Key result
Acute MI drives several-fold higher remote aortic endothelial and platelet activation in atherosclerotic mice.
Why the study?
Risk for acute atherothrombotic events in non-culprit arteries increases after acute MI, but the mechanisms of sustained pro-inflammatory endothelial alterations in remote vessels are unclear.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“However, despite these advances in knowledge, the current study leaves a number of unanswered questions. In particular, the study does not determine the actual mechanism (or mechanisms) for remote EC activation post-MI. For example, adhesion molecule expression was measured in the aorta, and MI might have reduced aortic blood flow velocity leading to lower endothelial shear stress (ESS), which has profound effects on EC function. Low ESS enhances expression of EC adhesion molecules and promotes monocyte adhesion, which in turn augment local inflammation and accelerate plaque growth.”
“Knowing that newer forms of antioxidants such as apocynin can lower the risk of a second heart attack or stroke gives us a new treatment to explore and could one day help reduce heart attacks and strokes.”
Acute myocardial infarction stimulates sustained pro-inflammatory and pro-thrombotic alterations in remote arterial endothelium, which persist longer in hyperlipidemia and are attenuated by Nox inhibition.
Background In the months after acute MI, risk for acute atherothrombotic events in non-culprit arteries increases several fold. Objectives We hypothesized that sustained pro-inflammatory and pro-thrombotic endothelial alterations occur in remote vessels after MI. Methods We studied wild type mice, atherosclerotic mice with double knockout (DKO) of the LDL receptor and Apobec-1, and DKO mice treated with the Nox-inhibitor apocynin were studied at baseline and 3 and 21 days after closed-chest MI. Ultrasound molecular imaging of P-selectin, VCAM-1, von Willebrand factor (VWF) A1-domain, and platelet GPIbα was performed. Intravital microscopy was used to characterize post-MI leukocyte and platelet recruitment in the remote microcirculation after MI. Results Aortic molecular imaging for P-selectin, VCAM-1, VWF-A1, and platelets was increased several fold (p<0.01) three days post-MI for both wild-type and DKO mice. At 21 days, these changes resolved in wild-type mice but persisted in DKO mice. Signal for platelet adhesion was abolished 1 hour after administration of ADAMTS13 which regulates VWF multimerization. In DKO and wild-type mice, apocynin significantly attenuated the post-MI increase for molecular targets, and platelet depletion significantly reduced P-selectin and VCAM-1 signal. On intravital microscopy, MI resulted in remote vessel leukocyte adhesion and platelet string or net complexes. On histology, high-risk inflammatory features in aortic plaque increased in DKO mice 21 days post-MI which were completely prevented by apocynin. Conclusions Acute MI stimulates a spectrum of changes in remote vessels including upregulation of endothelial inflammatory adhesion molecules, and platelet-endothelial adhesion from endothelial-associated VWF multimers. These remote arterial alterations persist longer in the presence of hyperlipidemia, are associated with accelerated plaque growth and inflammation, and are attenuated by Nox inhibition.
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Moccetti et al. (2018) studied Myocardial Infarction and Atherosclerosis (Preclinical model). Closed-chest myocardial infarction vs. Sham procedure was evaluated on Aortic molecular imaging signal for P-selectin, VCAM-1, VWF-A1, and platelets (increased several fold, p=<0.01). Acute myocardial infarction significantly increased remote aortic molecular imaging signals for P-selectin, VCAM-1, VWF-A1, and platelets several-fold (p<0.01) at 3 days, which persisted at 21 days in atherosclerotic mice.
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