Advanced cardiac and pulmonary failure: mechanical unloading and repair
2nd Funding Periode of KFO311
In the 2nd periode, the KFO311 wants (i) to better understand the biological effects of mechanical unloading and the pathomechanisms of tissue repair in acute and (pre-)terminal heart and lung failure, (ii) to define new reparative therapies in model organisms and translate previously identified therapeutic strategies towards clinical application, and (iii) to further develop evidence-based mechanical support therapies. Structurally, the KFO311 combines MHH’s expertise in Cardiology, Pneumology, Cardiothoracic Surgery, and Pathology, as well as our expertise in multimodal imaging in experimental models and patients. KFO311 benefits from close ties between MHH and several excellent associated institutes and from MHH’s central facilities and core units for preclinical research and clinical trials. MHH has defined (pre‑)terminal organ failure as one of its priority areas in research and clinical practice. Furthermore, we support young academic talents from clinic and science.
Optimization of transient and permanent cardiopulmonary support in patients with heart and lung failure
The goals of TP1 in the next funding period are extension of the data bank/biomaterial bank from patients with cardiac and respiratory failure, collection of heart tissue (VAD/HTx) and the development of scores for the prediction of short-term and long-term outcomes of patients with (pre-)terminal heart and lung failure. Together with TP2 we continue within the DETECT-ID registry now with parallel biopsies of skeletal muscle for the determination iron deficiency in the skeletal muscle compared to the myocardium and to circulating iron parameters. With continuous measurements of PA pressures in LVAD patients using the Cardio-Mems system we plan to optimize further LVAD settings. In the randomized DanGer-Shock-Study investigating Impella pump in patients with cardiogenic shock after myocardial, we will perform additional analyses of the efficiency of mechanical unloading.
Cardiac and skeletal muscle iron deficiency in acute heart failure and
dilated cardiomyopathy: Pathomechanisms and therapy
In the 2nd funding period we will investigate the regulation of cardiac iron homeostasis in the LV-endomyocardial biopsies from the DETECT-ID registry. We will characterize the function of isolated human cardiomyocytes from hearts with dilated cardiomyopathy with and without ID. In a new mouse model of cardiogenic shock we will investigate how cardiac iron deficiency affects the cardiac response to acute stress and if iron therapy is effective in the acute situation. We will investigate the effects of skeletal muscle iron deficiency on heart failure.
Brick1 as a secreted growth factor: repair and adaptation in acute myocardial infarction and chronic heart failure
In the second funding period, we propose to investigate Brick1’s endogenous function, its mechanisms of action, and its therapeutic potential. Using loss-of-function and gain-of-function approaches, we want to examine Brick1’s role in acute myocardial infarction and cardiac hypertrophy/failure. We want to analyze how Brick1 is released from myeloid cells and how it mediates its biological effects. We aim to develop a quantitative mass spectrometry assay to measure Brick1 in the circulation of mice and patients with acute myocardial infarction or heart failure. Finally, we want to explore Brick1’s therapeutic potential in mice with acute myocardial infarction, heart failure, or cardiogenic shock.
Molecular mechanisms and therapy concepts in peripartum heart failure
Based on the different pathologies associated with PPCM and the long-term need for cardiovascular medication, we hypothesize that PPCM patients need a high extent of personalized medicine to target their specific disease entity. We will focus on gene variants associated with cardiomyopathy in PPCM patients and their influence on the regulation of the dopamine receptor system, the Ca2+ sensitivity and the different adenylate cyclases in PPCM. We will investigate why PPCM patients have an increased cancer risk and whether there is a pathophysiological connection. A specific focus will be on genes involved in the cardiac DNA damage response (DDR) system.
