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 cIAP1^EC-/-cIAP2^{EC -/-} TNFR1^EC-/- 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.

Figure 1

Fig. 1: TNF signaling promotes PH-HFpEF. In PH-HFpEF, chronic congestion is associated with functional and morphological alterations of pulmonary vessels, which include muscularization of pulmonary venules, haemangiomatosis-like endothelial cell proliferation in pulmonary capillaries, and pulmonary arterial remodelling, resulting in chronically increased afterload of the right heart. TNF signaling in endothelial cells via TNFR1 and TNFR2 as well as non-canonical NFkB signaling contributes to PH-HFpEF via distinct pathways. Lack of cIAP1/2 promotes apoptosis and non-canonical NFkB signaling via NIK inflammatory responses. Both, inflammation and cellular apoptosis are crucial in the pathogenesis of PH-HFpEF. Figure was partly modified from: Hoeper, M.; …; Rosenkranz, S. 2017, Eur Heart J.

Clinical Relevance

HFpEF is a prevalent condition with high morbidity/mortality, which is frequently complicated by PH and RV dysfunction. Treatment options remain scarce, highlighting an urgent medical need. Systematic characterization of TNF/NFkB signaling will provide crucial information in 3 compartments (LV, pulmonary circulation, RV), and mouse experiments will be complemented by human data. The expected results will inform about novel therapeutic concepts, with inhibitors against specific TNF signal relay mediators being readily available for use in humans.

Approach

Preliminary data from our own group in collaboration with H. Kaskars group (B06) revealed the importance of TNF signaling in cardiovascular diseases (Figure 2).

Figure 2

Fig. 2: Cardiomyocyte analysis of the left and right ventricular wall of cIAP1EC-/- cIAP2-/- TNFR1EC-/-mice. (A) Quantification of cardio-myocyte cross-sectional area in LV of cIAP1EC-/- cIAP2-/- TNFR1EC-/- and controls. (B) Representative images of quantified cardiomyocytes. (C) Quantification of cardiomyocyte cross-sectional area in RV of cIAP1EC-/- cIAP2-/- TNFR1EC-/- and controls. (D) Representative images of quantified cardiomyocytes in RV (in collaboration with Paul Werthenbach, AG Kashkar).

Within this project, we will address the following aims:

Analysis of time-dependent cardio-pulmonary-renal pathology in HFpEF-PH
Characterization of TNF signaling in PH-HFpEF
Impact of non-canonical NFkB signaling on the cardio-pulmonary-renal phenoptype in HFpEF-PH
Pharmacological targeting of TNF / NIK signaling in HFpEF-PH

Publication Record on PubMed - Stephan Rosenkranz

Publication Record on PubMed - Marius Vantler

Publications generated during 1/2023-12/2025 with CMMC affiliation

2024 (up to June)

Ameri P, Mercurio V, Pollesello P, Anker MS, Backs J, Bayes-Genis A, Borlaug BA, Burkhoff D, Caravita S, Chan SY, de Man F, Giannakoulas G, Gonzalez A, Guazzi M, Hassoun PM, Hemnes AR, Maack C, Madden B, Melenovsky V, Muller OJ, Papp Z, Pullamsetti SS, Rainer PP, Redfield MM, Rich S, Schiattarella GG, Skaara H, Stellos K, Tedford RJ, Thum T, Vachiery JL, van der Meer P, Van Linthout S, Pruszczyk P, Seferovic P, Coats AJS, Metra M, Rosano G, Rosenkranz S, and Tocchetti CG (2024). A roadmap for therapeutic discovery in pulmonary hypertension associated with left heart failure. A scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Working Group on Pulmonary Circulation & Right Ventricular Function. Eur J Heart Fail26, 707-729. doi:10.1002/ejhf.3236.
Benza RL, Simonneau G, Ghofrani HA, Corris PA, Langleben D, Rosenkranz S, James White R, Cheng CC, Figueiredo Campos FTA, Kim HK, Souza R, Chang M, Rahner C, Meier C, and Hoeper MM (2024). Application of REVEAL Lite 2 and COMPERA 2.0 risk scores to patients with pulmonary arterial hypertension switching to riociguat in the REPLACE study. J Heart Lung Transplant. doi:10.1016/j.healun.2024.06.002.
Wissmüller M, Wartner V, Hohmann C, Adler J, Kramer T, Hellmich M, Gerhardt F, Baldus S, Rosenkranz S. Reply to: The puzzles surrounding the impact of face masks on 6-minute walking distance in pulmonary hypertension. Eur Respir J. 2024 May 16;63(5):2400529. doi: 10.1183/13993003.00529-2024. PMID: 38754949.

2023

Distler O, Ofner C, Huscher D, Jordan S, Ulrich S, Stahler G, Grunig E, Held M, Ghofrani HA, Claussen M, Lange TJ, Klose H, Rosenkranz S, Vonk-Noordegraaf A, Vizza CD, Delcroix M, Opitz C, Pausch C, Scelsi L, Neurohr C, Olsson KM, Coghlan JG, Halank M, Skowasch D, Behr J, Milger K, Remppis BA, Skride A, Jureviciene E, Gumbiene L, Miliauskas S, Loffler-Ragg J, Wilkens H, Pittrow D, Hoeper MM, and Ewert R (2023). Treatment strategies and survival of patients with connective tissue disease and pulmonary arterial hypertension: A COMPERA analysis. Rheumatology (Oxford). doi:10.1093/rheumatology/kead360.
Rosenkranz S (2023). [2022 ESC/ERS guidelines on the diagnostics and treatment of pulmonary hypertension : A focussed review]. Herz 48, 23-30. doi:10.1007/s00059-022-05155-1.
Rosenkranz S, Pausch C, Coghlan JG, Huscher D, Pittrow D, Grunig E, Staehler G, Vizza CD, Gall H, Distler O, Delcroix M, Ghofrani HA, Ewert R, Kabitz HJ, Skowasch D, Behr J, Milger K, Halank M, Wilkens H, Seyfarth HJ, Held M, Scelsi L, Neurohr C, Vonk-Noordegraaf A, Ulrich S, Klose H, Claussen M, Eisenmann S, Schmidt KH, Remppis BA, Skride A, Jureviciene E, Gumbiene L, Miliauskas S, Loffler-Ragg J, Lange TJ, Olsson KM, Hoeper MM, and Opitz C (2023). Risk stratification and response to therapy in patients with pulmonary arterial hypertension and comorbidities: A COMPERA analysis. J Heart Lung Transplant 42, 102-114. doi:10.1016/j.healun.2022.10.003.

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