Therapeutic hypothermia, also knwon as Targeted Temperature Management, refers to the intentional reduction of core body temperature below 36 °C in an effort to attenuate organ injury caused by a period of stopped blood flow. Although hypothermia has been applied therapeutically for more than 2000 years, the complex mechanisms of action across multiple organ systems are only partly understood and remain to be elucidated. Increased efforts in experimental and clinical research over the past 20 years have led to two standards of care. In 2002, following the publication of randomized controlled trials in the New England Journal of Medicine, therapeutic hypothermia, due to its induced neuroprotective properties, was included in the guidelines for post-cardiac arrest care for patients with return of spontaneous circulation. Three years later, therapeutic hypothermia was also included in the guidelines for perinatal asphyxia to attenuate hypoxic brain injury. However, in other clinical settings such as myocardial infarction, stroke, and traumatic brain injury, promising pre-clinical data could not or have not yet been effectively translated to the clinic to benefit the patient population.
Our research focuses on investigating the effects of therapeutic hypothermia and temperature management in both in vitro and cinlical settings for various medical situations. The core interest of our translational research is the investigation and development of cardio- and neurprotective strategies to optimize the applcation of therapeutic hypothermia and temperature management.
Myocardial ischemia is the most common cause of death worldwide. Ischemia (primary injury) and reperfusion (secondary injury) are the principal causes of tissue damage during myocardial infarction, cardiopulmonary bypass, and spontaneous return of circulation after cardiac arrest. Myocardial injury occurs via necrotic and apoptotic cell death mediated by a multitude of factors including reactive oxygen and nitrogen species, mitochondrial dysfunction, as well as the rapid transcriptional activation of pro-inflammatory genes. To better understand the cardioprotective effects induced by therapeutic hypothermia, we investigate the influence of various cooling protocol on cultured cardiomyocytes (primary murine and HL-1 cardiac myocytes and H9c2 myoblasts). Ischemia is simulated by serum and glucose deprivation at 0.2% oxygen (OGD). After simulated ischemic injury, cells are exposed to complete supplimented culture medium at 21% oxygen to mimic reperfusion. A dynamic time-temperature protocol is applied simulate therapeutic hypothermia. Analysis of morphological changes, mitochondrial function, cell viability, and the expression of cytotoxic and cytoprotective molecules are investigated.
Restriction of the blood supply to the brain occurs frequently during cardiac arrest and cardiopulmonary bypass (CPB) sugery, leading to longterm neurological impairment. Therefore, a major focus of our research is to discover possible intervention strategy to limit the deleterious effects of reduced brain perfusion.
We seek to understand the influence of hypothermia on ischemic (neonatal) brain cells, microglial cells, neurons, and neonatal hippocampal brain slices as an effort to discover potentially protective effects and unwanted side-effects. Different time-temperature protocols are applied on a cellular level and anazyled with regard to cell viablity, morphological changes and protein and RNA expressions.
In clincal studies, we seek to systematically investigate the influence of surgical variables such as body temperature, pharmaceutical immunosuppression, and blood transfusion during cardiopulmonary bypass on the long-term neuropsychological outcome of the patients. A pilot study for neuropsychological follow up examinations (i.e. Bayley score) was realised by enrolling children who underwent corrections of congenital heart defects (transposition of the great arteries, ventricular septal defect, or tetralogy of fallot) between 2007 and 2012.
Findings from systematically accompanied posteroperative patients can help to optimize surgical procedures and thereby, decrease the morbidity of a variety of congenital heart disease.Operative techniques for neuroprotection in a prospective manner in order to improve the quality of life of the patients.
Biomarkers are an important component in the comprehension of an individual patient's illness and response to new treatment strategies. Established biomarkers for a particular disease are used to determine efficacy, validation of new treatments as well as patient stratification to identify individuals who would benefit most from the treatment.
