Abstract P2124: Trans-valvular Unloading Protects Against Post-reperfusion Injury Via Hif-1a In Preclinical Models Of Acute Myocardial Infarction.

Abstract

Acute myocardial infarction (AMI) is a major cause of heart failure and mortality worldwide. Reducing left ventricular (LV) workload using a trans-valvular pump (TVP) and delaying reperfusion for 30 minutes reduces infarct size by 50% in preclinical models and is currently under clinical investigation. We hypothesized that LV unloading limits myocardial injury by activating hypoxia inducible factor 1-α (HIF-1α). Myocardial ischemia was induced by percutaneous balloon occlusion of the left anterior descending (LAD) artery for 90 minutes in adult male swine. The detailed study design is shown in Fig A. In Group A and B, no infarct was observed with or without TVP. In Groups C and D, infarct size was significantly lower with TVP activation (Fig B). During LAD occlusion without reperfusion, HIF-1α levels increased within the infarct zone (Group A), but were significantly lower with TVP activation (Group B). After reperfusion, HIF-1α levels decreased in Group C, but paradoxically, increased with TVP support (Group D; Fig C). To test whether HIF1α mediates cardioprotection with LV unloading, adult swine were treated with intracoronary delivery of a HIF-1α inhibitor (2-methoxyestradiol; 2ME) before reperfusion. Compared to DMSO-treated controls, 2ME increased infarct size despite LV unloading (Fig D). Conversely, compared to reperfusion alone, intracoronary delivery of a HIF-1α stabilizing agent (Roxadustat) before reperfusion significantly decreased infarct size both in the presence and absence of a TVP (Fig E). We identified a novel functional role for HIF-1α as a critical mediator of the cardioprotective effects associated with trans-valvular unloading before reperfusion.