Keeping the rhythm -- pro-arrhythmic investigations in isolated Göttingen minipig hearts

Abstract

Introduction: Cardiac arrhythmia is a potentially lethal condition. A better prediction and mechanistic understanding of human cardiac arrhythmia is dependent on the development of good animal models. Minipigs are increasingly being used in cardiovascular research and we hypothesize that Langendorff-perfused minipig hearts could serve as a novel model of pro-arrhythmia.

Methods: We studied arrhythmic biomarkers and overt arrhythmia using sharp electrode recordings and Langendorff-perfusion of minipig and dog hearts. Hearts were subjected to pharmacological blockade of repolarizing currents, chemical and surgical AV-block, and programmed electrical stimulation.

Results: Minipigs have significantly longer cardiac action potentials and QT intervals than dogs at comparable cycle lengths. In addition, minipigs were relatively resistant to arrhythmias in a variety of settings and arrhythmias were only observed in response to programmed electrical S1-S2 stimulation after surgical AV-ablation and combined I(Kr) and I(Ks) blockade. Accordingly, the short term variability of the action potential remained very low in minipigs. In addition, the electro-mechanical window (EMw) remained positive in both dog and minipig experiments, although the EMw approached negative values in dogs during I(Ks) blockade and β-adrenergic stimulation. Isoprenaline- or pacing-induced changes in frequency resulted in paradoxical transient effects on repolarization.

Discussion: The evidence presented indicates that Langendorff-perfused Göttingen minipig hearts are resistant to the development of arrhythmias in experimental settings known to be pro-arrhythmic in other species including dogs. A possible mechanistic explanation could be the long electrical systole compared to dogs, combined with a short vulnerable window, recorded in minipig hearts. We also find that EMw recordings from Langendorff perfused hearts are less sensitive to I(Ks) blockade than what has been reported from in vivo experiments, most likely due to the mechanical properties of the recording apparatus.