Abstract Body: Myocardial infarction (MI) is the most common cause of heart failure worldwide. Despite significant improvement in survival due to reperfusion therapy, progressive ventricular dilation, wall thinning, and mortality lead to heart failure. The substrate for this process likely occurs in the acute phase following MI as necrotic myocardium is replaced with inflamed granulation and scar tissue. Though necessary for proper wound healing, inflammation contributes to infarct expansion. We previously discovered that the type I interferon (IFN) response of the innate immune system promotes ventricular dilation and rupture. Here, we present results of spatial transcriptomics analysis of the IFN response to MI, which shows unexpected clustering at the borderzone (BZ).
We performed coronary artery ligation of wildtype (WT) and Irf3-KO mice (which lack the transcription factor needed to mount a type I IFN response) and monitored them from day 3 to day 7 post-MI during the window of susceptibility to ventricular rupture. Mice that spontaneously ruptured were rapidly collected and freeze-embedded to maintain the integrity of the transcriptome. Spatial transcriptomics revealed clustered IFN responses that localized to the BZ as well as immediately adjacent to sites of ventricular rupture as measured by moran’s I test statistic for Ifit1, Ifit3, and Rsad2 transcripts (0.39±0.061 vs. 0.04±0.012, p=0.04; 0.35±0.2 vs. 0.019±0.1, p=.019; 0.34±0.07 vs. 0.018±0.1, p=.018). By comparison, Irf3-KO mice had minimal clustered IFN responses and survival was markedly improved.
We next characterized the transcriptional niche underlying the sites of rupture by labeling the remote zone (RZ), borderzones (BZ1 and BZ2), and the ischemic zone (IZ) using summed counts of gene set scores derived from our published single-nuclei RNA-sequencing data. We find that the clustered IFN response at sites of ventricular rupture correlated most highly with mechanotransduction genes of BZ2 that directly borders the IZ (r=.83, p<0.001). Spatial transcriptomic analysis of IFN clusters in unruptured, infarcted hearts correlated most highly with actin organization transcripts of BZ1 or macrophage transcripts of IZ (r=.74, p<.001; r=.68, p<.001). Taken together, our data suggests that the clustered IFN response at mechanically sensitive hinge points between live and dead myocardium promotes catastrophic ventricular rupture of the infarcted heart.