Mechanical Tissue Resuscitation (MTR) activates the RISK pathway and widens the therapeutic window for treating acute myocardial infarction

Abstract

BackgroundReperfusion injury results in the continued loss of myocardial cells following revascularization of ischemic myocardium. Therapeutics which decrease myocardial cell death may improve the morbidity and mortality associated with AMI. MTR has been demonstrated to reduce infarct size when initiated at the time of reperfusion. Here we hypothesize that this therapeutic approach remains efficacious even when the initiated further into reperfusion.MethodsA left, anterior free‐wall ischemic lesion (85 min.) was created using reversible tourniquets in swine. Animals were randomized to receive either no treatment (Control) or MTR (−125 mmHg) beginning 90 min. after reperfusion. Following reperfusion, infarct size (IS), PMN accumulation and activation of the RISK salvage pathway were assessed.ResultsMTR reduced IS (24.2±4.8% vs. 50.3±2.7%, AN/AAR, p< 0.001) with no difference in the AAR (p=0.88). PMN accumulation within the AAR was also reduced by MTR (19.7±2.5 vs. 28.9±4.9 units). MTR increased the phosphorylation of ERK1/2 and AKT in epicardial tissue 2.1‐fold (p<0.01) and 2.0‐ fold (p=0.06), respectively.ConclusionsMTR provides robust protection from MI/R injury by activating the RISK pathway even when initiated 90 min. into reperfusion. This timing defines a clinically relevant window of opportunity for the treatment of MI/R injury and potentially expands the patient population who could derive benefit from such therapeutic intervention.