Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which w ....Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which we have shown to operate in various smooth muscles. This mechanism, termed store-based pacemaking, is entirely different to the currently held cardiac model but could readily achieve the same outcome. We will investigate the hypotheses that this pacemaker mechanism is also fundamental to mammalian heart pacemaking and conduction. Positive support for our hypotheses, as indicated by our findings on amphibian hearts and from pilot findings, may severely challenge the present model for cardiac pacemaking. Such an outcome will have major ramifications on present interpretation of cardiac function in health and disease and will be particularly important to interpretation of disorders associated with cardiac arrhythmias and heart conduction.Read moreRead less
Rhythmicity And Synchronicity In Uterine Smooth Muscle
Funder
National Health and Medical Research Council
Funding Amount
$291,823.00
Summary
Natural birth occurs through rhythmic contractions of the smooth muscle of the uterus. There is surprisingly little understanding of the mechanism of the pacemaker clock that both initiates and times each contraction in a coordinated manner to expel the fetus. This project is to challenge this knowledge gap using our findings on cellular rhythms that herald Ca2+ stores as a major pacemaker mechanism. First, we will use electrophysiology and calcium imaging techniques to test the hypothesis that ....Natural birth occurs through rhythmic contractions of the smooth muscle of the uterus. There is surprisingly little understanding of the mechanism of the pacemaker clock that both initiates and times each contraction in a coordinated manner to expel the fetus. This project is to challenge this knowledge gap using our findings on cellular rhythms that herald Ca2+ stores as a major pacemaker mechanism. First, we will use electrophysiology and calcium imaging techniques to test the hypothesis that rhythmicity and synchronicity of uterine contractions are underpinned by store pacemaking. Second, we will probe the role of current spread between cells via gap junctions as a mechanism of recruitment and will examine whether accessory cells termed interstitial cells subserve a role in pacemaking. These cells are present within the uterine wall but their function is unknown. We will probe their ion channel properties in relation to pacemaking using patch clamp techniques. Third, we will examine the role of labour hormones, such as oxytocin, in augmenting uterine contractions via interaction with the Ca2+ store mechanism and cell recruitment. These studies will provide new and fundamental insights into uterine pacemaking, an outcome that should be of great significance to understanding and better controlling birth-associated complications such as preterm delivery and failure to progress.Read moreRead less
Substrate Mapping And Ablation Of Ventricular Tachycardia
Funder
National Health and Medical Research Council
Funding Amount
$444,129.00
Summary
Sudden death is a tragic occurrence and can afflict Australians of all ages, racial and ethnic backgrounds. This research will aim to understand abnormalities in the heart muscle that cause dangerous heart rhythm abnormalities, which is the most common cause of sudden death. We will study ways to improve the technology of keyhole cardiac procedures so that it can be used to prevent these arrhythmias from occurring in the first place, and in improving the chance of long-term successful cure.
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
Regulation Of RyR2 Channels By Calmodulin In Healthy And Diseased Hearts
Funder
National Health and Medical Research Council
Funding Amount
$614,421.00
Summary
In the heart, RyR2 is responsible for intracellular Ca2+ release. The RyR2 is comprised of a Ca2+ channel and accessory proteins such as CaM that regulate channel activity. Evidence suggests that RyR2 regulation by CaM is altered in heart failure and human arrhythmia syndromes, but there has been no direct evidence for this. We will provide this direct evidence plus determine how CaM regulates RyR2 channels and intracellular Ca2+ release and how this leads to cardiac arrhythmias.
Ryanodine Receptor Inhibitors As Therapy For Ca2+ Store Overload Induced Arrhythmias
Funder
National Health and Medical Research Council
Funding Amount
$555,892.00
Summary
This study investigates a new therapeutic action recently discovered for flecainide, an antiarrhythmic agent that we find to completely prevent and inherited form of stress-induced arrhythmias called CPVT. The findings will provide the first detailed mechanistic understanding of an antiarrhythmic drug, findings that will also give a new direction for drug design to control common arrhythmias such as occur in diseases such as coronary artery disease.
Type 2 diabetes is the most common endocrine disease in the world and up to 60% of diabetic patients have heart disease. Heart disease is the most expensive heath condition and biggest cause of death in Australia. Diabetic patients often accumulate fat (triglyceride) within their heart cells, leading to diabetic heart disease. The present study sought to determine if diabetic patients with increased fat within their heart cells have more scarring which eventually results heart muscle dysfunction ....Type 2 diabetes is the most common endocrine disease in the world and up to 60% of diabetic patients have heart disease. Heart disease is the most expensive heath condition and biggest cause of death in Australia. Diabetic patients often accumulate fat (triglyceride) within their heart cells, leading to diabetic heart disease. The present study sought to determine if diabetic patients with increased fat within their heart cells have more scarring which eventually results heart muscle dysfunction.Read moreRead less