Persistent Microvascular Obstruction After Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse Remodeling.

Emerging evidence indicates that persistent microvascular obstruction (PMO) is more predictive of major adverse cardiovascular events than myocardial infarct (MI) size. But it remains unclear how PMO, a phenomenon limited to the acute/subacute period of MI, drives adverse remodeling in chronic MI setting. We hypothesized that PMO resolves into chronic iron crystals within MI territories, which in turn are proinflammatory and favor adverse remodeling post-MI. Canines (n=40) were studied with cardiac magnetic resonance imaging to characterize the spatiotemporal relationships among PMO, iron deposition, infarct resorption, and left ventricular remodeling between day 7 (acute) and week 8 (chronic) post-MI. Histology was used to assess iron deposition and to examine relationships between iron content with macrophage infiltration, proinflammatory cytokine synthesis, and matrix metalloproteinase activation. Atomic resolution transmission electron microscopy was used to determine iron crystallinity, and energy-dispersive X-ray spectroscopy was used to identify the chemical composition of the iron composite. PMO with or without reperfusion hemorrhage led to chronic iron deposition, and the extent of this deposition was strongly related to PMO volume (r>0.8). Iron deposits were found within macrophages as aggregates of nanocrystals (≈2.5 nm diameter) in the ferric state. Extent of iron deposits was strongly correlated with proinflammatory burden, collagen-degrading enzyme activity, infarct resorption, and adverse structural remodeling (r>0.5). Crystallized iron deposition from PMO is directly related to proinflammatory burden, infarct resorption, and adverse left ventricular remodeling in the chronic phase of MI in canines. Therapeutic strategies to combat adverse remodeling could potentially benefit from taking into account the chronic iron-driven inflammatory process.

Kali A ，Cokic I ，Tang R ，Dohnalkova A ，Kovarik L ，Yang HJ ，Kumar A ，Prato FS ，Wood JC ，Underhill D ，Marbán E ，Dharmakumar R ... -  《-》

Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair.

Huang CK ，Dai D ，Xie H ，Zhu Z ，Hu J ，Su M ，Liu M ，Lu L ，Shen W ，Ning G ，Wang J ，Zhang R ，Yan X ... -  《-》

Chronic manifestation of postreperfusion intramyocardial hemorrhage as regional iron deposition: a cardiovascular magnetic resonance study with ex vivo validation.

Kali A ，Kumar A ，Cokic I ，Tang RL ，Tsaftaris SA ，Friedrich MG ，Dharmakumar R ... -  《-》

Modulation of myocardial injury and collagen deposition following ischaemia-reperfusion by linagliptin and liraglutide, and both together.

Studies have indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce infarct size after myocardial ischaemia. Whether these agents modify cardiac remodelling after ischaemia is unclear. Furthermore, it is not known if combination of the two types of drugs is superior to either agent alone. We investigated the modulatory effect of the DPP-4 inhibitor linagliptin alone, the GLP-1 activator liraglutide alone, or the two agents together on myocardial infarct size, left ventricular contractile function and cardiac remodelling signals after a brief period of left coronary artery (LCA) occlusion. C57BL/6 mice were treated with vehicle, the DPP-4 inhibitor linagliptin, the GLP-1 activator liraglutide, or both agents together for 5 days, and then subjected to LCA occlusion (1 h) and reperfusion (3 h). Ischaemia-reperfusion increased reactive oxygen species (ROS) generation and expression of NADPH oxidase (p47(phox), p22(phox) and gp91(phox) subtypes), collagens, fibronectin and proinflammatory cytokines (interleukin 6, tumour necrosis factor α and monocyte chemoattractant protein-1) in the LCA-supplied regions. Pre-treatment with linagliptin or liraglutide reduced infarct size, protected cardiomyocytes from injury and preserved cardiac contractile function in a similar fashion. It is interesting that profibrotic (collagen deposition) signals were expressed soon after ischaemia-reperfusion. Both linagliptin and liraglutide suppressed ROS generation, NADPH oxidase and proinflammatory signals, and reduced collagen deposition. Addition of linagliptin or liraglutide had no significant additive effect above and beyond that of liraglutide and linagliptin given alone. In conclusion, linagliptin and liraglutide can improve cardiac contractile function and indices of cardiac remodelling, which may be related to their role in inhibition of ROS production and proinflammatory cytokines after ischaemia.

Wang X ，Ding Z ，Yang F ，Dai Y ，Chen P ，Theus S ，Singh S ，Budhiraja M ，Mehta JL ... -  《-》

Sphingosine-1-Phosphate Receptor Agonist Fingolimod Increases Myocardial Salvage and Decreases Adverse Postinfarction Left Ventricular Remodeling in a Porcine Model of Ischemia/Reperfusion.

Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for the treatment of multiple sclerosis and exerts antiapoptotic properties. We hypothesized that sphingosine-1-phosphate receptor activation with fingolimod during acute myocardial infarction (MI) inhibits apoptosis, leading to increased myocardial salvage, reduced infarct size, and mitigated left ventricular (LV) remodeling in a porcine model of ischemia/reperfusion. Ischemia/reperfusion was induced in pigs by balloon occlusion of the left anterior descending artery, followed by reperfusion. Animals randomly received fingolimod or saline (control). In short-term experiments, fingolimod treatment activated the cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways in the infarct border zone 24 hours after MI, leading to decreased cardiomyocyte apoptosis and reduced myocardial oxidative stress. These effects were abolished by specific inhibitors of both pathways, demonstrating that fingolimod-induced cardioprotection was mediated by reperfusion injury salvage kinase and survivor activating factor enhancement pathways. In long-term experiments, fingolimod significantly improved myocardial salvage, reduced infarct size, and improved systolic LV function measured by cardiac magnetic resonance 1 week and 1 month after MI. Importantly, fingolimod mitigated the development of adverse post-MI LV remodeling 1 month after MI. Specifically, fingolimod treatment led to a significant reduction in LV mass, LV dilatation, and neurohormonal activation, and it preserved LV geometry. Furthermore, fingolimod decreased interstitial fibrosis, cardiomyocyte hypertrophy, and chronic activation of Akt and extracellular receptor kinase 1/2 in the remote noninfarcted myocardium. Sphingosine-1-phosphate receptor activation with fingolimod during acute MI reduced infarct size via the reperfusion injury salvage kinase and survivor activating factor enhancement pathways, improved systolic LV function, and mitigated post-MI LV remodeling. Our data strongly support a cardioprotective role for sphingosine-1-phosphate receptor activation during MI.

Santos-Gallego CG ，Vahl TP ，Goliasch G ，Picatoste B ，Arias T ，Ishikawa K ，Njerve IU ，Sanz J ，Narula J ，Sengupta PP ，Hajjar RJ ，Fuster V ，Badimon JJ ... -  《-》