Perioperative elafin for ischaemia-reperfusion injury during coronary artery bypass graft surgery: a randomised-controlled trial

Abstract

BackgroundElafin is a potent endogenous neutrophil elastase inhibitor that protects against myocardial inflammation and injury in preclinical models of ischaemic-reperfusion injury. We investigated whether elafin could inhibit myocardial ischaemia-reperfusion injury induced during coronary artery bypass graft (CABG) surgery.Methods and resultsIn a randomised double-blind placebo-controlled parallel group clinical trial, 87 patients undergoing CABG surgery were randomised 1:1 to intravenous elafin 200 mg or saline placebo administered after induction of anaesthesia and prior to sternotomy. Myocardial injury was measured as cardiac troponin I release over 48 h (area under the curve (AUC)) and myocardial infarction identified with MRI. Postischaemic inflammation was measured by plasma markers including AUC high-sensitive C reactive protein (hs-CRP) and myeloperoxidase (MPO). Elafin infusion was safe and resulted in >3000-fold increase in plasma elafin concentrations and >50% inhibition of elastase activity in the first 24 h. This did not reduce myocardial injury over 48 h (ratio of geometric means (elafin/placebo) of AUC troponin I 0.74 (95% CI 0.47 to 1.15, p=0.18)) although post hoc analysis of the high-sensitive assay revealed lower troponin I concentrations at 6 h in elafin-treated patients (median 2.4 vs 4.1 μg/L, p=0.035). Elafin had no effect on myocardial infarction (elafin, 7/34 vs placebo, 5/35 patients) or on markers of inflammation: mean differences for AUC hs-CRP of 499 mg/L/48 h (95% CI −207 to 1205, p=0.16), and AUC MPO of 238 ng/mL/48 h (95% CI −235 to 711, p=0.320).ConclusionsThere was no strong evidence that neutrophil elastase inhibition with a single-dose elafin treatment reduced myocardial injury and inflammation following CABG-induced ischaemia-reperfusion injury.Trial registration number(EudraCT 2010-019527-58, ISRCTN82061264).

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

“…Elafin is a neutrophil elastase inhibitor that reverses severe PH in rats and improves angiogenesis in IPAH/HPAH PAEC by enhancing BMPR2 signaling in a caveolin-1-dependent manner (3). Elafin has been used in patients without PAH as a single-dose intravenous therapy (21) and is being developed for chronic subcutaneous administration in patients with PAH. In PAEC and iPSC-EC from two patients with IPAH/HPAH, Elafin and FK506 improved angiogenesis as judged by number of tubes and tube length, whereas in the other five patients, there was no change in either cell type ( Figures 3A and 3B).…”

Transcriptomic Analysis of the Association Between Diabetes Mellitus and Myocardial Infarction

“…PI3/elafin (peptidase inhibitor 3), a potent neutrophil serine proteinase inhibitor, plays an important role in preventing excessive tissue injury during inflammatory events [19]. It is reported that elafin protects against myocardial inflammation and injury in preclinical models of ischemic-reperfusion injury [26]. Mice investigation shows overexpression of elafin improves the cardiac function of MI mice [27].…”

Inflammation Activation Contributes to Adipokine Imbalance in Patients with Acute Coronary Syndrome

“…Since that inflammation is implicated as a bridging factor between ACS attack and adipokine imbalance in this study, another clinical setting likely predisposing to adipokine imbalance should be considered. Because that ischemia/reperfusion injury represents an acute attack [ 21 , 22 ], it is likely that inflammation could be activated in CHD patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) [ 19 – 21 ], which would lead to adipokine imbalance by the two revascularization procedures. And if so, statin pre-treatment before PCI/CABG is believed to reduce the incidence of adipokine imbalance.…”