Abstract
The β1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. The prevailing view has been that metoprolol acts mainly on cardiomyocytes. Here, we demonstrate that metoprolol reduces reperfusion injury by targeting the haematopoietic compartment. Metoprolol inhibits neutrophil migration in an ADRB1-dependent manner. Metoprolol acts during early phases of neutrophil recruitment by impairing structural and functional rearrangements needed for productive engagement of circulating platelets, resulting in erratic intravascular dynamics and blunted inflammation. Depletion of neutrophils, ablation of Adrb1 in haematopoietic cells, or blockade of PSGL-1, the receptor involved in neutrophil–platelet interactions, fully abrogated metoprolol’s infarct-limiting effects. The association between neutrophil count and microvascular obstruction is abolished in metoprolol-treated AMI patients. Metoprolol inhibits neutrophil–platelet interactions in AMI patients by targeting neutrophils. Identification of the relevant role of ADRB1 in haematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.
Highlights
The b1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients
We show that pre-reperfusion administration of i.v. metoprolol to AMI patients significantly reduces the incidence of microvascular obstruction (MVO), and that metoprolol inhibits deleterious neutrophil inflammatory responses both in patients and in animal models of IR
We found a significant interaction between metoprolol treatment and the correlation between leukocyte count and MVO: the significant positive correlation between neutrophil count and the extent of MVO was only present in control patients; in patients receiving i.v. metoprolol before reperfusion there was no sign of association between total leukocyte or neutrophil counts and the extent of MVO (Fig. 2c,d)
Summary
The b1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. Neutrophils bind to platelets and red blood cells, forming plugs[7] Upon reperfusion, these plugs are dispersed into the microcirculation, where they form embolisms, precluding tissue perfusion despite blood flow restoration in the large coronary arteries. These plugs are dispersed into the microcirculation, where they form embolisms, precluding tissue perfusion despite blood flow restoration in the large coronary arteries This phenomenon, known as microvascular obstruction (MVO), is a major contributor to IR injury and infarct size[1]. The beneficial effects of metoprolol are abolished by genetic ablation of Adrb[1] and are rescued by restitution of Adrb[1] expression only in haematopoietic cells These results identify the neutrophil dynamics as the target of the cardioprotective effect of metoprolol against myocardial IR injury
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