Abstract
Many novel therapies to treat myocardial infarction (MI), yielding promising results in animal models, nowadays failed in clinical trials for several reasons. The most used animal MI model is based on permanent ligation of the left anterior descending (LAD) coronary artery in healthy mice resulting in transmural MI, while in clinical practice reperfusion is usually accomplished by primary percutaneous coronary interventions (PCI) limiting myocardial damage and inducing myocardial ischemia–reperfusion (MI-R) injury. To evaluate a more similar murine MI model we compared MI-R injury to unreperfused MI in hypercholesterolemic apolipoprotein (APO)E*3-Leiden mice regarding effects on cardiac function, left ventricular (LV) remodeling and inflammation. Both MI-R and MI resulted in significant LV dilation and impaired cardiac function after 3 weeks. Although LV dilation, displayed by end-diastolic (EDV) and end-systolic volumes (ESV), and infarct size (IS) were restricted following MI-R compared to MI (respectively by 27.6% for EDV, 39.5% ESV, 36.0% IS), cardiac function was not preserved. LV-wall thinning was limited with non-transmural LV fibrosis in the MI-R group (66.7%). Two days after inducing myocardial ischemia, local leucocyte infiltration in the infarct area was decreased following MI-R compared to MI (36.6%), whereas systemic circulating monocytes were increased in both groups compared to sham (130.0% following MI-R and 120.0% after MI). Both MI-R and MI models against the background of a hypercholesterolemic phenotype appear validated experimental models, however reduced infarct size, restricted LV remodeling as well as a different distributed inflammatory response following MI-R resemble the contemporary clinical outcome regarding primary PCI more accurately which potentially provides better predictive value of experimental therapies in successive clinical trials.
Highlights
Abbreviations APOE*3-Leiden Apolipoprotein E3-Leiden CO Cardiac output ejection fraction (EF) Ejection fraction HC Hypercholesterolemic left anterior descending (LAD) Left anterior descending
Most animal models used for studying novel therapeutic strategies are typically characterized by permanent LAD coronary artery occlusion, whereas in contemporary clinical practice patients with acute myocardial infarctions (MI) receive rapid reperfusion therapy defined in the guideline as within 90 min from first medical contact with the emergency medical system till reperfusion[3]
This study aims to investigate the effects of myocardial ischemia–reperfusion (MI-R) compared to unreperfused MI on cardiac function, left ventricular (LV) remodeling and the post-ischemic inflammatory response against the background of a hypercholesterolemic phenotype in APOE*3-Leiden mice which are known to develop advanced aortic atherosclerotic lesions resembling their human counterparts when exposed to a hypercholesterolemic phenotype as a result of a cholesterol-enriched Western-type diet[27], and to test its suitability as an experimental murine MI-R model with respect to cost effectiveness and practical ease of use
Summary
Abbreviations APOE*3-Leiden Apolipoprotein E3-Leiden CO Cardiac output EF Ejection fraction HC Hypercholesterolemic LAD Left anterior descending. Most animal models used for studying novel therapeutic strategies are typically characterized by permanent LAD coronary artery occlusion, whereas in contemporary clinical practice patients with acute MI receive rapid reperfusion therapy defined in the guideline as within 90 min from first medical contact with the emergency medical system till reperfusion[3]. This scientific knowledge contributes to discussions about the relevancy of animal-derived data and whether these studies resemble the clinical setting with their human counterparts accurately which has been explicitly addressed before[12,20]. This study aims to investigate the effects of MI-R compared to unreperfused MI on cardiac function, LV remodeling and the post-ischemic inflammatory response against the background of a hypercholesterolemic phenotype in APOE*3-Leiden mice which are known to develop advanced aortic atherosclerotic lesions resembling their human counterparts when exposed to a hypercholesterolemic phenotype as a result of a cholesterol-enriched Western-type diet[27], and to test its suitability as an experimental murine MI-R model with respect to cost effectiveness and practical ease of use
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