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
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
Atrial Electrical Remodeling Due To Chronic Stretch: Defining The Substrate For Atrial Fibrillation
Funder
National Health and Medical Research Council
Funding Amount
$428,250.00
Summary
Background: Cardiac failure is a common heart disorder in which the pumping function of the heart is significantly weakened. Mitral regurgitation is a common condition where there is a leakage of blood from the left ventricle (lower heart chamber) back into the left atrium (upper heart chamber) during normal cardiac contraction. This puts a strain on the heart and may cause heart failure. Atrial septal defect is a common form of congenital heart disease which may not be diagnosed until adulthood ....Background: Cardiac failure is a common heart disorder in which the pumping function of the heart is significantly weakened. Mitral regurgitation is a common condition where there is a leakage of blood from the left ventricle (lower heart chamber) back into the left atrium (upper heart chamber) during normal cardiac contraction. This puts a strain on the heart and may cause heart failure. Atrial septal defect is a common form of congenital heart disease which may not be diagnosed until adulthood. There are several forms but the basic problem is leakage of blood from the left atrium into the right atrium .This also puts a strain on the heart and can cause heart failure. All 3 conditions are associated with a significantly increased risk of atrial fibrillation (AF). This abnormal fast irregular cardiac rhythm makes the pumping of the heart inefficient. People with AF may feel short of breath, tired, or develop palpitations. AF is an important cause of stroke and premature death and is the most common heart rhythm disturbance occurring in upto 10% of the over 70 age group. Even after repair of the leaky valve or atrial septal defect there is still a high risk of developing this rhythm. Purpose of the study: This study will try to understand why patients with these conditions are at risk of developing atrial fibrillation, and why this risk might persist after surgical correction when this is possible (mitral regurgitation and atrial septal defect). The study will utilise sophisticated new mapping techniques to gain original insights into the mechanism of this very common and as yet poorly understood heart rhythm disturbance. The study has the potential to determine the cause of atrial fibrillation in these patient groups and as such represent a quantum advance in our understanding of he mechanism of atrial fibrillation. It would be expected to form a foundation on which development of curative and preventative approaches may be based.Read moreRead less
Detection Of Metastases In Sentinel Nodes From Patients With Breast Cancer Using Proton Magnetic Resonance Spectroscopy
Funder
National Health and Medical Research Council
Funding Amount
$186,372.00
Summary
The objective is to develop magnetic resonance spectroscopy (MRS) for the rapid and accurate intra-operative detection of cancer cells in sentinel lymph nodes from breast cancer patients. Accurate intra-operative diagnosis of cancer in lymph nodes will enable informed decisions to be made regarding surgery and therapy and reduce the morbidity associated with complete clearance of axillary nodes. Using current histopathological techniques (frozen section) this is not possible. Proton MRS can dete ....The objective is to develop magnetic resonance spectroscopy (MRS) for the rapid and accurate intra-operative detection of cancer cells in sentinel lymph nodes from breast cancer patients. Accurate intra-operative diagnosis of cancer in lymph nodes will enable informed decisions to be made regarding surgery and therapy and reduce the morbidity associated with complete clearance of axillary nodes. Using current histopathological techniques (frozen section) this is not possible. Proton MRS can detect chemicals in malignant cells in lymph nodes with a greater sensitivity than histology and can detect micrometastases in 20 minutes. The MR diagnostic information can be obtained from fine needle biopsies (FNB) making the technique eminently suitable for rapid intra-operative diagnosis. The FNB technique has been shown to be a rapid and accurate method for the assessment of breast lesions, distinguishing benign lesions and invasive cancer with a sensitiviy and specificity of 95% and 96%, respectively. Here we propose to evaluate the use of MRS for the rapid and accurate assessment of sentinel nodes from breast cancer patients. Two blinded studies will be conducted comparing the MRS chemical fingerprints with serial section histopathological data. To evaluate the clinical significance of the MRS diagnosis, all patients will be entered into a prospective study correlating the MRS data with recurrence of disease within 3 and 5 year periods.Read moreRead less
Stretch Induced Pulmonary Vein Remodelling: Implications For The Initiation And Maintenance Of Atrial Fibrillation
Funder
National Health and Medical Research Council
Funding Amount
$569,823.00
Summary
