Effects on cardiac function, remodeling and inflammation following myocardial ischemia–reperfusion injury or unreperfused myocardial infarction in hypercholesterolemic APOE*3-Leiden mice

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.

Phosphorylcholine antibodies restrict infarct size and left ventricular remodelling by attenuating the unreperfused post‐ischaemic inflammatory response

“… 43 This underscores the complex interplay between different mechanisms of ischaemia and concomitant luxating cardiovascular risk factors and the necessity of selecting appropriate experimental models to investigate hypotheses correctly. 50 Following unreperfused MI, we showed that PC‐mAb therapy compared to control reduces circulating monocytes, accompanied by a reduced IS and restricted LV dilatation.…”

“…Additionally, myocardial ischaemia‐reperfusion injury in hypercholesterolaemic APOE*3‐Leiden mice preceded by a pre‐ischaemic Ly‐6C hi monocytosis resulted in a decreased LV function as well, but was paradoxically coinciding with a reduced IS 43 . This underscores the complex interplay between different mechanisms of ischaemia and concomitant luxating cardiovascular risk factors and the necessity of selecting appropriate experimental models to investigate hypotheses correctly 50 . Following unreperfused MI, we showed that PC‐mAb therapy compared to control reduces circulating monocytes, accompanied by a reduced IS and restricted LV dilatation.…”

“…Previously, we demonstrated PC‐mAb treatment to additionally preserve cardiac function following myocardial ischaemia‐reperfusion injury, 41 suggesting a point of no return regarding preservation of cardiac function in the absence of reperfusion, endorsing the relevance and impact of selecting different models of myocardial ischaemia. 50 …”

Post-ischemic Myocardial Inflammatory Response: A Complex and Dynamic Process Susceptible to Immunomodulatory Therapies

“…Below, anti-inflammatory and immunomodulatory therapies will be briefly highlighted. In addition, the selection of an appropriate animal model to ensure optimal translation of novel cardioprotective therapies from bench-to-bedside is of the utmost importance ( 248 , 249 ), ideally allowing for an atherosclerotic phenotype and myocardial ischemia–reperfusion injury ( 250 ).…”

Toll-Like Receptor 4 Activation Prevents Rat Cardiac Fibroblast Death Induced by Simulated Ischemia/Reperfusion

“…A recent report indicated that TLR4 deficiency contributes to less myocardial injury and inflammatory symptoms after the induction of I/R (29). The inflammatory reaction is a key hallmark of I/R, and its modulation has been shown to be beneficial in previous investigations (30,31). Specifically, the TLR4/NF-κB signaling pathway plays a pivotal role in I/R injury, promoting a marked expression of proinflammatory cytokines in cardiomyocytes under I/R conditions (32).…”