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
Role Of Homeobox Gene Nkx2-5 In Heart Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$227,340.00
Summary
This project seeks to define the developmental principles underlying chamber formation in the developing heart and how this becomes abnormal in inherited heart defects. The gene we study, Nkx2-5, encodes a protein which binds to DNA and regulates the expression of the genetic program for formation of the ventricles, the pumping chambers of the heart. We believe that Nkx2-5 is an Oexecutive regulator? of this program, controlling the timing and spatial expression of other regulators that then con ....This project seeks to define the developmental principles underlying chamber formation in the developing heart and how this becomes abnormal in inherited heart defects. The gene we study, Nkx2-5, encodes a protein which binds to DNA and regulates the expression of the genetic program for formation of the ventricles, the pumping chambers of the heart. We believe that Nkx2-5 is an Oexecutive regulator? of this program, controlling the timing and spatial expression of other regulators that then control expression of a host of genes required for muscle differentiation and the development of form (morphogenesis). Mutations in one copy of the human Nkx2-5 gene have recently been discovered to be associated with atrial septal defect, or Ohole in the heartO, a sometimes serious inherited defect in heart structure. Mouse embryos with a mutation in both copies of the gene have a much more serious defect in ventricle formation that is incompatible with life. The studies are designed to extend our understanding of the genetic regulation of chamber formation in the heart. We will firstly make a mouse model of the human disease using gene targeting technology, which allows us to make precise alteration in single genes in this animal. Secondly, we will apply new technology to the heart that will let us visualise molecular and cellular events at higher resolution. This technology, which uses fluorescent tags on cells and a laser to measure cell identity, has been used to great affect in the field of immunology, but can be adapted to the heart. We will use it to isolate and characterise the precious early cells that give rise to the heart in the embryo. It is in these cells that the human and mouse mutations have their first effects. Our studies have relevance to understanding and screening for human inherited heart abnormalities, and for understanding the general principles of heart formation that may reveal valuable ways to intervene in heart disease.Read moreRead less
Role Of Homeobox Gene Nkx2-5 In Heart Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$143,250.00
Summary
Congenital abnormalities of the heart occur in ~1 in 100 live births and 1 in 10 still births in Western populations. The genetic pathways underlying cardiac development are now being dissected with increasing vigour in an effort to understand both the morphological progressions and genetic basis of heart defects. Mutations in a cardiac gene called Nkx2-5, which encodes a transcriptional regulatory protein, can cause heart defects in human families and isolated individuals, most predominantly at ....Congenital abnormalities of the heart occur in ~1 in 100 live births and 1 in 10 still births in Western populations. The genetic pathways underlying cardiac development are now being dissected with increasing vigour in an effort to understand both the morphological progressions and genetic basis of heart defects. Mutations in a cardiac gene called Nkx2-5, which encodes a transcriptional regulatory protein, can cause heart defects in human families and isolated individuals, most predominantly atrial septal defect (hole in the heart) associated with an abnormality in electrical activity of the heart. Nkx2-5 is expressed in the precursor cells of the muscle and other lineages that make up the heart in the embryo, then in the muscle layer of the heart throughout foetal and adult life. Mouse hearts that lack the Nkx2-5 gene altogether arrest at an early stage of heart development showing a complete block to ventricular chamber formation. Mice lacking only one copy of the Nkx2-5 gene have ASD and electrical defects, similar to the human disease. Building on these findings we have developed a suite of new genetic reagents with which to gain a deeper understanding of the role of Nkx-5 in development and disease. These include a mouse strain from which Nkx2-5-positive muscle cells can be purified away from other cell types in the heart, and another mouse strain that represents a good model for common congenital heart defects. We will further investigate the role of Nkx2-5 in allocation of cell types in the heart, chamber formation and birth defects using these reagents.Read moreRead less
Homeodomain Nkx2-5-dependent Negative Feedback Loop Important In Heart Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,330,245.00
Summary
Congenital heart disease (CHD) is the cause of most deaths in children in the first year of life. We have identified a genetic pathway important for both normal cardiac development and CHD that involves the cardiac transcription factor Nkx2-5. This pathway controls a transition in embryos between cardiac cell specification and expansion. We will now explore the biochemical and genetic mechanisms underlying this pathway to help us understand CHD and identify its causative genes.
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
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 The Mammalian Grainyhead-like Gene Family In Neural Tube Closure
Funder
National Health and Medical Research Council
Funding Amount
$569,541.00
Summary
Failure of the skin to close over the brain and spinal cord during human development results in the devastating congenital birth defects anencephaly and spina bifida, known collectively as the neural tube defects. These are the second most common congenital birth defects affecting 1:1000 pregnancies. Anencephaly is not compatible with life and affected babies die at birth. In contrast children with spina bifida survive, but suffer from limb paralysis, bowel and bladder dysfunction, learning diff ....Failure of the skin to close over the brain and spinal cord during human development results in the devastating congenital birth defects anencephaly and spina bifida, known collectively as the neural tube defects. These are the second most common congenital birth defects affecting 1:1000 pregnancies. Anencephaly is not compatible with life and affected babies die at birth. In contrast children with spina bifida survive, but suffer from limb paralysis, bowel and bladder dysfunction, learning difficulties and psycho-social disturbances. Our laboratories have identified a family of genes essential for the colsure of the neural tube in mammals. The aim of this proposal is to understand the mechanisms of action with a view to developing new therapeutics that mey be used preventatively in these conditions. We also hope that these studies may facilitate the development of a genetic test to screen couples at risk.Read moreRead less
Structural And Functional Determinants Of Spatiotemporal Periodicity In Cardiac Impulse Propagation
Funder
National Health and Medical Research Council
Funding Amount
$211,320.00
Summary
Abnormal heart rhythms (cardiac arrhythmias) are responsible for much morbidity and excess mortality in Australia. Although many abnormalities leading to an abnormal heart rhythm may be successfully treated by medications or minimally invasive operative procedures there are several important ones which are not. These include the most common significant cause of an abnormal heart rhythm, atrial fibrillation, and the arrhythmias responsible for approximately half of sudden deaths, ventricular tach ....Abnormal heart rhythms (cardiac arrhythmias) are responsible for much morbidity and excess mortality in Australia. Although many abnormalities leading to an abnormal heart rhythm may be successfully treated by medications or minimally invasive operative procedures there are several important ones which are not. These include the most common significant cause of an abnormal heart rhythm, atrial fibrillation, and the arrhythmias responsible for approximately half of sudden deaths, ventricular tachycardia and ventricular fibrillation. Atrial fibrillation is a leading cause of stroke. Sudden death is associated with aging and is an increasing problem because of the rising mean age of the population. Recent negative attention on the side effects of medications used for the treatment of cardiac arrhythmias has appropriately increased interest in curative approaches requiring no onging medications. These procedures usually rely on mapping electrical activity in the heart and interrupting abnormal electrical pathways using radiofrequency electrical current. The procedures are unsuccessful when existing techniques fail to identify the underlying mechanism responsible for the abnormal heart rhythm or when the source of the abnormal beating cannot be localised within the heart. In this project we investigate the fundamental basis for a new approach to these problems. By examining the variability of the beat rate and the variability of the beat rate at different points within the heart we may be able to identify arrhythmia mechanisms and localise arrhythmia sources. In this project we will examine in groups of cells the structures and types of electrical circuits which give rise to certain types of beat-to-beat variability in the heart. This information will be essential for the interpretation of information obtained in later human studies and the subsequent development of new curative procedures for these problems.Read moreRead less