Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

CD40 activation increases infarct size and deteriorates left ventricular function in mice following acute myocardial infarction

G. Ampem1, S. Witkowski1, A. Lang1, P. Fiegenbaum1, S. Pfeiler1, S. Becher1, M. Kaldirim1, 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 Acute myocardial infarction (AMI) is associated with a profound inflammatory immune response that is critical in determining infarct size and left ventricular (LV) functional recovery. The interaction of immune cells and regulation of immune responses is modulated by co-stimulatory molecules. Among those, the CD40/CD40 ligand (L) dyad mediates pivotal pro-inflammatory signals that may deteriorate LV function post AMI. Interestingly, expression and activity of CD40/CD40L is altered in metabolic diseases such as Diabetes mellitus. Here, we mimic CD40L-mediated activation of CD40 by an agonistic monoclonal antibody (FGK45) in the post-ischemic phase of normo-glycemic mice with AMI. Methods C57BL/6J male mice (10-12 weeks old) underwent a 45 min occlusion of the left anterior descending coronary artery to induce experimental AMI. Following reperfusion, mice received intraperitoneally a single dose of FGK45 or IgG2a. Post-ischemic infarct size, LV function and cardiac immune cells were assessed at 1 and 7 days by triphenyltetrazolium chloride (TTC) staining, echocardiography and flow cytometry, respectively. Animal experiments were performed according to current regulations (i.e., EU Directive 2010/63/EU and German Animal Welfare Act (TierSchG)). Results CD40 activation by FGK45 increased infarct size (FGK45: 75.1 ± 2.6% vs. IgG2a: 61.7 ± 3.4%, p= 0.0080) as determined by TTC staining. LV function 1-day post-AMI was impaired by reduced stroke volume (FGK45: 18 ± 0.8 µl vs. IgG2a: 23.2 ± 0.8 µl, p <0.0001) and ejection fraction (FGK45: 28.9 ± 1.6% vs. IgG2a: 35.2 ± 1.2%, p= 0.004). 7 days post-AMI, FGK45 strongly affected immune cell infiltration in the infarcted myocardium evidenced by reduced frequency of regulatory CD4+ T cells (FGK45: 1.8 ± 2.2 per mg heart vs. IgG2a: 4.0 ± 1.1 per mg heart, p= 0.041) and increased number of cytotoxic CD8+ T cells (FGK45: 56.3 ± 12.6 per mg heart vs. IgG2a: 17.5 ± 2.2 per mg heart, p= 0.022). Impairment of LV was sustained (ejection fraction: (FGK45: 29.9 ± 2.7% vs. IgG2a: 40.1 ± 1.7%, p= 0.011)). Conclusion Mimicking pharmacological activation of CD40 deteriorates post-ischemic LV function and alters cardiac immune cell composition. Future experiments will investigate how enhanced CD40 activation, as present in dysmetabolic conditions, contribute to increased acute tissue damage and effector cell activation in AMI.

https://dgk.org/kongress_programme/jt2023/aP1375.html