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A01 - Ventricular cardiomyocyte signal compartmentation and functional reserve in HFpEF


Summary
HFpEF is a multifactorial systemic disease, characterized by cardiac structural remodeling and an inadequate augmentation of cardiac contractile function upon physiological stress. CM contractile function at baseline and its functional contractile reserve are regulated by compartmentalization of the main second messengers, cAMP and Ca2+, in highly controlled intracellular functional microdomains. We hypothesize that HFpEF is associated with molecular-level alterations in intracellular cAMP- and Ca2+ signaling microdomains, which limit the functional reserve of the CM. We aim at establishing alterations of β-adrenoreceptor -subtype /cAMP- and Ca2+ dynamics and the impact on the functional reserve with physiological inotropic stimuli (adrenergic, frequency, stretch) in metabolic vs non-metabolic HFpEF. In addition, we investigate the effects of acute metabolic stress on the cardiomyocyte functional reserve in HFpEF and explore underlying mechanisms.
Prof. Dr. Frank R. Heinzel, Dr. Paolo Annibale
A02 - Lipid-based control of the unfolded protein response in HFpEF


Summary
Obesity is a major contributing feature of HFpEF. Lipid overload occurring in HFpEF alters the homeostasis of the UPR (unfolded protein response) signaling pathway in cardiomyocytes. We have previously shown that UPR alterations are major driver of HFpEF pathogenesis. Here we set to comprehensively understand the role of the PERK (PKR-like endoplasmic reticulum kinase) arm of the UPR in HFpEF. To gain insights into the role of lipid biology in HFpEF, we will investigate the role of a lipid-based post-translational modification (PTM), S-palmitoylation, in PERK regulation in cardiomyocyte. Moving forward, we will dissect mechanisms of PERK-dependent modulation of cardiomyocyte response in HFpEF after exercise training - one of the few known beneficial interventions in this syndrome. Focusing on the fundamental mechanisms of lipid response in HFpEF- cardiomyocyte, we will contribute to the understanding of the metabolic alterations in this syndrome providing insights of scientific, and potentially clinical, relevance.
Gabriele Schiattarella, MD, PhD
A03 - Linking metabolism, mechanotransduction and endothelial dysfunction in HFpEF


Summary
Heart failure with preserved ejection fraction (HFpEF) is linked to co-morbidity induced systemic inflammation causing endothelial dysfunction and perturbed endothelial-myocardial signaling leading to functional and structural alteration in myocardium. Hallmarks of endothelial dysfunction in HFpEF are decreased endothelial nitric oxide synthase (eNOS) and increased reactive oxygen species (ROS) and TGFb production, finally leading to myofibrosis of left ventricular wall and impaired elasticity of the neighboring vessels. In our project, we aim to address the function of endothelial YAP/TAZ (YT) signaling, menchanotranscducers shown to respond to a variety of signals and to target the level of TGFb/BMP output under challenging hemodynamic conditions in the development of HFpEF. We combine mouse, zebrafish, and iPSC models in combination with ex vivo microfluidics to assess inflammatory, physical, and metabolic stress in endothelial cells (EC) and examine endothelial cardiomyocyte signaling and potential pharmacological intervention.
Prof. Dr. Ulf Landmesser, Prof. Dr. Holger Gerhardt
A04 - Kardio-pulmonale Interaktion bei HFpEF


Summary
The majority of patients with heart failure with preserved ejection fraction (HFpEF) develop secondary pulmonary hypertension (PH) and subsequent right ventricular (RV) failure. The underlying mechanisms are not well understood, but involve passive congestion, active vascular remodeling with impaired pulmonary gas exchange and systemic activation of the immune system. Here, we propose a mechanistic interdependence of these processes, in that active recruitment of immune cells into the lung´s perivascular space drives lung vascular remodeling thus impairing pulmonary gas exchange. The ensuing systemic hypoxemia will in turn promote systemic inflammation and accelerate the decline in left ventricular (LV) and right ventricular (RV) function.
Prof. Dr. Wolfgang Kübler, Dr. Jana Grune
A05 - Role of sex hormones on microbiome, immunity, and coronary microvascular dysfunction and rarefication in experimental HFpEF


