A novel minimally invasive and reproducible large animal ischaemia-reperfusion-infarction model: methodology and model validation

Ischaemic heart disease remains a leading cause of premature mortality and morbidity. Understanding the associated pathophysiological mechanisms of cardiac dysfunction arising from ischaemic heart disease and the identification of sites of novel therapeutic intervention requires a preclinical model that reproduces the key clinical characteristics of myocardial ischaemia, reperfusion and infarction. Here we describe and validate a refined and minimally invasive translationally relevant approach to induce ischaemia, reperfusion and infarction in the sheep. The protocol uses clinical cardiology devices and approaches and would be readily adopted by researchers with access to standard fluoroscopic instrumentation. In addition to being minimally invasive, the major refinements associated with the described methodology are the implantation of an intracardiac defibrillator prior to coronary engagement and use of an antiarrhythmic medication protocol during the procedure. These refinements lead to a reduction of intraoperative mortality to 6.7 %. The model produces key characteristics associated with the 4th Universal Definition of Myocardial Infarction including electrocardiographic changes, elevated cardiac biomarkers and cardiac wall motility defects. In conclusion, the model closely replicates the clinical paradigm of myocardial ischaemia, reperfusion and infarction in a translationally relevant large-animal setting and the applied refinements reduce the incidence of intraoperative mortality typically associated with preclinical myocardial infarction models.