Abstract Body (Do not enter title and authors here): Background: Autoimmune diseases affect ~10% of the population, the overwhelming majority of which are women. However, the impact of autoimmune disease, such as systemic lupus erythematosus (SLE), on outcomes following myocardial infarction (MI) are not well understood. Thus, we hypothesized that cardiac function and remodeling would be impaired following MI in a pristane-induced model of SLE. Methods: Adult female C57BL/6J mice were given a single injection of pristane 3 months prior to MI surgery. The left coronary artery was then permanently ligated for either 7, 28, or 56 days (D). Echocardiography was performed to assess cardiac function. Tissues were then collected for flow cytometry, including blood, kidney, and left ventricle (LV), which was separated into infarcted and remote areas. Plasma IgG was assessed by ELISA. LV cytokines were measured by real-time PCR. Results: Development of the SLE phenotype was confirmed by elevated levels of plasma IgG. SLE resulted in worse cardiac function at each time point, including LV dilation (increased internal diameter at diastole and end-diastolic volume), wall thinning, and decreased ejection fraction. SLE mice also had elevated wet lung weights at each time point, an indicator of pulmonary congestion. At D7, mRNA levels of inflammatory cytokines Il6 and Il18 were elevated in the infarct, while Col1a1 and Pecam1 were decreased, indicating impaired remodeling. At D7, SLE mice had increased LV CD45+ cells (p=0.003) and B cells (p=0.056), as well as circulating neutrophils (p=0.047). MI also led to expansion of total CD45+ cells, T cells, monocytes, and neutrophils in the kidney, with SLE exacerbating kidney neutrophil expansion (p=0.01). At D56, SLE mice had increased inflammatory cells in the remote area, including total CD45+ cells (p=0.03), CD3+ T cells (p<0.0001), and CD8+ T cells (p=0.003), and increased kidney CD45+ cells (p=0.03), neutrophils (p=0.002), and monocytes (p<0.0001). To investigate potential mechanisms associated with adverse outcomes in SLE, we measured genes associated with the type I interferon response at in the LV at D7. Ifng, Ifna2, Ifnb1, Ifne, Ifnar1, and Irfs 1, 2, 5, 7, and 9 were increased, but this effect was surprisingly attenuated in SLE. Conclusions: SLE is associated with adverse post-MI outcomes, including cardiac remodeling and inflammation, pulmonary congestion, and renal inflammation. These effects are associated with perturbation of the type I interferon response.