Lena Bosch1, Judith de Haan1, Tom Seijkens2, Claudia van Tiel3, Maike Brans1, Gerard Pasterkamp4, Esther Lutgens2, Saskia de Jager5. 1. Experimental Cardiology, University Medical Center Utrecht, the Netherlands. 2. Department of Medical Biochemistry, Academic Medical Center Amsterdam, the Netherlands; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany. 3. Department of Medical Biochemistry, Academic Medical Center Amsterdam, the Netherlands. 4. Department of Clinical Chemistry and Haematology, Center for Circulatory Health, University Medical Center Utrecht, Utrecht University, the Netherlands. 5. Experimental Cardiology, University Medical Center Utrecht, the Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, the Netherlands. Electronic address: S.C.A.dejager@umcutrecht.nl.
Abstract
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.
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.
Authors: Laura A Bosmans; Lena Bosch; Pascal J H Kusters; Esther Lutgens; Tom T P Seijkens Journal: J Cardiovasc Transl Res Date: 2020-03-28 Impact factor: 4.132