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
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
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.
Pre-clinical Development Of A Novel Anti-fibrotic, Anti-inflammatory Compound To Treat Diabetic Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$488,391.00
Summary
Diabetic patients are prone to developing chronic heart failure. In the diabetic heart, scar tissue accumulates within the muscle (fibrosis), impairing function. We have developed a new drug to treat fibrosis in diabetic kidney disease (FT-11), and have approval for pre-clinical development of this drug. We now aim to test whether FT-11 is also effective in reducing fibrosis in the diabetic heart, and whether this can prevent heart failure in an animal model of diabetic heart disease.
Heart failure (HF) is the most common cause of hospital admission in those over 65y, and has significant morbidity and mortality. We need to develop new strategies to treat HF. Plasma vasopressin (AVP) levels are elevated in HF, and may contribute to adverse outcomes. This proposal will assess the utility of blocking the vasopressin V1 and V2 receptors in a rat model of HF. We shall also measure AVP in humans with HF. The results of this work may result in new approaches to treat HF patients.
Randomized Controlled Trial Of CPAP On Cardiac Function In Patients With Heart Failure And Obstructive Sleep Apnoea
Funder
National Health and Medical Research Council
Funding Amount
$140,906.00
Summary
Heart failure is a very common condition associated with disabling symptoms. The main symptoms are breathlessness, usually during sleep or upon exercise, and fatigue. Recent research has identified that sleep apnoea, a condition that occurs in about 50% of subjects with heart failure, is likely to be responsible for these symptoms. Moreover, treatment specifically aimed at sleep apnoea, namely continuous positive airway pressure (CPAP) delived via a small electric pump and nasal mask worn during ....Heart failure is a very common condition associated with disabling symptoms. The main symptoms are breathlessness, usually during sleep or upon exercise, and fatigue. Recent research has identified that sleep apnoea, a condition that occurs in about 50% of subjects with heart failure, is likely to be responsible for these symptoms. Moreover, treatment specifically aimed at sleep apnoea, namely continuous positive airway pressure (CPAP) delived via a small electric pump and nasal mask worn during sleep, may also improve the symptoms of heart failure. The study will involve subjects with stable heart failure on optimal drug treatment who have evidence of obstructive sleep apnea on an overnight sleep study. Obstructive sleep apnoea (OSA) is a condition in which the throat intermittently narrows or blocks during sleep (often associated with snoring) causing cessation of airflow or apnoeas. Associated with the apnoeas are vigorous efforts by the chest muscles to breathe (creating negative vacuum-like pressures within the chest - and around the heart) at a time of falling oxygen levels. Previous research has suggested that these obstructive apnoeas are detrimental to the heart. Volunteers will be randomized to either a control or a CPAP treated group for a three month period. The control and CPAP groups will receive intensive advice about good eating and sleeping habits as weight gain and sleep loss are factors known to aggravate heart failure and obstructive sleep apnoea. In addition to the lifestyle advice, the CPAP group will also be treated with nasal CPAP. The variables which we will measure include severity of sleep apnoea, exercise capacity, heart function at rest and symptoms. Symptoms will be measured using 4 very detailed and validated questionnaires.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
Catheter Based Renal Denervation To Improve Outcomes In Congestive Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$619,194.00
Summary
In heart failure there is a large increase in sympathetic nerve activity that is detrimental to patient outcome, but the factors causing this increased activity are not well defined. There is evidence that renal nerves play a significant role. A novel catheter based technique allows silencing of these nerves. We will test whether this novel technique has the potential to improve the outcomes for patients with heart failure.
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.