An Ovine Model of Postinfarction Dilated Cardiomyopathy in Animals with Highly Variable Coronary Anatomy

Abstract

Studies on cardiac regeneration require large mammalian models of dilated cardiomyopathy (DCM) after acute myocardial infarction (AMI), and pig and sheep models are increasingly used in this field of preclinical research. Given the large interindividual variability in ovine left anterior descending artery (LAD) anatomy, protocols based on the coronary arteries to be ligated often lead to significant variation in infarct sizes and hence to heterogeneous results, ranging from no ventricular remodeling to acute, lethal left ventricular (LV) failure. We designed an ovine model of postinfarction DCM based on estimated infarct size rather than on a predetermined menu of coronary artery ligatures. In seven adult sheep we induced an anterolateral AMI of approximately 25% of the LV mass by ligating the branches of the LAD that, by visual inspection, would lead to such an infarct size. In 10 to 12 weeks, LV end-diastolic volume more than doubled and LV end-systolic volume almost tripled. LV ejection fraction decreased dramatically, as did LV percent fractional shortening and LV percent wall thickening. Infarct size (planimetry) was approximately 25% of the LV endocardial surface. We conclude that in sheep, an anterolateral AMI of approximately 25% of the LV mass--regardless of the coronary branches ligated to attain that infarct size--results in a model of postinfarction DCM that may prove useful in preclinical research on myocardial regeneration.

A Nonthoracotomy Myocardial Infarction Model in an Ovine Using Autologous Platelets

“…Sheep, however, do have some significant variability in the distribution of their left circumflex artery, leading to significant variation in infarct sizes [16]. Our group had previously reported on the efficacy of repeated embolizations to the left circumflex artery to induce heart failure [4].…”

“…Previous ovine models of postinfraction heart failure through the ligation of either the distal LAD or the diagonal branches off of the LAD have shown reproducible results. This has been attributed to the consistent territory of myocardium supplied by this artery as well as the lack of collateral vascularity [16–18]. …”

Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia‐Inducible Factor 1‐α (HIF1‐α) in an Ovine Model of Acute Myocardial Infarction

“…Importantly, CMR allowed comparisons to be performed on a paired basis. This was particularly advantageous, because sheep as a species display heterogeneous LAD artery distribution, with interindividual variations that make it difficult to achieve similar infarct sizes across the experimental population . The use of CMR at 3 time points allowed us not only to compare infarct size against the initial ischemic damage extension, but also to observe how it evolved over time.…”

Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction

“…In AMI, MRI allows to quantify and characterize the pattern of ischemic myocardial damage in terms of area at risk and infarct size, and thereby of salvaged myocardium, along with depicting microvascular damage. 41 As regards LV function, we have previously shown that echocardiographic parameters of systolic and diastolic LV performance in young adult sheep can be reliably extrapolated to the adult human, 42 this indicating that at least in this animal model echocardiography is useful to assess LV function.…”

“…Given the heterogeneity of the LAD artery distribution in sheep, 40 it was necessary to assess for infarct size on a paired analysis basis. We therefore carried out MRI within the first 72 hs after coronary occlusion and at the end of the follow up.…”