Rosenkranz, Stephan | Vantler, Marius - C 13

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.

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.

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

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