Summary
HFpEF is more often diagnosed in women, especially post menopause, but who on average face less effective care. We hypothesize sex differentially in HFpEF reflect 1) sex steroid impact directly or indirectly on gut microbiome, circulating metabolites, or immune system; in turn acting through 2) coronary microvascular dysfunction. Applying multi-omics technologies to animal models of HFpEF where endocrine sex can be manipulated, we will test this hypothesis and determine its specific microbial, immune and molecular drivers. Findings will be projected into the human setting by integrative and comparative analysis of host-microbiome data from this CRC and other sources.
Prof. Dr. Ralf Dechend, Dr. Sofia Forslund, PhD
A06 - Immune regulation of vascular rarefaction and diastolic myocardial remodeling


Summary
We aim to exploit two model systems, zebrafish and rat, to uncover cellular and molecular mechanisms of immune-vascular-cardiac interaction in HFpEF pathogenesis. Our goals are to understand how immune signaling participates in vascular and cardiac remodeling and to tackle the role of the gut microenvironment on the pathogenic pathway through its influence on immune homeostasis. Furthermore, involvement of immune signaling in cardiac metabolic derangement will be examined. Finally, we will identify therapeutic candidates, from commensal microbial metabolites, capable of regulating the multi-systemic crosstalk and test their efficacy in vascular and cardiac protection.
Dr. Suphansa Sawamiphak, Prof. Dr. Dominik N. Müller
A07 - Sterile inflammation and innate immunity in HFpEF


Summary
Low-grade inflammation induced by comorbidities is recognized to underlie HFpEF-specific remodelling. S100A8/A9 and the NLRP3 inflammasome are important contributors to sterile inflammation and splenic monocytopoeisis in the comorbidities associated with HFpEF. The projects explores the role of innate immunity in HF, evaluating whether systemic vs. cardiac deregulation of the alarmin S100A9 and NLRP3 inflammasome activity triggers HFpEF vs. HFrEF and how this influences splenic activity and potentially the cardiosplenic axis.
Prof. Dipl. Ing. Sophie Van Linthout, PhD
A08 - Metabolic reprogramming steered by ISGylation in HFpEF


Summary
Obesity is a major contributing feature of HFpEF and known to stimulate chronic low-grade inflammation. Cells respond to inflammatory stimuli with reprogramming of their posttranslational modification pathways and activation of protein ISGylation. This project pursues the hypothesis that chronic inflammation in cardiometabolic HFpEF provokes a metabolic adaptation of the heart possibly through the activation of the ISG15 machinery. By combining system biochemistry with computational metabolic modeling, this project will investigate the metabolic alterations occurring in the heart and define how the ISG15 system intersects in the regulation of cardiac metabolic capability in HFpEF.
Prof. Dr. Antje Beling, PD Dr. Nikolaus Berndt
A09 - Lipid-mediated mitochondrial dysfunction in HFpEF during obesity


Summary
Obesity is a main pathogenic driver of HFpEF and accompanied by pronounced disturbances of lipid metabolism which, to a large extent, are based on adipose tissue (AT) dysfunction. In parallel, obesity results in cardiac mitochondrial dysfunction during HFpEF. It is currently unknown whether this mitochondrial dysfunction results from an intrinsic cardiac damage or whether it is, more likely, a cardiac response to systemic, non-cardiac dysfunction finally inducing HFpEF. Thus, the main research question of this project has been defined as follows: Does AT-lipid metabolism control cardiac and mitochondrial function in HFpEF, in particular in obese phenotypes? To answer this question, we will manipulate lipid uptake in AT-specific knockout mouse models which will be challenged with HFpEF. To delineate critical cardiac pathways relevant for AT-controlled cardiac function, the mouse model will be complemented by a Drosophila model (lean/obese) of heart failure with diastolic dysfunction and impaired lipid uptake in the fly fat body.
Prof. Dr. Ulrich Kintscher, Prof. Dr. Stephan Sigrist
A10 - Connecting the gut microbiota to the cardiorenal axis in HFpEF


