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

Lena Bosch, Judith de Haan, Tom Seijkens, Claudia van Tiel, Maike Brans, Gerard Pasterkamp, Esther Lutgens, Saskia de Jager

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11 Citations (Scopus)


Background: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in non-ischemic heart failure (HF). Small molecule inhibitors of CD40-TRAF6 have shown to be effective in multiple animal-models of chronic inflammatory disease, such as obesity and atherosclerosis. Methods & results: Mice were subjected to transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD40-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks after TAC with a reduced end systolic volume (TAC-placebo group: 71.9 ± 8.8 vs TAC-CD40-TRAF6 inhibitor: 53.7 ± 6.1 μl, p = 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 ± 2.8 vs TAC-CD40-TRAF6 inhibitor: 35.5 ± 3.3%, p = 0.02). Within the myocardium, CD40-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardiomyocyte hypertrophy was observed in the CD40-TRAF6 inhibitor group compared to placebo. Conclusion: CD40-TRAF6 inhibition improves cardiac function in non-ischemic HF 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.
Original languageEnglish
Pages (from-to)141-144
Number of pages4
JournalInternational Journal of Cardiology
Early online date2019
Publication statusPublished - 15 Mar 2019

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