Advanced cardiac and pulmonary failure: mechanical unloading and repair
The number of patients with advanced cardiac and pulmonary failure is constantly increasing. Their treatment requires clinical experience, interdisciplinary commitment, and, in many cases, the most advanced medical devices, including microaxial pumps, extracorporal membrane oxygenation (ECMO), and ventricular assist devices (VAD) - all very well established at Hannover Medical School (MHH). These intra- and extracorporal devices may transiently or permanently unload failing organs, replace organ function, prevent therapy-related adverse side effects, provide time for endogenous or exogenous repair, or represent an ultimate destination therapy for end-stage heart failure. However, these treatments are often not evidence-based and cost-intensive, and may be associated with severe complications. What is more, the mechanistic underpinnings of mechanical unloading and support in advanced cardiac and pulmonary failure are only incompletely understood. Thus, basic and translational research in this area is urgently needed and promises (i) insight into the biological effects of mechanical unloading in end-stage cardiac and pulmonary failure, (ii) discovery of novel biological and pharmacological therapies, (iii) identification of innovative applications and evidence-based development of future unloading and support strategies. Based on the outstanding scientific and clinical expertise of the participating MHH Departments and Institutes, this Clinical Research Unit (KFO) will explore the effects of mechanical unloading on local and systemic pathomechanisms in advanced cardiac and pulmonary failure to improve current and/or develop novel therapeutic strategies. In an early translational approach, novel approaches will be evaluated in preclinical and clinical trials. The KFO unites cardiovascular, pulmonary, surgical, and imaging expertise on a preclinical and clinical level. Preclinical and clinical trials will greatly benefit from established networks between clinical departments, highly-specialized institutes, and excellent core facilities at MHH. MHH is one of the leading University hospitals in Germany and a center for supramaximal care for patients with the most complex diseases. Basic and clinical research in advanced organ failure has been defined as one of the focus areas at MHH. In the long-term, this KFO initiative will strengthen the national and international role of MHH as a center of excellence in advanced cardiac and pulmonary failure.
Optimization of transient and permanent cardiopulmonary support in patients with heart and lung failure
In a joint registry, project 1 studies all patients with acute or terminal cardiopulmonary failure treated with apparative techniques such as extracorporeal membrane oxygenation (ECMO), percutaneously implanted right or left ventricular microaxial pumps (eg Impella), and left ventricular assist devices (VAD) implanted operatively. Long-term goal of project 1 is the optimization of drug and device therapy. Blood and tissue specimens of these patients will be collected prospectively in the Hannover Unified Biobank (HUB) and will be provided to all other projects. Project 1 is the central project for translational/clinical questions and a unified database will allow comparison of data regarding underlying diseases, treatment strategies, and outcomes. These data will be aligned with the results from the experimental projects of the clinical research group 311. Hence follows the development of new therapeutic approaches and the translation into clinical (pilot) studies.
Iron-regulatory proteins during cardiac pressure overload and unloading: Impact on heart failure, reverse remodeling and muscle atrophy
Cardiac and skeletal muscle dysfunction plays an important role for the impaired exercise tolerance and poor prognosis of heart failure in patients with iron deficiency. We postulate that heart failure leads to a dysregulation of local iron homeostasis in the heart and the skeletal muscle. We will investigate the functional consequences of tissue-specific iron dysregulation for muscle atrophy in heart failure. We anticipate that this project will lead to a better understanding of tissue-specific iron homeostasis in heart failure and mechanical unloading, and may reveal new therapeutic opportunities for the treatment of advanced heart failure.
Reverse remodeling and recovery in (pre)terminal heart failure
Prolonged mechanical overload induces maladaptive cardiac hypertrophy that may progress to heart failure. Previous in vitro research on cardiomyocyte hypertrophy has been carried out mainly in rat cardiomyocytes, and may therefore not be extrapolated to human cardiomyocytes. Based on protocols established in the Zweigerdt lab, we will use cardiomyocytes from human pluripotent stem cells to establish a human cell culture model for cardiomyocyte hypertrophy induction and its inhibition. We plan to use this model for a high-throughput screen of pharmacological agents to identify new antihypertrophic compounds. The Wollert lab has discovered previously uncharacterized antihypertrophic polypeptides which will also be explored in this system. Pharmacological compounds and polypeptides will then be explored during mechanical loading and unloading in vivo. Our ultimate goals are to better understand basic mechanisms and to develop new therapeutic strategies for the inhibition and regression of maladaptive hypertrophy.
Preterminal heart failure caused by hypertrophy and atrophy: STAT3-dependent regulation of myosine heavy chain proteins
In TP4, we postulate that cardiac unloading by VAD or ECMO via mechanical stimuli and systemic effects impacts on anabolic and catabolic processes at the sarcomere and via alterations of non-muscle myosines on metabolic and secretory mechanisms in cardiac cells. In preliminary studies, the non-muscle myosins Myo5a and –b were identified in the heart, which regulate as molecular motors the cardiac energy substrate uptake and recycling processes. During tumor disease, STAT3-dependent processes could lead by metabolic changes to cardiac atrophy. Whether these signaling pathways are important for healing processes during cardiac unloading therapies and how the healing process could be influneced by their modulation is unknown. Therefore, we hypothesize that specifically the STAT3, miR-199a-5p and Ube2o circuit as well as Myo5a und Myo5b influence unloading therapy effects on the heart with regard to sarcomere homeostasis, cardiac metabolism, vascular regeneration and fibrosis. This project will help to gain a better understanding of biological processes in the heart during unloading therapies with the aim to develop novel concepts during VAD and ECMO therapy that prevents adverse effects and promote healing processes in the diseased heart.