Summary
Chronic kidney disease (CKD) may contribute to the development of HFpEF, but the underlying mechanisms are poorly understood. The subproject investigates the importance of CKD-associated microbiota and microbial metabolites for inflammation and cardiac remodelling. In order to specifically investigate the role of the microbiota and its metabolites, we use in particular gnotobiotic mouse models, microbiota transfers and metabolite treatments. Thus, this subproject will make an important contribution to the understanding of the heart-kidney axis and mechanistically investigate the role of the microbiome as a link between these important organs in HFpEF.
Dr. Nicola Wilck
B01 - Atrial mechanical and secretory function in human HFpEF


Summary
Atrial remodeling is a hallmark feature of HFpEF, often associated with atrial fibrillation, and linked to increased mortality. Atrial secretory (dys-)function has been linked to a variety of processes associated with remodeling and might represent a driver of the HFpEF phenotype (e.g. via micro-RNAs). The consortium proposes an altered upstream pathway of atrial secretion during HFpEF linked to mechanical and electrical (i.e. atrial fibrillation) cardiac dysfunction. We specifically investigate the role of intercellular interaction and disease/trigger specific atrial secretory activity in human HFpEF using state of the art in-vivo and in-vitro methods to establish the atria as an important endocrine organ that reacts towards and might even mediate HFpEF-related systemic dysfunction.
PD Dr. Felix Hohendanner, Dr. Kun Zhang,
Prof. Dr. Volkmar Falk
B02 - Myocardial immune cell activation and fibrosis


Summary
HFpEF is hemodynamically characterized by an increase in left ventricular stiffness correlated with a rise in extracellular matrix. The project focuses on the integrin network and stiffness sensing and their contribution to modulate fibrosis as they regulate collagen formation and the cardiac invasion of inflammatory cells and fibrocytes. Hereby, this project will provide insights into how mechanosensitive pathways differ between HFpEF and HFrEF. Building on these findings, we will evaluate specific integrins as therapeutic targets to improve HFpEF treatment using small molecules.
Prof. Dr. Carsten Tschöpe
B03 - Hypertension and metabolic stress associated changes in cardiac cell populations


Summary
Normal function of the human heart relies on highly heterogeneous cell populations with specialized functions. In response to systemic stress and/or injury, reparative processes such as fibrosis occur contributing to adverse remodeling and promoting mechanical dysfunction, arrhythmias and heart failure. To obtain insights into trigger-response patterns in HFpEF, we will apply single-nucleus RNA-sequencing (snRNA-seq) to study the composition of cardiac cell populations in biopsies of HFpEF patients and murine models of diastolic dysfunction. We will characterize cardiac cell states and types, their expression networks and cellular circuits, and locate these in space. By comparing changes between non-failing hearts and HFpEF we will discern fundamental causes of maladaptive cardiac remodeling, characterize heterogeneous cellular responses and infer new therapeutic strategies.
Prof. Dr. Norbert Hübner
B04 - A systems and translational approach to titin dynamics in HFpEF


Summary
The giant protein titin forms the elastic backbone of the sarcomere. It is extensively spliced and phosphorylated to adjust cardiac filling in health and disease. Here, we will combine our genetic with interventional animal models and human engineered heart tissue to dissect titin’s contribution to cardiac growth, metabolism, and filling and its relation to heart failure with preserved ejection fraction (HFpEF). Our focus on titin biomechanics and isoform expression in male versus female will contribute to an improved mechanistic understanding of HFpEF, assessment of diastolic dysfunction, and the adaptation of titin based stiffness as a basis for targeted therapy.
Prof. Dr. Michael Gotthardt
B05 - Molecular plasticity of HFpEF


Summary
HFpEF is a heterogenous clinical syndrome with incomplete mechanistic understanding. To improve our understanding of the molecular disease mechanisms, we will perform in-depth proteomic analyses of well phenotyped HFpEF patients and our central HFD+L-NAME mouse model both under resting conditions as well as under disease mitigating exercise conditions. We will also explore disease-specific alterations in proteostasis by studying protein ubiquitination in heart and skeletal muscle tissues in a sex-specific manner. The acquired molecular signatures will be bioinformatically connected to changes in key clinical and pathophysiological readouts to improve patient stratification, identify new biomarkers and potential new therapeutic targets.
Dr. Philipp Mertins
B06 - Imaging structure/function relations in HFpEF - from pathomechanism to artificial-intelligence based classification


