Perivascular Excitation Tunnelling: a Novel Mechanism of Cardiac Ischaemia-Reperfusion Arrhythmias

• Applicant: Enaam Chleilat, Ph.D.
• Subject Area: Cardiology, Angiology ; Anatomy and Physiology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468413847

Restoring blood flow after an ischaemic period is essential to limit sustained myocardial damage. Paradoxically, sudden reperfusion can give rise to fatal cardiac arrhythmias. These ischaemia-reperfusion arrhythmias (IRA) form the focus of the present proposal. Spatiotemporal heterogeneity of electrophysiology is a key driver of IRA. I hypothesise that the swift restoration of a near-normal extracellular environment in myocardium along the reperfused coronary artery can give rise to formation of preferential conduction pathways that allow re-entrant excitation. If confirmed, it would motivate the development of new strategies for preventing IRA, for example using modified reperfusion protocols.In pilot experiments, panoramic optical mapping of Langendorff-perfused rabbit hearts was used to record epicardial transmembrane voltage across the whole heart by means of a voltage-sensitive dye. I have observed preferential recovery of electrical excitability in myocardium along the main branch of a coronary vessel (‘perivascular excitation tunneling’, PVET), upon reperfusion with normal solution after a period of no-flow or ‘ischaemic’ perfusion. In a subset of hearts, this resulted in re-entrant arrhythmias. Individual aspects of ischaemia such as local hyperkalaemia, hypoxia or acidosis need careful investigation to see which factor(s) drive PVET and re-entrant arrhythmia occurrence. Also, coronary artery morphology will be assessed, as it may be another determinant of PVET. Experimental findings will be used to inform a computational model of IRA to explore arrhythmia inducibility and to suggest ‘smart reperfusion’ approaches that may allow one to reduce IRA occurrence. As part of the project, these approaches will be experimentally validated.The observation of PVET-based re-entry and arrhythmogenesis offers a novel mechanistic explanation for IRA. Pilot work provided a first ex vivo experimental validation of the existence, and computational models corroborated the putative link between PVET and IRA. The project will develop refined experimental and computational models of PVET, identify key drivers of PVET, and explore improved reperfusion strategies that may prevent or limit the occurrence and/or duration of PVET-induced arrhythmias. This would offer not only new fundamental insight into mechanisms underlying IRA, but be of potential translational relevance for patients with myocardial ischaemia undergoing cardiac revascularisation.

• DFG Programme: WBP Position