Abstract 452: Primary Left Ventricular Unloading Reduces Infarct Size by Increasing Myocardial Levels of Stromal Derived Factor One Alpha (SDF1a) in Acute Myocardial Infarction

Abstract

Stromal derived factor 1 alpha (SDF1a) is a constitutively expressed cardioprotective chemokine that is rapidly degraded by proteases. We reported that compared to Primary Reperfusion (PR), first reducing myocardial oxygen demand by activating a trans-valvular pump (Impella CP) while delaying coronary reperfusion (Primary Unloading; PU) reduces infarct size in acute myocardial infarction (AMI). We now hypothesize that PU reduces proteolytic degradation of SDF1a thereby increasing SDF1a signaling via the receptor CXCR4 in AMI. Methods: AMI was induced by occlusion of the left anterior descending artery (LAD) for 90 min in male swine (n=4/group). In the PR group, the LAD was reperfused for 120 min. In the PU group, after 90 min of ischemia an Impella CP was activated and the LAD left occluded for an additional 30 min, followed by 120 min of reperfusion. Whole-transcript expression analysis was performed on RNA from the infarct zone using Porcine 1.0 ST microarrays and ConsensusPathDB programs. Quantitative polymerase chain reaction, western blots, and activity assays determined expression and activity of the SDF1a signaling pathway. Sham operated LV samples served as controls. Results: Compared to PR, PU reduced fibrotic and inflammatory gene expression including reduced transcript levels of matrix-metalloprotease-2 (MMP2), MMP9 and dipeptidyl peptidase-4 (DPP4). Compared to PR, PU increased SDF1a protein levels within the infarct zone. Gel zymography confirmed reduced activity levels of MMP2 and MMP9 within the infarct zone after PU, not PR. Compared to PR, PU attenuated DPP4 protein levels and activity and protein levels of CXCR7, an SDF1a sequestration receptor, within the infarct zone. To explore a functional role for SDF1a in PU, adult male swine received intra-coronary injections of AMD3100, a CXCR4 receptor antagonist, after Impella CP activation. Loss of CXCR4 activity attenuated cardioprotective signaling via Akt, Erk and GSK3b and increased infarct size compared to vehicle treated controls. Conclusion: We introduce a novel mechanism by which PU limits proteolytic degradation and CXCR7 mediated sequestration of SDF1a, thereby increasing cardioprotective signaling via SDF1a and overcoming a critical barrier to SDF1a therapeutics in AMI.