Zusammenfassung
Cardiovascular MRI (CMR) is the gold standard for quantitative assessment of anatomy, function, and hemodynamics, as well as myocardial tissue changes such as fibrosis, inflammatory response, and fatty infiltration. B06 investigates the hypothesis that innovative CMR imaging combined with artificial intelligence will enable improved differentiation of prevalent HFpEF pathologies. To this end, a CMR-based Heart Failure Remodeling Index (CMR-HRI) will be developed and pathomechanisms of HFpEF phenotypes will be analyzed.
Prof. Dr. Sebastian Kelle, Prof. Dr.-Ing. Anja Hennemuth
B07 - Mechanisms, therapeutics and diagnostic potential of circular RNAs in HFpEF


Summary
Our work program consists of three specific, interconnected work packages (WP) and is strongly integrated into the CRC. The overall goal is to investigate how circular RNAs are mechanistically involved in cardiac remodeling and diastolic dysfunction. We have established and published relevant methods for cardiac phenotyping, RNA sequencing and analysis. Specifically, we aim (1) to improve our understanding about the function and potential therapeutic modulation using in vitro and ex vivo models of HFpEF, (2) to establish a new cell-type specific circRNA-based therapeutic approach of HFpEF and (3) to test whether selected circulating noncoding RNAs can serve as stratification markers in various cohorts of patients with HFpEF. The ambition and vision of this project is to develop a next generation therapeutic approach for HFpEF patients within the first funding period of the CRC and beyond.
Prof. Dr. Thomas Thum
Z01 - Animal models and human Engineered Heart Tissue


Summary
The insufficient mechanistic understanding and lack of effective treatments for HFpEF relates to inadequate animal and tissue models replicating human disease. Here, we will use a modular approach to combine diverse risk factors and harmonize phenotyping from small to large animal models to generate clinically compatible data. To complement the in vivo data, we provide patient derived stem-cells differentiated into cardiomyocytes and grown in 2D and 3D. The project is responsible for a harmonized phenotyping infrastructure, SOPs, guidance for improved experimental design, and the generation and sharing of compatible datasets between projects.
Prof. Dr. Frank Heinzel, Prof. Dr. Michael Gotthardt, Dr. Alessio Alogna
Z02 - Multilevel human HFpEF phenotyping


Summary
The central aim of Z02 is to build a unique cohort of 400 HFpEF patients that allows a CRC-wide deep mechanistic and molecular patient phenotyping. Phenotyping will not only include the cardiovascular system, but also skeletal muscle, kidney, and adipose tissue, including metabolism, microbiome, proteome and inflammasome, thereby, focusing on systemic triggers associated with HFpEF. Besides robust clinical data, Z02 will generate a unique human HFpEF biorepository including blood, serum, urine and tissue obtained from heart, skeletal muscle and adipose tissue biopsies, as well as gut microbiome samples. Z02 will also get access to similarly phenotyped patient data from matched patients at riks for HFpEF (N=400, pre-HFpEF), and with HFmrEF and HFrEF (N=180). Follow-up in all cohorts will allow understanding of the dynamic nature of the syndrome.
Prof. Dr. Frank Edelmann, Prof. Dr. Geraldine Rauch, Prof. Dr. Carsten Tschöpe
Z03 - Phenomapping and Systems Modelling


Summary
In this CRC, the different subprojects are investigating diverse mechanistic causes of heart failure (HF) that can lead to potentially different HF subtypes. In this Z03 subproject, the data and information obtained in the preclinical and clinical CRC subprojects (areas A, B as well as Z01 and Z02) will be pooled, analyzed, and the data modeled to identify and interpret differences and commonalities that exist across different HF subtypes. Thus, Z03 supports the CRC not only by providing an overarching data analysis and interpretation level, but its information and findings will also help the CRC subprojects to interpret their own results and enable adjustment of experimental designs.
Prof. Dr. Roland Eils, Prof. Dr. Titus Kühne