Atrial fibrillation (AF) is the most common heart rhythm disorder to affect humans, occurring in 2% of adults. It is a chaotic rhythm disorder of the top chambers of the heart that results in frequent hospitalization for falls, chest pain, palpitations, heart failure and stroke. In addition, it is associated with an increased mortality. Evidence suggests an important role of the pulmonary veins (PV; veins draining blood from the lungs back to the heart) in the initiation and maintenance of AF. H ....Atrial fibrillation (AF) is the most common heart rhythm disorder to affect humans, occurring in 2% of adults. It is a chaotic rhythm disorder of the top chambers of the heart that results in frequent hospitalization for falls, chest pain, palpitations, heart failure and stroke. In addition, it is associated with an increased mortality. Evidence suggests an important role of the pulmonary veins (PV; veins draining blood from the lungs back to the heart) in the initiation and maintenance of AF. However, why these structures promote AF remains unknown. Several conditions predisposing to the development of AF are associated with atrial stretch (such as heart failure). These conditions have documented abnormalities within the atria but the changes that occur within the PVs are unknown. It has even been suggested that pulsatile stretch, as caused by blood flow, in the appropriately predisposed patient, may be enough to trigger AF. As such there has been an intensive search to identify the abnormalities that occur within the PVs. In patients with AF, the PVs demonstrate distinctive electrophysiological properties compared to those without AF. However, the effect of stretch, a common predisposing factor, on the electrophysiological properties of the PV is not known. Preventing electrical activity from the PVs interacting with the heart by ablation has provided a glimpse at our ability to cure AF. However, further improvements in our procedural technique, the ability to prevent the occurrence of this rhythm disorder, and the development of noninvasive strategies to cure AF, hinges on the better understanding of the mechanisms initiating and maintaining this condition. In particular, the electrophysiological changes within the PVs that predispose patients to the development of AF need to be investigated. This series of studies will evaluate the effect of acute and chronic stretch on the PVs in humans to determine why these structures promote AF.Read moreRead less
Mechanism Of Breast Cancer Metastasis: Tumour Cell Remodelling Of The Extracellular Matrix
Funder
National Health and Medical Research Council
Funding Amount
$377,331.00
Summary
The main complication in breast cancers leading to death is metastatic relapse. This research aims to understand the role for a protease that promotes spread of breast cancer to the lymph nodes and lungs. The outcomes will identify a novel process that leads to lymph node metastasis and offer a new target for therapies that prevent relapse and tests to identify breast cancer patients at risk of relapse.
Effects Of N-3 Polyunsaturated Fatty Acids On Post Surgical Atrial Fibrillation: A Prospective Randomised Study
Funder
National Health and Medical Research Council
Funding Amount
$536,529.00
Summary
Consumption of fish and fish oil has been associated with protective effects for deaths from heart disease in many studies. The effects are consistent and quite strong and appear to be unrelated to blood cholesterol levels. The effects are more likely due to the possibility that fish oil, which contains n-3 fats, can suppress abnormal heart rhythms which can cause 'sudden cardiac death'. This has been shown in animal studies, and recently we have shown that they can also suppress abnormal heart ....Consumption of fish and fish oil has been associated with protective effects for deaths from heart disease in many studies. The effects are consistent and quite strong and appear to be unrelated to blood cholesterol levels. The effects are more likely due to the possibility that fish oil, which contains n-3 fats, can suppress abnormal heart rhythms which can cause 'sudden cardiac death'. This has been shown in animal studies, and recently we have shown that they can also suppress abnormal heart rhythms in humans. Patients undergoing coronary bypass surgery are particularly susceptible to abnormal heart rhythms in the upper chambers of the heart in the days immediately following surgery. While these abnormal rhythms are rarely life threatening, they can result in increased post-surgical complications and a longer hospital stay with associated increased costs to the health system. In this study we will determine whether providing high dose fish oil for 3 weeks immediately preceding coronary bypass surgery, will result in a reduction in the proportion of patients experiencing post-surgical abnormal heart rhythms. We will also examine the effects of n-3 fats on the incidence of other complications following bypass surgery and also the length of hospital stay. In addition, we will gather data which will provide insight into the mechanisms by which n-3 fatty acids produce their well documented benefits to patients with cardiovascular disease. The significance of this study is its ability to provide a protective strategy in heart disease in which the mechanism is understood, which is effective, and importantly, which will have the potential to provide savings to the health care system through a reduction in hospital stay.Read moreRead less
The Role Of Subcapsular Sinus Macrophages In Lymph Node Metastases
Funder
National Health and Medical Research Council
Funding Amount
$451,010.00
Summary
This project tackles the problem of lymph node metastases using complementary studies in mouse models and human patients with melanoma. It takes the novel approach of examining the local geographical factors in the lymph node and focusses on a rare cell called the subcapsular sinus macrophage that may be a critical determinant of the clinical outcome. This will result in innovative strategies for primary prevention of not only melanoma but other cancer cell metastases.