Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure*

Background: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in nonischemic heart failure (HF). Small molecule inhibitors of CD4O-TRAF6 have shown to be effective in multiple animal models of chronic inflammatory disease, such as obesity and atherosclerosis. Methods &results: Mice were subjected lo transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD4O-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks atter TAC with a reduced end systolic volume (TAC-placebo group: 71.9 +/- 8.8 vs TAC-CD4O-TRAF6 inhibitor: 53.7 +/- 6.1 IA, p 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 +/- 2.8 vs TAC-CD4O-TRAF6 inhibitor: 35.5 3.3%, p 0.02). Within the myocardium, CD4O-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardioniyocyte hypertrophy was observed in the CD4O-TRAF6 inhibitor group compared to placebo. Conclusion: CD4O-TRAF6 inhibition improves cardiac function in non-ischemic HE in mice. This effect is mediated by a reduction in macrophage and T-cell influx in the myocardium accompanied by a reduction in cardiac fibrosis and hypertrophy. (C) 2019 The Authors. Published by Elsevier B.V.