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.
Analysis Of Atrial Electrical Remodelling In Patients With Paroxysmal And Persistent Atrial Fibrillation
Funder
National Health and Medical Research Council
Funding Amount
$127,516.00
Summary
I am a cardiologist undertaking further training in the management of electrical abnormalities of the heart. My research will focus on the mechanisms responsible for atrial fibrillation, the most common serious heart rhythm disorder. I intend to do this by examining the nature of the electrical activity in patients with atrial fibrillation and comparing this to electrical activity in patients without this disorder, who are undergoing treatment procedures for their electrical disorder.
Atrial fibrillation (AF) is the most common cause for an irregular heart beat. Catheter ablation is the only potential cure and involves passing wires via veins in the leg into the heart to deliver discrete small burns(ablation) around the pulmonary veins (PV), the major source for AF. Unfortunately 30-50% of patients have recurrent arrhythmia due to reestablishment of electrical connections. This multicentre internation trial examines whether more (maximal) ablation will improve the outcomes of ....Atrial fibrillation (AF) is the most common cause for an irregular heart beat. Catheter ablation is the only potential cure and involves passing wires via veins in the leg into the heart to deliver discrete small burns(ablation) around the pulmonary veins (PV), the major source for AF. Unfortunately 30-50% of patients have recurrent arrhythmia due to reestablishment of electrical connections. This multicentre internation trial examines whether more (maximal) ablation will improve the outcomes of the procedure.Read moreRead less
Characterisation Of CFAE Wavefront Propogation In Human Persistent AF
Funder
National Health and Medical Research Council
Funding Amount
$418,612.00
Summary
Atrial fibrillation can be eliminated by a relatively new treatment called catheter ablation, which involves modification of the electrical properties of the heart using thin wires (catheters) passed up from the leg. Targeting areas where catheters record abnormal electrical activity improves results of catheter ablation, although it is uncertain what these recordings represent. The aim of this study is to characterize these abnormal electrical signals in an attempt to improve ablation outcomes.
Understanding The Mechanisms Of Atrial Fibrillation: High Density Intra-operative Mapping
Funder
National Health and Medical Research Council
Funding Amount
$94,025.00
Summary
We hypothesize that: During atrial fibrillation, regions acting as short cycle length drivers will demonstrate characteristic sinus rhythm electrophysiology including conduction slowing and abbreviated refractoriness. We aim to correlate the nature of electrical activity in atrial fibrillation with that in sinus rhythm. We will focus on particular anatomic locations that have been shown to be regions of anisotropy and sites where short cycle length rotors have been observed. The anatomic locat ....We hypothesize that: During atrial fibrillation, regions acting as short cycle length drivers will demonstrate characteristic sinus rhythm electrophysiology including conduction slowing and abbreviated refractoriness. We aim to correlate the nature of electrical activity in atrial fibrillation with that in sinus rhythm. We will focus on particular anatomic locations that have been shown to be regions of anisotropy and sites where short cycle length rotors have been observed. The anatomic location and electrophysiologic (EP) characteristics of these regions will vary according to the underlying atrial substrate. We aim to characterise the differences in atrial electrophysiology in AF and sinus rhythm between different pathophysiologic substrates. With high density mapping targeted to critical anatomic sites it will be possible to determine the EP mechanism of short cycle length rotors. We aim to characterise the EP mechanism of these short cycle length regions by analysis of recordings from high density mapping plaques.Read moreRead less