Ionic calcium underpins many of the vital functions undertaken by the cells of the cardiovascular system. Understanding how the level of calcium is regulated, by the complex intracellular machinery within cells, is the basis for understanding normal physiological control of the conduction and coordination of contraction throughout the cardiac cycle of the beating heart. Normally the cardiac cycle is very stable, however, it is apparent that cardiac disease, such as abnormal cardiac membrane physiology, structural heart disease or acute ischaemia, can disturb this stability leading to other activation patterns, or arrhythmias, some of which can be life threatening. Individuals with structural or functional abnormalities in their myocardium are not in life threatening arrhythmias all of the time; they are simply at increased risk of developing such rhythms. There is often some triggering incident that initiates the arrhythmia, which is why we study calcium regulation of intracellular and intercellular processes to look for evidence that will lead to important advances in understanding the genesis of these rhythm disturbances.

Primary human cardiac cells and especially those reflecting a specific human disease phenotype are both difficult to obtain and propagate in culture. Somatic cells may be reprogrammed to generate induced pluripotent stem cells (iPSCs) that share many of the properties of embryonic stem cells and can thus differentiate into all cells of the human body. At the Medical School in Swansea, we are using human induced pluripotent stem cells (hiPSCs) to produces human differentiated cardiac myocytes (hiPSC-CMs). The cells produced are being studied as isolated cells, or as multicellular arrays allowing us to study cell to cell interactions to gain an appreciation of the signalling mechanisms crucial to the function of cardiomyocytes.

We adopt an approach that brings together aspects of physiology, pharmacology, biochemistry, biophysics and mathematical modelling, allowing the emergence of truly interdisciplinary investigation. Calcium signalling in cardiac myocytes is investigated using a variety of imaging techniques, including high speed and confocal microscopy. Cardiac action potentials are studied with sharp electrode and patch clamp electrophysiology techniques. Further characterisation of the cells is obtained using immunohistochemical techniques.

Our studies reveal that intracellular calcium signalling systems show universal patterns of behaviour that become apparent whether studying a single cellular element of the heart or as a highly complex well organised system in an integrated array of cells. Results obtained in our laboratory predict that such behaviour is critical to a normal physiology and that perturbations of these signalling systems may trigger pathological situations. In addition to disease modelling, it is hoped that hiPSC-CMs will prove to be an important source of cells for patient-specific cardiotoxicity drug testing, drug discovery and regenerative medicine.

Publications

  1. & Endothelium derived relaxant factor. Journal of the Royal College of Physicians of London 19
  2. & EDRF coordinates the behaviour of vascular resistance vessels. Nature 329
  3. & Investigation of the vasoconstrictor action of subarachnoid haemoglobin in the pig cerebral circulation in vivo. British Journal of Pharmacology 97
  4. & EDRF-mediated dilatation in the rat isolated perfused kidney: A microangiographic study. British Journal of Pharmacology 98
  5. & (1990). Nitric oxide in arterial networks. Presented at Nitric oxide from L-arginine: a bioregulatory system: proceedings of a Symposium on Biological Importance of Nitric Oxide. ICS897,

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