Abstract 19308: Metoprolol Protects Against AMI Through the Inhibition of Psgl1-Dependent Neutrophil-platelet Interactions
Introduction: Early intravenous administration of metoprolol has been shown to reduce infarct size and improve long-term cardiac function in the randomized clinical trial METOCARD-CNIC led by our group. However, the mechanisms underlying its favorable benefits remain unclear. PSGL1-dependent neutrophil-platelet interactions have critical implications on microvascular obstruction and neutrophil infiltration both of which determine the extent of infarct size. We hypothesized that intravenous administration of metoprolol before reperfusion blocks neutrophil-platelet interactions formation limiting the extent of infarct size.
Methods & Results: Using a mouse model of myocardial ischemia/reperfusion injury we confirmed that intravenous metoprolol administration prior to reperfusion significantly reduces infarct size. Neutrophil migration and infiltration evaluated in the injured myocardium after 6h of reperfusion was reduced in metoprolol’s treated mice. Neutrophil depletion, lack of beta-1-adrenergic receptor and PSGL1 blockade abrogated metoprolol’s cardioprotective effect. Interestingly, restitution of β1AR expression in circulating cells rescues the metoprolol′s cardioprotection. With a model of intravital microscopy we showed metoprolol systemic administration reduces neutrophil-platelet interactions after TNFα local inflammation. Additionally, metoprolol was capable to reduce epinephrine-induced neutrophil-platelet coaggregates formation in human blood. Finally, the extent of microvascular obstruction evaluated by cMRI in METOCARD-CNIC patients was significantly reduced by the pre-reperfusion administration of metoprolol.
Conclusion: Intravenous administration of metoprolol exerts cardioprotection against AMI by inhibiting acute deleterious neutrophil-platelet interactions at reperfusion.
Author Disclosures: J. Garcia-Prieto: None. I. Garcia-Lunar: None. M. Gomez-Parrizas: None. R. Fernandez-Jimenez: None. G. Pizarro: None. V. Sreeramkumar: None. R. Villena-Gutierrez: None. R. Martinez-Bourio: None. A. Hidalgo: None. V. Fuster: None. B. Ibanez: None.
- © 2015 by American Heart Association, Inc.