Abstract

Purpose: Infarct Size (IS) and No-Reflow (NR) are important clinical prognosticators of left ventricular (LV) remodeling and dysfunction after acute myocardial infarction (AMI) and both represent important therapeutic targets. Vagal nerve stimulation (VNS) may offer a novel cardioprotective treatment strategy for additional infarct size limitation during reperfusion therapy. VNS was recently shown to limit infarct size in rodents when started prior to, or at the very onset of ischemia. However, its effects on infarct size and no-reflow, have not been investigated in a translational ischemia-reperfusion model. Accordingly, we validated the effects of VNS on infarct size and no-reflow in a porcine model using a translational protocol with treatment starting just prior to reperfusion. Methods: Anesthetized pigs (10 Control, 13 VNS) underwent mid LAD occlusion for 45 min followed by reperfusion. All pigs received a cuff electrode around the left and right cervical vagal trunk but only in VNS pigs, stimulation was started 5 min prior to reperfusion and continued for 20 min. After 120 min of reperfusion, infarct size (% area at risk) and no-reflow (% IS) were assessed using tetrazolium and thioflavin S staining, respectively. Hemodynamics, metabolic and regional function were evaluated as well. Results: VNS decreased heart rate (19±2%, p=0.001) and cardiac output (19±2%, p=0.02) compared with controls, without increasing adverse cardiac events. At the end of the reperfusion period, VNS did not affect systemic hemodynamics, myocardial metabolism or global and regional LV function. The areas at risk were comparable between Control and VNS (26±1% and 27±1% of LV, p=0.60). VNS significantly reduced infarct size compared with controls (67±2% and 54±5% of IS, p=0.03). In addition, VNS was associated with a significant reduction of no-reflow (from 54±6% to 32±6% of IS; p=0.03). No correlation was observed between infarct size or no-reflow reductions and decrease in heart rate (p=0.12 and p=0.19). Conclusions: The present study demonstrates for the first time that the application of VNS during early reperfusion limits infarct size and no-reflow, independent of bradycardia, in a large animal model of ischemia-reperfusion. Thus, VNS may offer a novel, safe and feasible adjunctive therapy of AMI.

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