Editors' ChoiceCardiology

Stunning neutrophils changes the forecast: No more showers

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Science Translational Medicine  03 May 2017:
Vol. 9, Issue 388, eaan3775
DOI: 10.1126/scitranslmed.aan3775

Abstract

Metoprolol inhibits neutrophil-platelet interactions and reduces microvascular obstructions after acute myocardial infarction.

Patients who present with a heart attack caused by coronary artery obstruction are almost universally treated with metoprolol because it improved outcomes in early clinical trials. The drug is a selective β-1 adrenergic receptor (AdrB1) blocker that is thought to provide benefit by reducing the frequency and force of cardiac contraction, thereby reducing oxygen demand in the setting of limited supply. Unfortunately, when occluded vessels are reperfused with catheter-based angioplasty as standard treatment after a heart attack, showering microemboli and formation of neutrophil-platelet plugs can cause microvascular obstruction (MVO), which increases the extent of injury and the risk of developing heart failure.

García-Prieto et al. now report that metoprolol reduces infarct size and MVO not by targeting heart muscle cells but instead by targeting neutrophils, the first responders of the innate immune system. After adjusting for baseline characteristics and infarct size, metoprolol treatment immediately prior to reperfusion was associated with 24% less MVO based on analysis of human cardiac MRIs from a clinical trial of heart attack patients. Peripheral blood neutrophil counts correlated with the extent of MVO only in patients in the placebo arm of the trial. This prompted the authors to examine whether metoprolol influences neutrophils in a mouse model of cardiac ischemia-reperfusion. Giving metoprolol 10 min prior to reperfusion reduced microscopic evidence of neutrophil-containing microvascular plugs, as well as overall infarct size. In contrast, metoprolol had no effect in mice that had been depleted of neutrophils (using anti-Ly6G antibodies) or in mice genetically deficient in AdrB1 (Adrb1–/–). Bone marrow chimeras involving wild-type and Adrb1–/– mice reinforced the findings by revealing the metoprolol-dependent cell to be of hematopoietic origin. Mechanistic studies using genetic or pharmacologic AdrB1 blockade inhibited in vitro and in vivo neutrophil migration, oxidative bursting, and neutrophil-platelet interactions. Taken together, the authors propose that metoprolol reduces MVO by “stunning” neutrophils: inhibiting their migration, reducing their microvascular abundance, and limiting their ability to precipitate microvascular plug formation.

Metoprolol is a widely prescribed drug with a decades-old safety record. Its newfound ability to modulate neutrophil abundance and function prompts consideration of which clinical settings it might provide benefit (treatment of excessive inflammation) and which it might present obstacles (neutrophil-dependent clearance of infections). As for the heart, its ability to reduce MVO is a stunningly pleasant surprise.

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