Glutathione Transferase-derived Compounds As Therapeutic Agents
Funder
National Health and Medical Research Council
Funding Amount
$418,516.00
Summary
Inhibition of cardiac calcium ion channels may be an effective new way of improving heart performance in patients with heart failure. This project will investigate how a glutathione transferase enzyme inhibits calcium ion channels in the heart and if small fragments of a muscle specific glutathione transferase can be used to specifically modify cardiac ryanodine receptor function. These fragments will provide the basis for the development of a new therapeutic approach.
Urotensin-II In Human Heart: Investigation Of Mechanisms Involved In Cardiac Function
Funder
National Health and Medical Research Council
Funding Amount
$255,990.00
Summary
The normal function of the body is maintained by naturally occurring compounds. Some for example affect the heart, fine tuning it to make it beat faster or slower, or beat with greater or less force when required in different situations in health and disease. We were the first to show just recently that a small protein which occurs naturally in the body, called urotensin-II can affect the way the heart beats. We showed that extremely tiny amounts increase the force of the heart beat. Our finding ....The normal function of the body is maintained by naturally occurring compounds. Some for example affect the heart, fine tuning it to make it beat faster or slower, or beat with greater or less force when required in different situations in health and disease. We were the first to show just recently that a small protein which occurs naturally in the body, called urotensin-II can affect the way the heart beats. We showed that extremely tiny amounts increase the force of the heart beat. Our findings indicate that urotensin-II is the most potent heart stimulator identified to date. In patients with heart failure, short term stimulation of heart contraction is beneficial, supplying the heart and other organs with vital oxygen and nutrients. However, in the long term excessive stimulation causes worsening of the patients condition. Very little is currently known about the way in which urotensin-II alters heart function. The goal of our study is to understand the mechanism involved in urotensin-II mediated effects on the heart. This will involve identifying the location of urotensin-II and its receptors in the heart, and determining what signalling changes occur after the interaction of urotensin-II with its receptors. Urotensin-II must first be cleaved from a larger drug. We will determine where in the heart this cleavage occurs and whether the process is crucial to the ability of urotensin-II to stimulate contraction of the heart. Since stimulators of heart contraction are detrimental to patients with heart failure in the long term, we will determine whether these patients have more urotensin-II in their blood than patients who do not have heart failure. If the levels of urotensin-II are higher in heart failure patients, it may indicate a need to interfere with the interaction of urotensin-II with its receptors.Read moreRead less
Single-Beat Preload Recruitable Stroke Work Measurement Of Cardiac Contractility In Three Mammalian Models.
Funder
National Health and Medical Research Council
Funding Amount
$241,980.00
Summary
The accurate measurement of the inherent pumping capacity of the heart muscle is difficult because (i) most measurements currently in use cannot accurately discriminate between the contribution of the heart muscle and that of the vascular system to the results obtained, and (ii) the measurements which can discriminate currently require invasive measurements and procedures that frequently restrict their use. The overall purpose of this proposal is to more rigorously validate a promising method we ....The accurate measurement of the inherent pumping capacity of the heart muscle is difficult because (i) most measurements currently in use cannot accurately discriminate between the contribution of the heart muscle and that of the vascular system to the results obtained, and (ii) the measurements which can discriminate currently require invasive measurements and procedures that frequently restrict their use. The overall purpose of this proposal is to more rigorously validate a promising method we have developed that will (i) make accurate assessment possible from a single cardiac beat in both experimental animals and human subjects; (ii) reduce the number of experimental animals required for such measurements by permitting sequential measurements in the same animals; (iii) make it possible to perform such measurements non-invasively in human subjects.Read moreRead less
Anthracyclines Disrupt Ca2+ Signalling In Cardiomyocytes: A Contribution To Cardiac Toxicity
Funder
National Health and Medical Research Council
Funding Amount
$525,620.00
Summary
Anthracyclines are one of the most effective drugs used in chemotherapy, but cause side effects resulting in serious heart problems which can be fatal. The link between anthracycline therapy and the problems they cause in the heart is not fully defined. We will investigate mechanisms leading to these side effects and define specific targets of anthracyclines in the heart. It is hoped this will lead to the design of new drugs which counteract the side effects of anthracycline treatment.
Clinical trials and experimental investigations have demonstrated that a diet rich in fish oil, containing high levels of omega 3 fatty acids, provides protection against arrhythmias and sudden cardiac death associated with heart failure. Surprisingly little is known about how these dietary omega 3 lipids alter the electrical and mechanical function of cardiac muscle cells when incorporated into the membrane of these cells. The goal of this study is to examine how experimental omega 3 diet treat ....Clinical trials and experimental investigations have demonstrated that a diet rich in fish oil, containing high levels of omega 3 fatty acids, provides protection against arrhythmias and sudden cardiac death associated with heart failure. Surprisingly little is known about how these dietary omega 3 lipids alter the electrical and mechanical function of cardiac muscle cells when incorporated into the membrane of these cells. The goal of this study is to examine how experimental omega 3 diet treatment can modify the heart muscle cell structure and function. In particular we will determine which cellular mechanisms may be important in conferring selective benefit of dietary intervention on pre-failing heart function. For this study we will use mice which exhibit signs of heart failure induced by hormone overproduction (angiotensin II) and by elevation of blood pressure (by surgical constriction). Mice will be fed omega-3 and omega-6 diets and experiments to investigate cardiac muscle cell structure and function will be carried out using a variety of electrical recording, microscopic and molecular biology techniques. Diet-induced changes in the capacity of the heart cells to regulate calcium will be investigated using cells loaded with fluroescent indicators. Single cell electrical recording techniques (patch clamp) will also be used in combination with ECG measurement to evaluate how arrhythmic activity arising from electrically and mechanically unstable cells can be suppressed by omega-3 diet intervention. Finally we will take the first step towards validating the rodent experimental findings in a clinical setting with measurements of calcium transporters and channel expression in human specimens from cardiac surgery patients.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
The Human Cardiac Transient Outward Potassium Channel,Kv4.3:A Study Of Its Pharmacology And Modulation By Disease States
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
The contraction of the heart is triggered by electrical activity.For every heart beat,electrical activity known as an action potential,occurs.This involves a rapid change in voltage inside the heart cells which must then be quickly restored to the normal resting level or sudden death ensues. Both the initial rapid change (known as depolarisation), and its restoration to normal, (repolarisation), are produced by electrical currents flowing through the cell membrane.The currents responsible for re ....The contraction of the heart is triggered by electrical activity.For every heart beat,electrical activity known as an action potential,occurs.This involves a rapid change in voltage inside the heart cells which must then be quickly restored to the normal resting level or sudden death ensues. Both the initial rapid change (known as depolarisation), and its restoration to normal, (repolarisation), are produced by electrical currents flowing through the cell membrane.The currents responsible for repolarisation are mainly carried by potassium ions.A number of these outward potassium channels exist and the present study is concerned with one of the most important of them, known as the transient outward current. The transient outward current has recently been found to be modulated by disease states,such as thickening of the heart muscle and heart failure.It is also known to be blocked by a number of drugs,some of which are used to treat abnormal heart rhythms.It is therefore of particular interest to clinical cardiologists This channel has been difficult to study in the past because it is usually mixed with several other currents in experiments on living heart cells.The gene which codes for it was identified in 1996 and we now have a cell-line in tissue culture in our laboratory which has only this particular channel,allowing us to study it systematically in isolation from other currents.This study forms the basis of our application.Read moreRead less