Characterization of the post-myocardial infarction immune responses in aged mice

Aging, a major risk factor for cardiovascular diseases, is often accompanied by systemic alterations of the immune system such as the accumulation of terminally differentiated T cells, a reduction in naïve T cells and an overregulated production of pro-inflammatory cytokines. Several longitudinal studies could show the correlation between advanced immunosenescence and cardiovascular risk. Yet, how this alteration in the immune system impacts post-myocardial infarction repair and outcome is still to be investigated. To characterize the post-MI immune response in aged C57BL6/J mice, we performed echocardiography assessments, and in parallel we characterized the immune system via flow cytometry and bulk RNA sequencing to compare functional readouts with immunological and transcriptomic data. In order to mitigate immunosenescence and further scrutinize the effect of an aging immune compartment, we transferred neonatal thymi to aged recipient mice as well as transferred CD4+ T cells from young and aged donor mice into aged CD4 KO recipient mice. Herein, we could show that the post-MI outcome in the late remodeling phase is worse in aged mice when compared to young and that the worse outcome correlates with the frequency of antigen-experienced, pro-inflammatory CD44+ T cells in the aged animal. Furthermore, we could show that the myocardial injury has a detrimental modulatory effect on the immune system in chronic MI. While the acute MI only had minor additive effects on the age-dependent enrichment of pro-inflammatory gene sets, chronic MI had additive effects on gene set enrichment associated with pro-inflammatory T cell mechanisms, especially IFN-γ and fibrotic remodeling. Additionally, we could show that, while transplantation of neonatal thymi had an impact on the immune compartment, it did not significantly impact post-MI outcome in aged recipient mice. Furthermore, due to limitations in the survivability of the aged CD4 KO model, no conclusive statement could be made. However, the observed survivability rates after MI were similar among all other experimental mouse models.