Abstract
Early metoprolol administration protects against myocardial ischemia–reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.
Highlights
Despite major improvements in reperfusion strategies and coadjuvant therapies, myocardial infarction (MI) remains a leading cause of mortality and morbidity worldwide [21, USA1 3 Vol.:(0123456789) 55 Page 2 of 11Basic Research in Cardiology (2020) 115:5530]
Pooling of data from all ischemia duration protocols revealed that pigs receiving i.v. metoprolol had significantly higher long-term LVEF than those injected with vehicle (Fig. 8)
Using a pig model of reperfused ST-elevation MI (STEMI), we have shown that early i.v. injection of metoprolol is able to delay the time-dependent progression of irreversible myocardial damage
Summary
Since the extent of irreversible injury progresses in a time-dependent manner, early blood flow restoration (reperfusion) is associated with lower IS, and this translates into better long-term outcomes [3, 33]. Interventions to delay the progression of ischemic damage could theoretically extend the 120 min window for selecting PPCI over fibrinolysis, allowing more patients to benefit from the best reperfusion strategy. The fact that i.v. metoprolol reduced IS only when injected long before reperfusion suggests that it might slow the rate of ischemic death (i.e. infarction progression) To address this question, we studied the trajectories of IS progression in the presence or absence of i.v. metoprolol in a pig model of STEMI. All pigs underwent cardiac magnetic resonance (CMR) imaging examinations at 7 and 45 days after STEMI induction
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