Abstract Fri029: Cardiomyocyte-Specific Deficiency of Core-binding Factor β Reduces Cardiac and Systemic Inflammation after Myocardial Infarction.

Introduction: The core-binding factor beta (CBFβ) is a critical co-factor of the RUNX genes (RUNX1,2 and 3) and is required for their transcriptional activity. In cardiomyocytes, RUNX1 is known to drive adverse cardiac remodelling post-myocardial infarction (MI) and can be targeted therapeutically to improve cardiac contractile function post-MI. We have generated a tamoxifen-inducible cardiomyocyte-specific CBFβ deficient mouse in order to understand the mechanisms underpinning the beneficial effect of RUNX inhibitors. We have discovered a new role for RUNX genes in the immune response post-MI. Methods: To investigate the role of CBFβ in post-MI development, cardiac-specific CBFβ-deficient (CBFβ Δ/Δ ) male mice and wildtype control littermates (CBFβ fl/fl ) underwent left anterior descending coronary artery ligation. Heart contractile function was monitored by echocardiography. Resident leukocytes from heart and spleen tissues were collected for flow cytometry at various time points (1-week and 4-week post-MI). Results: 1) CBFβ Δ/Δ mice had significantly improved global longitudinal strain (GLS, %) compared to CBFβ fl/fl mice (-30.92±1.46 vs. -15.18±2.0, p<0.001) at 4-week post-MI. 2) Myocardial infiltration of leukocytes of hearts in CBFβ fl/fl mice were more than double of that for CBFβ Δ/Δ mice (401.4±53.77 x10^3 vs. 166.7±46.22 x10^3, 7 vs. 6, p<0.001, two-way ANOVA) at 1-week post-MI, which was accompanied with decreased leukocytes in the spleen (201.1±53.04 x10^3 vs. 360±61.15 x10^3, 7 vs. 6, p<0.01) and lower tissue weight of spleens (31.86±1.45mg vs. 36.47±1.53mg, p<0.05) for CBFβ Δ/Δ mice compared with that of control mice at 4-week post-MI. 3) Higher Foxp3+CD4+CD3+ T cells among all CD3+ T cells (2.93±0.79% vs. 0.75±0.14%, n=7 vs. 6, p<0.05) were detected in hearts and significantly lower proportions of activated effector and/or effector memory T-cells accounted for all immune cells in spleen tissues of CBFβ Δ/Δ mice (1,878±0.1931% vs. 2.644±0.1829%, n=7 vs. 6, p<0.05) compared to CBFβ fl/fl mice at 1-week post-MI. Interestingly, there was a significantly negative linear regression between the proportion of splenic T E/EM and cardiac Foxp3+ for CBFβ fl/fl mice, while no association was seen for CBFβ Δ/Δ mice. Conclusions: These data demonstrate that cardiomyocyte-specific CBFβ-deficiency improves cardiac contractility and reduces cardiac and systemic inflammation post-MI.