Relationship between early and late events in the cardiac cycle as control points for therapeutic intervention

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Heart failure is a major cause of disability and death worldwide, and approximately 50% of heart failure-related deaths are sudden and may be explained by abnormal electrical signals in the heart (arrhythmias). Heart failure patients have a 6- to 9-fold increased risk of sudden cardiac death compared to the general population. According to the "Heart of England screening study" the mortality risk for heart failure patients is 9% per year with a prevalence of ~6.6% of the population at 50 years of age (and which increases rapidly with age). In this study we will examine the interrelationships between electrical signals and calcium metabolism in heart cells with special emphasis on an integrative approach to understanding cell signalling. There is good evidence that heart failure is linked to changes in calcium signalling within cells which not only controls the force of contraction (and the ability of the heart to pump blood) but also affects electrical activity. The contraction of the heart, which is compromised in heart failure, is initiated by an electrical signal which causes calcium to be released inside the cell and it is the time course and amplitude of this calcium signal which is a major determinant of contraction force. However, the signal is not one way since calcium also affects electrical activity, especially later when the cell has to return its voltage to normal levels before the next beat. Our goal is to develop the scientific understanding needed to optimise both electrical and calcium signalling with drugs and/or by manipulation of key protein expression in the cell.Using biophysical techniques, we will examine how the cell responds to measured changes in the expression of proteins that control heart cell voltage and how these changes affect the later electrical and calcium signalling events that occur in the cell. Using pharmacological agents we will dissect the electrical causes of normal and abnormal electrical activity together with how they are modulated by changes in calcium signalling. At the same time, we will probe how changes in voltage affect the calcium signalling mechanisms by using computer-generated electrical currents and feeding them into the cell to break feedback loops between calcium signalling and electrical currents to allow analysis. All of the data will be incorporated into computer models to allow us to re-integrate and test our understanding of how the electrical and calcium signalling changes work together to contribute to the disease state. At this point we will be able to identify how mixtures of drugs can be used to improve contraction strength while, at the same time, minimise arrhythmia risk.It is also known that signalling pathways between the heart cell surface membrane and the intracellular store of calcium may become disrupted due to micro-anatomical changes in cell structure. It is not clear how heart cells adapt to these changes although we know that the intracellular calcium store release system becomes more 'leaky'. Using a novel form of illumination inside the cell (namely 2-photon excited flash photolysis) with special molecules that can react to the illumination, we will probe how microscopic elements of the calcium store respond to our artificially generated trigger signals. This will reveal the extent of this subcellular problem and therefore identify the utility of developing new therapeutic agents to ameliorate the leaky calcium store release. We will also be examining how subcellular signal transduction systems/pathways affect the integrated response of the system, to further refine possible points of control in the defective electrical and calcium signalling systems in the failing heart.