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Statins Promote Cardiac Infarct Healing by Modulating Endothelial Barrier Function Revealed by Contrast-Enhanced
Geert J Leenders1, Mirjam B Smeets1, Maaike van den Boomen1
1From the Department of Biomedical Engineering, Biomedical NMR, Eindhoven University of Technology, The Netherlands (G.J.L., M.v.d.B., M.N., G.J.S., J.J.P., K.N., K.V.); Laboratory of Experimental Cardiology (M.B.S.) and Department of Cardiology (F.A.), University Medical Center Utrecht, The Netherlands; Department Precision and Decentralized Diagnostics, Philips Research Eindhoven, The Netherlands (M.B., D.v.S.); Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands (G.J.S.); and Department of Cardiology, St. Antonius Hospital Nieuwegein, The Netherlands (F.A.).
Insights
Statins improve heart attack healing by reducing blood vessel leakage and inflammatory cell entry into damaged heart tissue. This enhances recovery and prevents further heart damage after myocardial infarction (MI).
Area of Science:
- Cardiovascular Research
- Endothelial Biology
- Pharmacology
Background:
- Endothelial barrier function is critical for wound healing and is impaired in atherosclerosis preceding myocardial infarction (MI).
- Statins are known to modulate endothelial function beyond lipid-lowering effects.
Purpose of the Study:
- To noninvasively assess the effect of statins on endothelial permeability during the inflammatory and reparative phases of post-MI healing.
- To correlate endothelial permeability with left ventricular (LV) remodeling and functional outcomes.
Main Methods:
- Contrast-enhanced cardiac magnetic resonance imaging (MRI) for noninvasive permeability mapping in mouse models (C57BL/6, ApoE-/-) with and without statin treatment.
- Correlation of MRI findings with LV volumetry, histology, flow cytometry, and gene expression (Vegfa, Angpt1) in infarct regions.
Main Results:
- Atherosclerotic (ApoE-/-) mice exhibited increased infarct vascular permeability compared to controls, predicting greater LV dilation.
- Statin treatment significantly reduced infarct vascular permeability in ApoE-/- mice, indicating improved endothelial barrier function.
- Statins normalized the unbalanced Vegfa/Angpt1 expression ratio and reduced inflammatory leukocyte infiltration (CD45+, LY6Chi monocytes) in the infarct zone.
Conclusions:
- Statins effectively lower vascular permeability in the infarcted myocardium, thereby reducing the influx of detrimental inflammatory leukocytes.
- Improved endothelial barrier function and reduced inflammation mediated by statins contribute to better left ventricular outcomes post-MI.
Objective:
The endothelium has a crucial role in wound healing, acting as a barrier to control transit of leukocytes. Endothelial barrier function is impaired in atherosclerosis preceding myocardial infarction (MI). Besides lowering lipids, statins modulate endothelial function. Here, we noninvasively tested whether statins affect permeability at the inflammatory (day 3) and the reparative (day 7) phase of infarct healing post-MI using contrast-enhanced cardiac magnetic resonance imaging (MRI).
Approach And Results:
Noninvasive permeability mapping by MRI after MI in C57BL/6, atherosclerotic ApoE-/-, and statin-treated ApoE-/- mice was correlated to subsequent left ventricular outcome by structural and functional cardiac MRI. Ex vivo histology, flow cytometry, and quantitative polymerase chain reaction were performed on infarct regions. Increased vascular permeability at ApoE-/- infarcts was observed compared with C57BL/6 infarcts, predicting enhanced left ventricular dilation at day 21 post-MI by MRI volumetry. Statin treatment improved vascular barrier function at ApoE-/- infarcts, indicated by reduced permeability. The infarcted tissue of ApoE-/- mice 3 days post-MI displayed an unbalanced Vegfa(vascular endothelial growth factor A)/Angpt1 (angiopoetin-1) expression ratio (explaining leakage-prone vessels), associated with higher amounts of CD45+ leukocytes and inflammatory LY6Chi monocytes. Statins reversed the unbalanced Vegfa/Angpt1 expression, normalizing endothelial barrier function at the infarct and blocking the augmented recruitment of inflammatory leukocytes in statin-treated ApoE-/- mice.
Conclusions:
Statins lowered permeability and reduced the transit of unfavorable inflammatory leukocytes into the infarcted tissue, consequently improving left ventricular outcome.
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