Our Research
Molecular Basis of Arrhythmias
What underlies arrhythmias? Are there common causal factors shared with any arrhythmias, otherwise each arrhythmia has specific molecular changes? This project try to uncover molecular mechanisms in the cardiac conduction system that leads to arrhythmias. We also hope these causal factors including ion channel remodelling, transcriptional dysregulation, and non-coding RNAs could be therapeutic targets. To examine this, we have several animal arrhythmia models (e.g., athlete model, heart failure models). We have reported that some miRNAs upregulated by disease signals inhibit quality and quantity of pacemaking ion channels that causes arrhythmias. Endurance exercise can, for example, upregulate miR-423-5p in the sinus node and miR-211-3p and miR-432 in the atrioventricular node that is attributed with resting bradycardia and heart block, but what sort of exercise-induced stimuli upregulate those miRNAs remains unclear. Are they haemodynamic stress, neuroendocrine peptides, or autonomic signal? We are currently investigating to identify exercise-induced stimuli and signal transduction causing electrical remodelling in the cardiac conduction system. Beyond that, the research will impact arrhythmia therapies through development of novel anti-arrhythmic strategies.
Micromorphology of Conduction System
The cardiac conduction system is a 'wiring system' in the heart. The most upper region 'sinus node (sinoatrial node)' regularly generates electrical impulses that determines the heart rate. For the atrioventricular conduction, there is the 'atrioventricular node (compact node)' slowing the impulse conduction that gives a time gap between atrial and ventricular contraction. A cardiac impulse is then transferred to subendocardially located 'His-Purkinje network' for fast conduction that makes rapid and strong ventricular contraction to provide the blood circulation to the whole body. Thus, the distribution of the cardiac conduction system is optimised for efficient pumping motion via alternative contraction of the atria and ventricles. Once the conduction system network is broken, it may cause arrhythmias. However, it remains unclear how displaced of the conduction system distribution leads to electrical disturbance. It has also been elusive the detailed intracellular morphology of each region of the cardiac conduction system. Recently advanced imaging technologies can be applied to this project. We have been figuring out the micromorphology of the cardiac conduction system with micro-CT scanning, serial block face scanning electron microscope, and confocal laser scanning microscope etc.
Regeneration Therapy for Arrhythmias
As well as discovering therapeutic targets including miRNAs, we also aim to develop artificial cardiac pacemaker cells for a novel bradyarrhythmia therapy. To pursue this, we need more understanding of the biology of the cardiac pacemaker tissue. This includes the molecular signature, transcriptional regulation of pacemaking ion channels, energy demand and regulation in the SAN, primary pacemaking site. We are studying how the SAN are different from the working myocardium comprising the atria and ventricles, and what molecules are involved in the SAN specification and development. We hope some of these molecules have a function to reprogram other cell types into pacemaker cells.
