mice) with heart failure. I predict that overexpression of this gene will improve heart function in models of heart failure. If the hypothesis is correct, activating genes that are activated in the athlete's heart maybe a potential tool for improving heart function, quality of life and life span in patients with heart failure.Read moreRead less
Cardiac-specific Therapy Targeting Hypertrophy And Apoptotis
Funder
National Health and Medical Research Council
Funding Amount
$542,683.00
Summary
We have discovered that certain pathological responses in the heart are mediated by an unusual type of signalling protein. The aim of the proposed studies is to determine whether this unusual signalling mechanism can provide a good target for development of new therapeutic approaches to prevent or treat heart failure.
Sympathetic Nervous System Activation In Renal Failure. Its Contribution To Pathogenesis And Progression.
Funder
National Health and Medical Research Council
Funding Amount
$490,796.00
Summary
Cardiovascular morbidity and mortality is exceedingly high in patients with chronic renal failure and particularly end stage renal disease. Recent studies suggest that sympathetic activation contributes substantially to the development of hypertension, progression of renal disease and cardiovascular prognosis in these patients. Increased sympathetic nerve firing has been demonstrated in end stage renal disease by the use of clinical microneurography, which has been attributed to uremia-related t ....Cardiovascular morbidity and mortality is exceedingly high in patients with chronic renal failure and particularly end stage renal disease. Recent studies suggest that sympathetic activation contributes substantially to the development of hypertension, progression of renal disease and cardiovascular prognosis in these patients. Increased sympathetic nerve firing has been demonstrated in end stage renal disease by the use of clinical microneurography, which has been attributed to uremia-related toxins. However, renal transplant recipients with excellent graft function and no signs of uremia still exhibit increased sympathetic nerve firing. Most interestingly, bilateral nephrectomized patients have nerve firing rates comparable to that of normal control subjects without renal disease. These data suggest that the diseased kidneys exert excitatory effects on the sympathetic nervous system independent of correction of uremia. The proposed study aims to comprehensively investigate the pattern of sympathetic activation both centrally (microneurography) and regionally (radiotracer dilution methodology) in patients with chronic renal failure and end stage renal disease . The effect of the centrally acting sympatholytic drug rilmenidine on sympathetic activity in the setting of renal disease will be assessed. Patients with ESRD waitlisted for kidney transplantation will be studied before and after transplantation. Some of the transplant recipients will also have undergone uni- or bilateral nephrectomy before transplantation which will enable us to further explore the role of the diseased kidneys in sympathetic activation. The results of this study may prove to have significant implications for treatment and prevention of cardiovascular morbid events frequently associated with renal disease.Read moreRead less
Coronary artery disease is the largest single cause of death in Australia, and commonly manifests as heart attack and angina. Congenital heart disease is the most common birth defect. We have identified a gene, Crim1, that is important for heart and coronary artery development. Investigating how this gene functions will lead to a greater understanding of congenital heart disease and may lay the foundation for therapeutics to regenerate damaged hear tissue.
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.
Targeting PI3K-regulated MicroRNAs To Treat Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$532,593.00
Summary
Current therapeutics largely delay heart failure progression rather than regressing it. New therapeutic strategies with the capability of improving function of the failing heart are thus greatly needed. The primary goal of this study is to determine whether novel regulatory genes can enhance cardiac function in a setting of heart failure. Ultimately, technologies that target these genes may lead to innovative pharmacotherapies in the clinical management of heart failure.
How Does The Mitochondria Regulate Cardiac L-type Ca2+ Channel Function?
Funder
National Health and Medical Research Council
Funding Amount
$328,267.00
Summary
Oxygen is vital to cellular metabolism and function. Oxygen delivery to cells is critical and a lack of oxygen such as occurs during a heart attack can be lethal. The L-type Ca2+ channel is a protein in the membrane of heart muscle cells responsible for regulating the entry of calcium into heart muscle cells. It plays a role in maintaining the heart beat and contraction. We have found that a lack of oxygen (hypoxia) alters the function of the L-type Ca2+ channel and its response to adrenergic st ....Oxygen is vital to cellular metabolism and function. Oxygen delivery to cells is critical and a lack of oxygen such as occurs during a heart attack can be lethal. The L-type Ca2+ channel is a protein in the membrane of heart muscle cells responsible for regulating the entry of calcium into heart muscle cells. It plays a role in maintaining the heart beat and contraction. We have found that a lack of oxygen (hypoxia) alters the function of the L-type Ca2+ channel and its response to adrenergic stimulation (adrenaline).This may be one of the ways that rhythm disturbances or sudden cardiac death occurs with a heart attack. The activity of the L-type Ca2+ channel is sensitive to changes in reactive oxygen species caused by changes in oxygen concentration. The reactive oxygen species are generated from a part of the cell responsible for maintaining the cell's energy requirements (the mitochondria). Oxidative stress is a feature of various cardiovascular pathologies and we are now interested in determining the effect of oxidative stress on function of the L-type Ca2+ channel and the role of the mitochondria in generating reactive oxygen species. Oxidative stress can damage mitochondria leading to an increase in production of reactive oxygen species. We will determine how oxidative stress damages the mitochondria and how this then alters the channel function, directly or indirectly. The information gained will provide insight into how reactive oxygen species influence L-type Ca2+ channel function and the mechanisms that contribute to pathology involving reactive oxygen species such as heart failure and arrhythmia.Read moreRead less