Background: Reperfusion after an ischaemic period can lead to fatal arrhythmias, in part due to heterogeneities in electrophysiology (EP) across the affected tissue. In previous work done in rabbits, we observed preferential recovery of electrical excitability in the myocardium along the main branch of the reperfused coronary vessel (‘perivascular excitation tunnelling’, PVET) upon recovery from no-flow ischaemia or local exposure to ischaemic solution to normal solution. In a subset of hearts, this resulted in re-entrant arrhythmias, which represents a hitherto not considered mechanism of arrhythmogensis. In these experiments, there appeared to be a link between size of ischaemic zones and probability of PVET-induced arrhythmias, suggesting that small animal model may underestimate the significance of this mechanism.

Objective: To determine in a pig model whether PVET as a mechanism underlying ischaemia-reperfusion (I/R) arrhythmias is translationally relevant and, if so, to reduce acute reperfusion arrhythmia events.

Methods: Langendorff-perfused ex vivo hearts from 50 kg, 6-month old, Munich hybrid minipigs were loaded with a voltage-sensitive dye. Epifluorescence imaging was used to track action potential propagation on the epicardial surface of the heart. The heart was perfused both globally (via the aorta) and locally (via the cannulated circumflex coronary artery) with an oxygenated physiological saline solution. Local perfusion was subsequently switched to and from hyperkalaemic solution to introduce regional block of excitability. Reperfusion was either one-step (returning the entire locally-perfused tissue to oxygenated physiological saline solution), or two-step, where the distal part of the ischaemic tissue was reperfused earlier than the proximal part.

Results: In minipigs, the incidence of PVET was 75% (n= 3 of 4), compared to in large rabbits where it is ~50% (n= 4 of 8). In rabbits, a ‘distal-first’ two-stage reperfusion of the blocked vessel reduced PVET-induced arrhythmias. In minipigs, PVET developed within the first-perfused distal tissue. This did not give rise to re-entry, as the proximal part was still inexcitable – acting as a shield against break-through excitation. Upon subsequent 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 allow 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. Testing this strategy in pigs is ongoing.

Conclusion: Whether PVET-based re-entry upon coronary reperfusion occurs in the clinical setting is in interesting question for cardiac EP. The pig serves as a good translational model for human cardiac EP disturbances, and it shows a high incidence of PVET upon reperfusion after acute regional left-ventricular ischaemia. To protect from PVET-based arrhythmogenesis, inexcitable proximal tissue can serve as a temporary conduction block zone, shielding the heart from rhythm disturbances before full recovery of the ischaemic zone. Controlling recovery of ischaemic area in a two-step reperfusion approach, where distal tissue is exposed to fully-physiological solution, while the proximal tissue is initially perfused with oxygenated but cardioplegic solution, may constitute an improved interventional tactic.