Abstract 1045 Inhibition of CD40-TRAF6 signaling in the subacute phase following acute myocardial infarction improves left ventricular function and alters cardiac immune cell infiltration

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
Inhibition of CD40-TRAF6 signaling in the subacute phase following acute myocardial infarction improves left ventricular function and alters cardiac immune cell infiltration
S. Witkowski¹, G. Ampem¹, A. Lang¹, A. Du Plessis¹, M. Kaldirim¹, P. Fiegenbaum¹, S. Pfeiler¹, S. Becher¹, C. Elster¹, M. Barcik¹, M. Benkhoff¹, F. Bönner¹, A. Polzin¹, C. Jung¹, H. Winkels², E. Lutgens³, M. Kelm¹, N. Gerdes¹
¹Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Düsseldorf, Düsseldorf; ²Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Köln; ³Cardiovascular Medicine, Experimental CardioVascular Immunology Laboratory, Mayo Clinic, Rochester, MN, US;
Background Following acute myocardial infarction (AMI), immune cells infiltrate the infarcted myocardium where they initiate pro-inflammatory responses. Later, however, immune cells facilitate resolution of inflammation and regulate myocardial healing processes. Increased and persistent immune cell infiltration is associated with long-term or excessive pro-inflammatory processes that promote adverse cardiac remodeling, compromising left ventricular (LV) function after AMI. The CD40-CD40L dyad, a co-stimulatory pathway that is crucial for pro-inflammatory immune responses, mediates its intracellular signaling via tumor necrosis factor-associated factors (TRAFs). We have generated a small molecule inhibitor of CD40-TRAF6 interaction (so called TRAF-STOP), the main pro-inflammatory CD40 signaling pathway active in monocytes and macrophages. Here, we sought to study the effect of TRAF-STOP during the acute and subacute phase following AMI, with a focus on cardiac immune cell composition and LV function. Methods C57BL/6J male mice (10-12 weeks old) underwent a 45 min occlusion and subsequent reperfusion of the left anterior descending coronary artery to induce AMI. Mice were treated either starting at day 7 before or at day 5 after AMI with TRAF-STOP or control. Composition of cardiac immune cells and LV function were assessed at 14 and 28 days by flow cytometry, histology and echocardiography, respectively. Animal experiments were performed according to current regulations (I.e., EU Directive 2010/62/EU and German Animal Welfare Act (TierSchG)). Results CD40 inhibition by TRAF-STOP including the acute phase affected neither LV function nor cardiac immune cell composition at day 28 after AMI. However, CD40 inhibition starting in the subacute phase (d5) improved LV function at day 14 (EF [%]: control 22.2 ± 1.2 vs. TRAF-STOP 27.7 ± 1.5, p= 0.022) and day 28 (EF [%]: control 28.9 ± 1.7 vs. TRAF-STOP 22.6 ± 1.6, p= 0.05) post AMI. TRAF-STOP treatment reduced cardiac infiltration of non-classical Ly6C^low monocytes (cells per mg heart: control 215.9 ± 22.8 vs. TRAF-STOP 157.4 ± 11.7, p= 0.04) and tended to reduce cytotoxic CD8⁺ T cells (cells per mg heart: control 12.8 ± 0.9 vs. TRAF-STOP 10.2 ± 0.8, p= 0.064) at day 28. Conclusion Continuous inhibition of CD40 signaling beginning day 5 after AMI modifies immune cell composition and improves LV function. Future research will determine the mechanisms involved in functional preservation and immune alteration by CD40-TRAF6 inhibition after AMI.
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