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Heart failure with preserved ejection fraction (HFpEF) is an age-related cardiometabolic condition, which is associated with vascular inflammation in cardiac tissue, pulmonary congestion and right ventricular (RV) dysfunction over time. Patients with HFpEF frequently develop pulmonary hypertension (PH) which is associated with poor outcome. Remodeling of pulmonary vessels contributes to combined post- and pre-capillary PH (CpcPH), leading to impaired RV-PA coupling. Metabolic inflammation, which is linked to signal relay by tumor necrosis factor (TNF), appears as a key driver of both cardiac and pulmonary pathology, and high TNF levels are predictive of incident risk of HFpEF. In this project, we will characterize TNF signaling as a potential key mediator between metabolic stress, microvascular dysfunction, and cardiac / pulmonary vascular pathology in HFpEF. Preliminary work (1) enables us to utilize our newly developed model of HFpEF-CpcPH, largely resembling human disease; and (2) provided strong evidence that TNF/NFkB signaling is implicated in cardio-pulmonary-renal phenotype. Data indicate that NIK dependent non-canonical NF-κB signaling promotes lung inflammation and RV hypertrophy in cIAP1EC-/- cIAP2EC -/- TNFR1EC-/- mice. Therefore, we aim to characterize (1) the time-dependent cardio-pulmonary-renal pathology in HFpEF-PH; (2) TNF signaling pathways in HFpEF-PH; and (3) non-canonical NFkB signaling in HFpEF-PH. Finally, (4) we aim to apply a pharmacological approach targeting TNF / NIK signaling to modulate HFpEF and PH. Expected data will improve our knowledge about inflammatory disease conditions in HFpEF-PH and will provide important impetus for developing novel therapeutic strategies.
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Tilmann Kramer, Phillip Nattmann,Felix Gerhardt, Patrycja Stafiej,Daniel Dumitrescu,Henrik ten Freyhaus,Max Wissmueller,Christopher Hohmann,Stephan Baldus,Stephan Rosenkranz
ESC HEART FAILURE (2024)
Die Kardiologieno. 1 (2024): 14-26
Rheumatology (Oxford, England)no. 4 (2024): 1139-1146
Hunter Gillies,Murali M. Chakinala, Benjamin T. Dake, Jeremy P. Feldman, Marius M. Hoeper,Marc Humbert,Zhi‐Cheng Jing, Jonathan Langley,Vallerie V. McLaughlin, Ralph W. Niven,Stephan Rosenkranz, Xiaosha Zhang,
Pulmonary Circulationno. 1 (2024)
Hunter Gillies,Murali M. Chakinala, Benjamin T. Dake,Jeremy P. Feldman,Marius M. Hoeper,Marc Humbert,Zhi-Cheng Jing, Jonathan Langley,Vallerie V. McLaughlin, Ralph W. Niven,Stephan Rosenkranz, Xiaosha Zhang,
Springer-Lehrbuch Herz-Kreislaufpp.63-77, (2024)
ERJ open researchno. 1 (2024)
David G. Kiely,Richard Channick, Dayana Flores,Nazzareno Galie, Gwen MacDonald,J. Tim Marcus, Lada Mitchell,Andrew Peacock,Stephan Rosenkranz,Ahmed Tawakol,Adam Torbicki,Anton Vonk Noordegraaf,
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