Circumventing Cardiac Reperfusion Arrhythmias in a Translational Pig Model

Introduction: Reperfusion after an ischaemic period can lead to fatal arrhythmias. Typically, these arrhythmias are attributed to heterogeneities in the border of the reperfused myocardium. In previous work done in rabbits, we instead observed arrhythmias in the myocardium along the main branch of the reperfused coronary vessel (‘perivascular excitation tunnelling’, PVET) upon reperfusion. In this work, we assessed if PVET is a dominant mechanism of ischaemia-reperfusion arrhythmias in a large animal model and whether a two-step reperfusion method can prevent these arrhythmias.

Methods: Langendorff-perfused pig hearts were used. A single coronary artery (typically the left marginal artery) was cannulated and perfused with either physiological or cardioplegic solution to mimic ischaemia while reducing the time needed to get electrical inexcitability. A voltage-sensitive dye (Di-4-ANBDQPQ) was added to the perfusate, allowing optical imaging of action potential propagation during baseline, ischaemia, and reperfusion. Reperfusion was either one-step (sudden re-flow), or two-step, where the distal part of the ischaemic tissue was reperfused earlier than the proximal part.

Results: PVET occurred in 8 of the 9 pig hearts subjected to direct reperfusion, which lead to arrhythmias in 5 of the hearts. By comparison, the two-step reperfusion led to PVET in 2 out of 4 hearts with none of the hearts displaying arrhythmias. Re-entrant arrhythmias are prevented in the first step, as the proximal part was still inexcitable – acting as a shield against break-through excitation. Upon the second step, i.e. reperfusion of the proximal tissue, any PVET-based re-entry that may develop in that tissue had a much reduced path length and the associated excitable gap was too short to sustain re-entrant excitation. Subdividing reperfusion after acute ischaemic events into two spatially distinct domains meant that arrhythmogenic mechanisms were still present, but they were pathophysiologically silent.

Conclusion: PVET-based re-entry occurs in hearts with similar size, anatomy, and electrophysiology to humans, indicating it may be clinically relevant. We have developed a reperfusion approach that allows controlled recovery while preventing arrhythmias. Subsequent work will use a catheter-based approach to enable the two zones to be perfused simultaneously. Here, distal tissue would be exposed to fully-physiological solution, while the proximal tissue would be initially perfused with oxygenated but cardioplegic solution. This catheter will be tested in pig ex vivo and in vivo to identify if this constitutes an improved interventional tactic.