We explore the potential for cold-shock proteins, specifically RBM3, as a biomarker for therapeutic hypothermia and translate our findings to the clinical practice. Preliminary work to characterize the kinetics of RBM3 gene expression under cooling has already been done. Currently, we are working in cooperation with BioTeZ Berlin Buch GmbH and the Center of Excellence for Cardiac Arrest and Targeted Temperature Management at the Charité Universitätsmedzin Berlin on a pilot study to investigate RBM3 regulations in patients undergoing treatment for out-of-hospital cardiac arrest. The study involves measuring RBM3 (RNA and protein) levels in blood before and after the application of therapeutic hypothermia from adults who were resuscitated from out-of-hospital cardiac arrest. For the same purpose we conduct studies to elucidate expression profiles of cold-shock-proteins in brain tissue.
Long-term EArly Development Research
Investigating the Development of Children with (Congenital) Heart Disease
Research efforts in the past years have led to the advancement of diagnosis and treatment of children with congenital heart disease. Fortunately, the majority of our small patients now survive to adulthood. With this development, research is now focusing on the long-term development of these children.
Having a congenital heart defect can be a challenge for the development of infants and toddlers. There is already a body of research pointing towards delays in language, cognition and motor development in some children of these children. However, we still do not know exactly which children have a higher risk than other children and therefore need special support and care. We developed the LEADER project in order to investigate development of children with (congenital) heart disease systematically during the first years of life, to shed light on the following questions:
How do children with congenital heart disease develop in comparison to healthy children?
Are there differences between different types of congenital heart disease when it comes to development?
Which medical protective factors predict favorable development during the first years of life?
Which protective factors in the environment of a child predict favorable development?
Which risk factors predict development delays?
In this study, families of children with Tetralogy of Fallot, Ventricular Septal Defect or Transposition of the Great Arteries, who underwent operation before the age of 10 months at our clinic, can participate. With these children, we conduct an age-appropriate developmental assessment at 3 time points: at age 12 months, at age 24 months and at age 36 months.
In this study, families of children with Hypoplastic Left Heart Syndrome (HLHS) can participate. Also with these children, we conduct a developmental assessment at 3 time points: at age 12 months, at age 24 months and at age 36 months.
In this study, we focus on the development of children who underwent cardiopulmonary resuscitation (CPR). Undergoing CPR is a very specific risk factor for future development, as in some cases, CPR is associated with oxygen deficiency in the brain. In this study, we measure different laboratory values, so called biomarkers, which might predict developmental delays already at an early stage. In this study, we follow children up at 6, 12, 24 and 36 months after CPR.
Who is conducting the studies?
The LEADER-Project is developed by the Department of Congenital Heart Disease - Pediatric Cardiology at German Heart Center Berlin and is supported by the Competence Network for Congenital Heart Defects. The “Fördergemeinschaft Deutsche Kinderherzzentren e.V.” finances part of the project. All studies are approved by the ethics committee of the Charité.
What are our goals?
We aim to improve knowledge of developmental delays in children with (congenital) heart disease. We would like to understand whether and to what extent these children have developmental delays and which risk factors and protective factors can be identified. This is an important prerequisite for the development of tailored preventive programs and early interventions, with the goal of optimized aftercare for our young patients. These children need to have the same chances in life as any healthy child!
If you are interested in one of the ongoing studies or scientific results, do not hesitate to contact us.
Deutsches Herzzentrum Berlin
Abteilung für Angeborene Herzfehler – Kinderkardiologie
Augustenburger Platz 1
Tel.:+49 30 4593 2808
Fax:+49 30 4593 2862
Principal investigator: Priv.-Doz. Dr. med. Katharina Schmitt
Co-investigators: Dr. rer. med. Hannah Ferentzi
Dr. med. Constanze Pfitzer
Dr. med. Peter Kramer
Dr. med. Lisa-Maria Rosenthal
Study nurse: Anke Olsson
Senior physician of the Pediatric Intensive Care Unit: Dr. med. Oliver Miera
Head physician of the Department of Congenital Heart Disease - Pediatric Cardiology: Prof. Dr. med. Felix Berger