SFB 1470:  Multilevel mechanistic characterisation of Heart Failure with Preserved Ejection Fraction - Towards a novel classification of HFpEF for targeted therapies

• Subject Area: Medicine ; Biology ; Computer Science, Systems and Electrical Engineering
• Term: since 2022
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437531118

The prevalence of heart failure (HF) is increasing and morbidity and mortality are unacceptably high. Diagnosis and clinical management of HF are currently guided by left ventricular ejection fraction (LVEF), as HF with preserved ejection fraction (HFpEF) is considered a distinct disease than HF with reduced ejection fraction (HFrEF). In HFrEF, treatment strategies have been developed to improve prognosis, but they have proven ineffective in HFpEF, so that we are still unable to offer specific therapies to this large subset of HF patients (~50%). In this CRC, we follow an interdisciplinary approach from organism to organ to cell to molecule towards characterizing HFpEF as a systemic and heterogeneous disorder. Our central hypothesis is that dysregulation of systemic hemodynamic, metabolic and inflammatory pathways contributes to distinct HFpEF phenotypes with specific pathophysiological features, which differentially respond to targeted therapies. Leveraging our expertise in multi-omics, advanced imaging, functional phenotypic analysis, AI and modeling, will provide an improved basis for a comprehensive mechanistic understanding of the disorder to guide innovative therapies to the individual patient.We have designed our research program around defined mechanical, metabolic, inflammatory, and immunological triggers, their respective downstream signaling pathways and specific cardiac response patterns. We connect young and established basic scientists and clinicians with expertise in translational cardiology, functional genomics, cell and molecular biology, systems medicine, proteomics, metabolomics and bioinformatics to towards improved deep phenotyping and classification of HFpEF in relevant animal models and patients as a basis for individualized therapy.We emphasize training the next generation of heart failure researchers, focusing on good scientific practice, equal opportunities, patient involvement and the principles of 3R to foster a culture of cooperation, communication and cross-topic activity. Together, we will provide the basis for an improved mechanistic understanding and classification of HFpEF that combines advanced imaging, multi-omics and classical risk factor analysis, thereby building the foundation for causal, individualized therapies. We believe that our approach will be instrumental to improving the management of HFpEF as one of medicine´s largest unmet clinical needs.

• DFG Programme: Collaborative Research Centres

Current projects

• A01 - Ventricular cardiomyocyte signal compartmentation and functional reserve in HFpEF (Project Heads Annibale, Paolo ;  Heinzel, Ph.D., Frank ;  Hohendanner, Ph.D., Felix )
• A02 - Lipid-based control of the unfolded protein response in HFpEF (Project Head Schiattarella, Gabriele )
• A03 - Linking metabolism, mechanotransduction and endothelial dysfunction in HFpEF (Project Heads Gerhardt, Holger ;  Landmesser, Ulf )
• A04 - Cardio-pulmonary interaction in HFpEF (Project Heads Grune, Jana ;  Kübler, Wolfgang )
• A05 - Role of sex hormones on microbiome, immunity, and coronary microvascular dysfunction and rarefication in experimental HFpEF (Project Heads Dechend, Ralf ;  Forslund-Startceva, Sofia )
• A06 - Immune regulation of vascular rarefaction and diastolic myocardial remodeling (Project Heads Müller, Dominik N. ;  Sawamiphak, Suphansa )
• A07 - Sterile inflammation and innate immunity in HFpEF (Project Head van Linthout, Ph.D., Sophie )
• A08 - Metabolic reprogramming steered by ISGylation in HFpEF (Project Heads Beling, Antje ;  Berndt, Nikolaus )
• A09 - Lipid-mediated mitochondrial dysfunction in HFpEF during obesity (Project Heads Kintscher, Ulrich ;  Sigrist, Stephan J. )
• A10 - Connecting the gut microbiota to the cardiorenal axis in HFpEF (Project Head Wilck, Nicola )
• B01 - Atrial mechanical and secretory function in human HFpEF (Project Heads Falk, Volkmar ;  Hohendanner, Ph.D., Felix ;  Zhang, Kun )
• B02 - Myocardial immune cell activation and fibrosis (Project Head Tschöpe, Carsten )
• B03 - Hypertension and metabolic stress associated changes in cardiac cell populations (Project Head Hübner, Norbert )
• B04 - A systems and translational approach to titin dynamics in HFpEF (Project Head Gotthardt, Michael )
• B05 - Molecular plasticity of HFpEF (Project Heads Edelmann, Frank ;  Mertins, Philipp ;  Pieske, Burkert )
• B06 - Imaging structure/function relations in HFpEF - from pathomechanism to artificial-intelligence based classification (Project Heads Hennemuth, Anja ;  Kelle, Sebastian )
• B07 - Mechanisms, therapeutics and diagnostic potential of circular RNAs in HFpEF (Project Head Thum, Ph.D., Thomas )
• V - Central Administrative Project (Project Heads Gotthardt, Michael ;  Pieske, Burkert )
• Z01 - Animal models and human Engineered Heart Tissue (Project Heads Alogna, Alessio ;  Gotthardt, Michael ;  Heinzel, Ph.D., Frank ;  Schiattarella, Gabriele )
• Z02 - Multilevel human HFpEF phenotyping (Project Heads Edelmann, Frank ;  Grittner, Ph.D., Ulrike ;  Pieske, Burkert ;  Rauch, Ph.D., Geraldine ;  Tschöpe, Carsten )
• Z03 - Phenomapping and Systems Modelling (Project Heads Eils, Roland ;  Kühne, Titus )

• Applicant Institution: shared FU Berlin and HU Berlin through:; Charité - Universitätsmedizin Berlin
• Participating University: Medizinische Hochschule Hannover
• Participating Institution: Charité - Universitätsmedizin Berlin; Deutsches Herzzentrum der Charité (DHZC); Max-Delbrück-Centrum für Molekulare Medizin (MDC)
• Co-Applicant Institution: Freie Universität Berlin; Humboldt-Universität zu Berlin
• Spokespersons: Professor Dr. Michael Gotthardt, since 11/2022; Professor Dr. Burkert Pieske, until 11/2022