Ex vivo therapy of PAH utilizing hiPSC derived ECs in a SuNx PAH Rat model and development of an organ specific BMPR2 KO animal model in rats
Major goal is to finally establish the new, innovative therapy concept, based on the replacement of the dysfunctional pulmonary endothelial cells by (functionalized) hiPSC derived endothelial cells in an ex vivo lung perfusion system (EVLP). This cellular ex vivo therapy will be evaluated in the sugen/normoxic PAH rat model, established in the first funding period. In addition, the impact of loss of function mutations in the BMPR2 gene, which can be detected in 70% of the patients with familial PAH, will be addressed in a clinically more relevant animal model. Thus, a novel BMPR2 knock out (KO) rat model will be developed for evaluation of the cell therapy concept and for generation of clinically more relevant data.
Department of Cardiothoracic, Transplantation and Vascular Surgery
Role of ECMO therapy in cardiopulmonary regeneration and cognitive function during heart and lung failure in mice
Ventilation of patients with severe acute lung injury is frequently not sufficient to reach adequate peripheral oxygenation. Therefore, extracorporeal membrane oxygenation (ECMO) has emerged in recent years as important therapy of patients with respiratory insufficiency due to acute lung injury.
In the second funding period of TP 7, we aim to decipher clinically unresolved aspects of ECMO therapy in a mouse model of VV- and VA-ECMO. First, we wish to determine to what extent ECMO contributes to reduction of ventilation-dependent bacterial infections in patients with respiratory insufficiency. Second, the effect of ECMO therapy on cognitive functions will be examined in respective mouse models.
Impact of a long non-coding RNA on unloading and repair during cardiac remodeling
The aim in the second funding period is to translate these results to human ex-vivo models and to the porcine TAC model as a clinically relevant animal model, to study the in vivo effects of a lncRNA therapy during cardiac unloading. For example, effectiveness of lncRNA inhibitors will first be tested in the organ care system (OCS) in order to select the best adjuvant therapeutic option during unloading in the porcine model. In complementary studies using primary human cardiac fibroblasts, we will validate and further extend the mechanistic studies through promoter analysis and specific ChIP-Seq and ATAC-Seq experiments. Finally, we will perform a combination of cardioprotective therapies in the mouse TAC model aiming to identify novel disease target.
Molecular imaging and modulation of fibrosis and inflammation in cardiac pressure overload and relief
In project 10, quantitative imaging assays based on magnetic resonance imaging (MRI) and positron emission tomography (PET) will be combined for noninvasive detection of biological changes in the heart in response to cardiac pressure overload and relief. In addition, crosstalk with other organs and systems will be investigated by whole-body imaging. The multimodal approach will facilitate an in depth characterization of various aspects of inflammation and fibrosis, along with their changes over time. Imaging will also be used to guide targeted molecular therapies and to determine the success of treatment (“image-guided therapy”). The hypotheses generated in experimental animals will be cross-validated in human tissue samples from failing hearts, which will serve to provide the basis for successful clinical translation.
Ex vivo therapy of ischemic cardiomyopathy
Based on previous experiments on the Organ Care System (OCS) Heart and our data on biofunctionalization of artificial materials, we will evaluate high-density fibrin- and spider silk constructs as matrices for patch development. Patches will be endothelialized ex vivo in the OCS Heart based on established in vitro protocols. They will be used for extensive coronary and myocardial ex vivo reconstructions. Tensile strength, endothelial adherence and immigration, biocompatibility and thrombogenicity will be compared to commercially available patch materials. Retention of the endothelial cells will be evaluated under coronary perfusion. Finally, ex vivo treated hearts will be replanted and functionally analyzed.
Pathology platform for heart and lung tissue and Liquid Biobanking
In the second funding period the KFO311 profits by an established and unique infrastructure for the rapid processing of fresh human tissue and body fluids, as well as biobanking and long-term storage.
We are thus generating readily available, expert-assessed and extremely valuable tissues from human and animal hearts and lungs, as well as standardized fluid samples. This will add value to KFO311 and the related research groups.
To provide a comprehensive overview of available samples and sample quality, a sample platform will be implemented, in which all samples are visible.