Arg389Gly beta-1-adrenergic receptor polymorphism determines neutrophil-stunning-associated cardioprotection by metoprolol

Abstract

Abstract Background Cardioprotective strategies to limit infarct size (IS) have become crucial. The damaged inflicted on the myocardium is the result of the processes of Ischemia and Reperfusion (I/R). In the clinical trial METOCARD-CNIC, it was shown that the intravenous (i.v.) pre-reperfusion administration of the β1-selective antagonist metoprolol reduces IS and improves long-term cardiac function in patients after acute myocardial infarction (1). However, the small sample size precludes a definite conclusion. Despite not having demonstrated a solid clinical benefit in terms of hard endpoints reduction, the clinical guidelines for the management of ST-Elevation Myocardial Infarction (STEMI) recommend the early administration of i.v. β-blockers in patients undergoing Primary Coronary Intervention. Additionally, our group has recently described that the beneficial effect of metoprolol against myocardial I/R injury is due to neutrophil stunning (2), which represents a one-of-a-kind property not shared by other i.v. β-blockers, such as atenolol or propranolol (3). Purpose Since β1-adrenergic receptor (ADRB1) is one of major targets of pharmacological therapy, great efforts are now underway to account for the relevance of the polymorphic variation. Here we explore whether the cardioprotection exerted by metoprolol is dependent on genetic polymorphisms in human ADRB1. Methods Patients included in the METOCARD-CNIC trial were grouped into the different variants for the ADRB1, rs1801252 and rs1801253 (SerGly49 and Arg389Gly, respectively), which might affect their response to the beta-1 modulation exerted by metoprolol on neutrophils and thus its cardioprotective effect. Additionally, the polymorphic-dependent effect of metoprolol on neutrophil migration was evaluated in healthy volunteers, whose neutrophils were exposed across the transwell filter to the CXCL1 in the presence or absence of metoprolol. Drug-receptor interaction properties were evaluated in silico. Results We found that Arg389Gly polymorphism of the human ADRB1 impacts the cardioprotective effect of metoprolol in STEMI patients. Therefore, Arg389 homozygosity was associated with lower infarcts (Figure 1) and better long-term left ventricle ejection fraction when metoprolol was intravenously administered prior reperfusion. Moreover, the disrupting effect of metoprolol on neutrophil migration was only observed in Arg389 homozygote volunteers (Figure 2). These differences were attributed to alterations in the drug-receptor complex stability when Gly residues are present in position 389 of the ADRB1. Conclusions From our perspective, these results are the first showing a polymorphic implication in drug response against myocardial I/R injury. All the data presented refine cardiovascular pharmacotherapy, and have major implications for the prospective clinical trial design aiming at positioning metoprolol as the beta-blocker of choice to reduce hard endpoints in STEMI patients.CardioprotectionNeutrophil migration