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Chronic heart failure is associated with inflammatory deterioration of the bone marrow vascular niche

Session Cellular cross talk in heart failure

Speaker Jedrzej Hoffmann

Congress : ESC Congress 2019

  • Topic : basic science
  • Sub-topic : Basic Science - Cardiac Diseases:Heart Failure
  • Session type : Advances in Science
  • FP Number : 6091

Authors : J Hoffmann (Frankfurt am Main,DE), W Abplanalp (Frankfurt am Main,DE), T Rasper (Frankfurt am Main,DE), A Fischer (Frankfurt am Main,DE), B Assmus (Giessen,DE), P Wild (Mainz,DE), T Koeck (Mainz,DE), AM Zeiher (Frankfurt am Main,DE), S Dimmeler (Frankfurt am Main,DE)

Authors:
J Hoffmann1 , W Abplanalp2 , T Rasper2 , A Fischer2 , B Assmus3 , P Wild4 , T Koeck4 , AM Zeiher1 , S Dimmeler2 , 1JW Goethe University, Cardiology - Frankfurt am Main - Germany , 2JW Goethe University, Institute of Cardiovascular Regeneration, Centre for Molecular Medicine - Frankfurt am Main - Germany , 3Department of Cardiology, University of Giessen, Medical Clinic I - Giessen - Germany , 4Johannes Gutenberg University Mainz (JGU), Preventive Cardiology and Preventive Medicine, Center for Cardiology - Mainz - Germany ,

Citation:

Introduction: Inflammation plays a crucial role in many aspects of cardiovascular disease. Particularly, acquired mutations of hematopoietic stem cells (HSC) leading to clonal expansion of inflammatory cells (CHIP) are increased with age and are associated with an enhanced risk of cardiovascular disease. The bone marrow (BM) vascular niche plays a crucial role in maintenance and regulation of HSC functions. Previous studies in mice showed the reduction of a specific Endomucin-high (H-type) endothelial cells (EC) subpopulation by aging. However, the impact of cardiovascular disease is unclear. Therefore, we aimed to investigate the effects of age and heart failure (HF) on the vascular BM cell composition in mice and humans.
Methods and Results: Aging mice showed an age-dependent decrease of type H (Emcn-high) BM ECs (p=0.004), whereas the BM frequencies of type L (Emcn-low) ECs did not significantly differ (P=0.18). Importantly, we also observed a marked reduction of type H EC in chronic ischemic mice (P=0.016 vs. sham) indicating that chronic ischemic HF induces similar alterations of the vascular stem cell niche. Importantly, type H ECs were also significantly reduced in ischemic HF patients (n=16) compared with control subjects (n=8; P=0.0003). To gain insights into the mechanisms underlying the changes in the vascular niche, we performed single cells RNA sequencing of human BM ECs. These studies confirmed the decrease in Emcn-expressing ECs in ischemic HF patients, which was accompanied by significantly increased expression of inflammatory genes, including IL1b (P<0.0001 vs. control). Inflammatory EC phenotypes and IL1b expression in HF could be further confirmed at protein level using cytospin immunostainings. Finally, we comprehensively evaluated phenotype-associated differences in the bone marrow plasma proteomes of healthy individuals (n=19) and patients with chronic ischemic (n=22) and non-ischemic (n=19) HF, using proximity extension assays. Here, we identified 182 proteins significantly differentially regulated in CHF versus CTRL. Among the top upregulated proteins the BM environment of patients with CHF showed a striking enrichment of inflammatory and ECM remodeling components.
Conclusions: Our data show for the first time an impact of chronic heart failure on the bone marrow vascular niche in humans. These changes seem to be strongly associated with increased inflammatory response and bone matrix remodeling in CHF. Specifically, the induction of the inflammatory cytokine IL1b may contribute to the disturbed phenotype suggesting that inhibition of IL1b (e.g. by canakinumab) may be used as a novel strategy to prevent or reverse the deterioration of the vascular BM niche.

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