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bioRxiv · 10.1101/2023.11.29.569031

Perivascular Excitation Tunnelling: a Novel and Preventable Cause of Cardiac Reperfusion Arrhythmias

Chleilat, E.·Puig Walz, T.·Han, B.·Quinn, T. A.·Kohl, P.·Zgierski-Johnston, C.
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Abstract

BackgroundReperfusion after myocardial ischaemia can lead to deadly arrhythmias, in part due to heterogeneities in electrophysiology (EP) across affected tissue. There is a need to understand the spatiotemporal dynamics of ischaemia-reperfusion arrhythmias (IRA), so that reperfusion strategies to prevent them can be found. MethodsLangendorff-perfused rabbit isolated hearts were loaded with a voltage-sensitive dye. Epifluorescence imaging was used to track action potential propagation across the cardiac surface. The heart was simultaneously perfused globally (via the aorta) and locally (via cannulation of a single coronary artery) with an oxygenated physiological saline solution. Local perfusion was subsequently switched to and from solutions that mimic aspects of ischaemia (acidosis, hypoxia, hyperkalaemia, or a simulated ischaemia solution combining all three) or to no-flow. Subsequently, different reperfusion strategies were tested to reduce IRA re-entries. The most successful strategy for preventing re-entry was tested in Langendorff-perfused isolated pig hearts to assess the clinical relevance of the observed mechanism and treatment strategy. ResultsUpon sudden reperfusion of the cannulated coronary artery in rabbit hearts we observed a preferential recovery of electrical excitability along the vessels main branch ( perivascular excitation tunnelling, PVET). This resulted in re-entry in roughly half of the hearts. Hyperkalaemia and hypoxia, but not acidosis, were sufficient to lead to conduction block, PVET, and re-entry, with both PVET and re-entry more frequently observed after hyperkalaemia than hypoxia. PVET was also present in pigs and PVET-based re-entries were successfully prevented in rabbit and pig hearts by two-step reperfusion, first of the distal majority of the previously ischaemic region, and then of the remaining tissue from the proximal point. With this strategy, any PVET that developed in the distal tissue was blocked by the still inexcitable proximal tissue. Upon reperfusion of the proximal tissue, there was a reduced path length for PVET. As a consequence, the associated excitable gap was too short for re-entrant excitation. ConclusionsWe observed a novel arrhythmia mechanism upon coronary reperfusion (PVET), which suggests that preferential recovery of myocardial excitability along the reperfused vessel is an important mechanism underlying IRA formation. PVET-induced re-entry reliably occurred in both rabbit and pig hearts and could be prevented by two-step reperfusion. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/569031v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@139a095org.highwire.dtl.DTLVardef@5dc811org.highwire.dtl.DTLVardef@f9db75org.highwire.dtl.DTLVardef@1b6f66b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Chleilat, E., Puig Walz, T., Han, B., Quinn, T. A., Kohl, P., Zgierski-Johnston, C.. 2023-11-30. Perivascular Excitation Tunnelling: a Novel and Preventable Cause of Cardiac Reperfusion Arrhythmias. https://doi.org/10.1101/2023.11.29.569031

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