Human iPS cell based myocardial tissue as model of heart failure and cardiac assist device therapy: molecular characterization and identification of therapeutic strategies
In this project, we will differentiate iPS cells of healthy individuals as well as of patients with genetic cardiomyopathy to cardiomyocytes and use these to assemble a three-dimensional bioartificial heart tissue (BCT). The BCT will be subjected to (over-)stretching and unloading in the bioreactor, in order to establish a human in vitro model of cardiac unloading in heart failure patients with ventricular assist devices (VAD). After establishing this model we will analyze the transcriptome and proteome of the BCTs under different loading and unloading conditions to find novel molecular mechanisms of cardiac unloading and to use our findings to establish novel therapeutic strategies that could ultimately help to improve the success rate of VAD therapy in patients.
Ex-vivo gene therapy of pulmonary arterial hypertension by therapeutically functionalized iPS cell derived endothelial cells after preconditioning in an ex- vivo lung perfusion system (EVLP)
Pulmonary atrial hypertension is a progressive disease, with 60% of patients dying during the first 5 years after diagnosis. The underlying defect mainly affects cells of the lung vasculature (endothelial cells and smooth muscle cells) and leads to increase in blood pressure in pulmonary circulation. Available drug treatments at best can temporarily alleviate the symptoms. Therefore, in this research project a new curative treatment concept based on cell therapy should be developed initially in a rat model. Utilization of an ex vivo lung perfusion system allows to explant the impaired lung, treatment ex vivo and re -transplantation of the treated organ. The impaired lung endothelium will be replaced by functional endothelial cells derived from human induced pluripotent stem cells which should lead to complete restored lung function after re-transplantation of the treated organ.
Evaluation of extracorporeal membrane oxygenation as lung barrier protective therapy in bacterial ALI/ARDS
Streptococcus pneumonia is the most prevalent pathogen in community acquired pneumonia (CAP). Severe courses of pneumococcal pneumonia are characterized by pathogen-driven damage of the alveolar epithelial barrier which frequently results in respiratory insufficiency (ALI/ARDS). Importantly however, invasive ventilation regimen required to achieve sufficient peripheral oxygenation in pneumonia patients is known to further aggravate acute damage of the epithelial barrier. Extracorporeal membrane oxygenation (ECMO) as cardiopulmonary support system has become increasingly more important to the treatment of respiratory insufficiency in critically ill patients. The aim of project TP7 as part of the Clinical Research Unit 311 is to evaluate the importance of ECMO as pulmonary relief therapy in a defined animal experimental model of toxin-induced ALI/ARDS. We believe the current project will help us to improve the clinical application of ECMO for the treatment of respiratory insufficiency in critically ill patients.
Reversing mechanical stress induced remodelling in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a mean survival time of 3 years. New treatment options are urgently warranted. IPF is characterized by a vast remodeling of the alveolar compartment which results in a loss of alveoli and replacement by non-functional tissue and scarring. Mechanical stress is fundamentally linked to the pathogenesis of IPF and thought to drive the disease by TGF-β activation. The exact mechanisms induced by mechanical stress however are only rudimentarily understood. The intended project aims to investigate mechanisms induced by increased mechanical load in IPF applying molecular biology and new imaging techniques. The focus lies on TGF-β signaling induced by mechanical stress and the role of avβ6 integrin and CXCR4 in this context. In mice and humans with pulmonary fibrosis CXCR4 and avβ6 integrin will be imaged by positron emission tomography (PET) in vivo and correlated with cell and molecular biology findings.
Long noncoding RNA H19 during unloading and repair of dysfunctional myocardial tissue
Therapeutic options of patients with advanced cardiac failure are limited. The implantation of left ventricular assist devices (LVAD) lead to an improved survival of patients; however with an increased risk of severe adverse effects. Unfortunately during cardiac unloading the minority (5%) of failing hearts recover, which implies the eager need for new adjuvant therapies for fostering cardiac functional regeneration during unloading. Noncoding RNAs regulate the vast majority of the genome and serve as powerful therapeutic targets in many diseases. We now aim to develop of a cardiomyocyte-specific viral based delivery approach to modulate a specific long noncoding RNA to functionally improve dysfunctional hearts during unloading therapy.
Molecular imaging and modulation of fibrosis and inflammation in cardiac pressure overload and relief
The aim of this project is to combine novel imaging techniques for magnetic resonance imaging (MRI) and positron emission tomography (PET) for non-invasive imaging of biological changes in cardiac pressure overload and relief. Using this multimodal approach, the activity of inflammation and fibrosis will be quantified and investigated in depth. This enables detailed insights into disease progression and therapy effects. In addition, in a model of cardiac pressure overload and relief, the effect of an innovative radionuclide-based treatment will be tested. Translation of the innovative approaches into clinical practice and close collaboration with researchers within the clinical research unit are intended.
The transfer project sets out to develop a comprehensive surgical treatment strategy for ischemic heart failure using an ex vivo-perfusion model of unloaded hearts. In a first stage hearts undergo a ubiquitous coronary decalification followed by a treatment with endotheilial cells, progenitor cells to activate angiogenesis and cardiomyocytes. Cellular reconstitution is based on induced pluripotent stem cells (IPSCs). Fundamental part of the project is the development of a sophisticated ex vivo perfusion and treatment platform that will be based on the Organ Care System (OCS). The OCS Heart has originally been developed by company Transmedics for cardiac protection and transportation. The system will be adapted for microsurgical techniques, cell treatment and functional as well as molecular diagnostics. In addition, it will be upgraded by a simulation protocol of acute ischemic heart failure.