The cardioprotection granted by metoprolol is restricted to its administration prior to coronary reperfusion

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Abstract

Background

Myocardial infarct size is a strong predictor of cardiovascular events. Intravenous metoprolol before coronary reperfusion has been shown to reduce infarct size; however, it is unknown whether oral metoprolol initiated early after reperfusion, as clinical guidelines recommend, is similarly cardioprotective. We compared the extent of myocardial salvage associated with intravenous pre-reperfusion-metoprolol administration in comparison with oral post-reperfusion-metoprolol or placebo. We also studied the effect on suspected markers of reperfusion injury.

Methods

Thirty Yorkshire-pigs underwent a reperfused myocardial infarction, being randomized to pre-reperfusion-metoprolol, post-reperfusion-metoprolol or placebo. Cardiac magnetic resonance imaging was performed in eighteen pigs at day 3 for the quantification of salvaged myocardium. The amounts of at-risk and infarcted myocardium were quantified using T2-weighted and post-contrast delayed enhancement imaging, respectively. Twelve animals were sacrificed after 24 h for reperfusion injury analysis.

Results

The pre-reperfusion-metoprolol group had significantly larger salvaged myocardium than the post-reperfusion-metoprolol or the placebo groups (31 ± 4%, 13 ± 6%, and 7 ± 3% of myocardium at-risk respectively). Post-mortem analyses suggest lesser myocardial reperfusion injury in the pre-reperfusion-metoprolol in comparison with the other 2 groups (lower neutrophil infiltration, decreased myocardial apoptosis, and higher activation of the salvage-kinase phospho-Akt). Salvaged myocardium and reperfusion injury pair wise comparisons proved there were significant differences between the pre-reperfusion-metoprolol and the other 2 groups, but not among the latter two.

Conclusions

The intravenous administration of metoprolol before coronary reperfusion results in larger myocardial salvage than its oral administration initiated early after reperfusion. If confirmed in the clinical setting, the timing and route of β-blocker initiation could be revisited.

Introduction

The intravenous (i.v.) administration of the β-blocker metoprolol during ongoing ischemia has been shown to increase myocardial salvage [1]. However, the mechanisms responsible for the observed cardioprotection remain elusive. Clinical guidelines recommend the oral administration of β-blockers in patients with acute myocardial infarction (MI) [2]; though, whether the oral administration of metoprolol, initiated early after coronary reperfusion, as current clinical practice guidelines recommend [2], exerts similar effect on myocardial salvage is also unknown.

Indirect evidence suggest that the early i.v. initiation of β-blockers before mechanical reperfusion result in less cardiovascular events and improved myocardial recovery [3], however a study systematically comparing the pre-reperfusion β-blocker administration vs. the oral post-reperfusion route of administration is lacking. The understanding of the impact of the time of β-blocker initiation may have clinical implications, since the early i.v. route of β-blocker initiation is not encouraged [2], [4].

Recent literature supports the notion that metoprolol can block the migration of neutrophils both in vitro [5] and in vivo [6], and also display antiapoptotic properties in different conditions like heart failure [7]. Both mechanisms (neutrophil infiltration and apoptosis) have been proposed as major contributors to reperfusion injury [8], [9]. Therefore, we hypothesized that the cardioprotective effect of metoprolol could be mediated via reduction in reperfusion injury, and therefore restricted to its administration before the restoration of coronary flow.

The aims of the present work were to compare the extent of myocardial salvage associated with the pre-reperfusion i.v. administration of metoprolol in comparison with its oral post-reperfusion initiation. We additionally studied the effect of metoprolol administration on suspected markers of myocardial reperfusion injury.

Section snippets

Study design

A reperfused anterior MI was induced in thirty male Yorkshire Albino pigs (weight 28 ± 0.5 kg). Animals were randomized 1:1:1 to 1) i.v. metoprolol before reperfusion followed by oral metoprolol after reperfusion (pre-reperfusion-metoprolol group), 2) i.v. placebo before reperfusion followed by oral metoprolol after reperfusion (post-reperfusion-metoprolol group) or 3) i.v. placebo before reperfusion alone (placebo group). Eighteen animals underwent cardiac magnetic resonance imaging (MRI) 72 h

Results

All three groups showed a similar mean heart rate during the procedure (66 ± 2, 69 ± 3 and 66 ± 3 bpm for the pre-reperfusion-, post-reperfusion-metoprolol and placebo groups, respectively; P = NS).

Discussion

Myocardial infarct size has been shown to be a strong predictor of cardiovascular events [16]. Beyond early reperfusion (the major determinant of cardioprotection [17]), therapies that can reduce the size of MI are strongly needed [18].

β-blockers are of clinical value in the setting of acute MI, with a large body of evidence showing mortality reductions when administered early [19]. The use of oral β-blockade constitutes a class I indication in clinical practice guidelines [20]; however, its

Conclusions

In an animal model of acute myocardial infarction, we have studied the effect of metoprolol on myocardial infarct size and on suspected markers of reperfusion injury. Here we show that the cardioprotective effect of metoprolol, as evaluated 3 days post-AMI, is restricted to its administration prior to reperfusion (during ongoing ischemia). The cardioprotection granted by the intravenous pre-reperfusion-metoprolol administration was associated with a significant reduction in myocardial apoptosis

Acknowledgements

BI was granted by the Working Group on Ischemic Heart Disease of the Spanish Society of Cardiology, SP by a Fellowship of Fundación CajaMadrid, and GV is a Juan de la Cierva investigator of MEC. GV and LB are members of CIBEROBN-Institute Carlos III and are funded by PNS 2006-10091 from MEC, Spain.

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [30].

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