Prof. Dr. med. Otmar Pfister Department of Clinical Research Profiles & Affiliations OverviewResearch Publications Projects & Collaborations Projects & Collaborations OverviewResearch Publications Projects & Collaborations Profiles & Affiliations Projects & Collaborations 4 foundShow per page10 10 20 50 Targeted correction of plasma sodium levels in hospitalized patients with hyponatremia: a randomized, controlled, parallel-group trial with blinded outcome-assessment - The Hyponatremia Intervention Trial (HIT trial) Research Project | 6 Project MembersHyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. It can be caused by the underlying disease, prescribed drugs, or aspecific stimuli such as nausea and pain. Hyponatremia may be life-threatening if it develops acutely and causes cerebral edema with neurological symptoms. The treatment of acute symptomatic hyponatremia is therefore straight forward and implies the administration of hypertonic saline to treat cerebral edema. In contrast, the rationale for treatment of chronic hyponatremia - the most prevalent subtype - is less evident. There are no intervention studies to show that correcting chronic hyponatremia improves outcomes.Importantly, there is increasing data showing an association between chronic hyponatremia and complications such as falls or attention deficit, as well as increased risk of fractures and osteoporosis. It has also been reported that hyponatremia is associated with a poorer prognosis of cardiac, hepatic, kidney and pulmonary diseases as well as the overall outcome of ICU patients resulting in a significant association with an increased mortality and readmission risk. However, it is unclear whether these are merely associations or indicate causality: despite several retrospective analyses showing improvement of readmission and mortality rates, as well as some small uncontrolled studies reporting reduction of adverse events with plasma sodium correction, there is a complete lack of randomized clinical trials investigating whether correction of hyponatremia counteracts the increased risk of readmission and mortality. Thus, there is clinical equipoise on whether chronic hyponatremia should be treated or not. Therefore, the aim of this intervention study is to determine the benefits and harms of a targeted correction of plasma sodium concentration on the combined endpoint 30-day mortality and rehospitalization rate. Patients will be randomly assigned to targeted correction of plasma sodium concentration or standard care alone. Study Design: Pragmatic randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center study with blinded outcome assessment.Patients: Hospitalized patients with chronic hypotonic hyponatremia <130mmol/l. Patients requiring acute treatment with 3% saline infusion due to severe symptomatic hyponatremia, patients on dialysis, patients with acute liver failure, encephalopathic complications of liver failure or hepatorenal syndrome will be excluded. Intervention: Targeted correction of plasma sodium concentrationComparison: Current standard careOutcome measures: The primary objective is to investigate whether targeted correction of hyponatremia compared to standard care alone reduces the combined risk of death or rehospitalization within 30 days. Secondary objectives will include: Short- (30 days) and longterm (1 year) risk of death and rehospitalization; other clinical outcomes (neurocognition, quality of life, falls, fractures, length of hospital stay); Safety of the intervention; Exploratory analysis of biomarkers for hyponatremia. Main statistical hypothesis and sample size calculation:The intervention is superior to standard care by reducing the patients risk of death or re-hospitalization within 30 days from 23% to 18%. 2050 patients are required to detect an effect that is relevant for patients, clinicians and policy makers, i.e. an absolute reduction of 5% of the primary outcome (combined mortality and rehospitalization rate) with a statistical power of 80% (two-sided significance level 5%). With an assumed drop-out rate of 10 %, 2278 patients should be recruited.Importance: This study will influence future hyponatremia management on a national and international level regardless of its outcome:If the intervention results in a significant reduction of mortality and rehospitalization rate, hyponatremia awareness and its consecutive treatment during hospitalization will change substantially.If the intervention shows no effect on mortality and rehospitalization rate, hyponatremia will be recognized more as a marker of severity of the disease and not as its cause. Current treatment guidelines will be adapted. Regulators of cardiac progenitor cells: focus on cancer drug targets Research Project | 2 Project MembersIncreased apoptosis and premature senescence of cardiac progenitor cells (CPCs) result in impaired cardiac adaptation and enhanced susceptibility of anthracycline-exposed hearts to stressors. This may apply to targeted cancer drugs as well, given their targets are expressed in the heart and involved in the regulation of cardiac homeostasis. Fms-like tyrosine kinase 3 (Flt3) is an important drug target for solid tumor and acute myeloid leukemia treatment. We recently demonstrated that Flt3 is expressed on cardiomyocytes and CPCs, and that its activation protects against apoptosis and improves post-myocardial infarction remodeling and function in mice. Further preliminary data support the hypothesis that Flt3-signaling participates in the regulation of CPCs. In this study, we will test the hypothesis that disruption of Flt3-signaling disturbs CPC homeostasis and function and facilitates cardiac disease. We will (i) characterize the role and mechanisms of Flt3-signaling in the maintenance of the cardiac cellular homeostasis and determine the functional consequences of its disruption in the mouse heart, (ii) identify roles and molecular mechanisms of Flt3 signaling in the regulation of quiescence and in vitro proliferation and differentiation capacities of CPCs, and (iii) determine whether disruption of intrinsic Flt3 signaling facilitates cardiac disease in response to additional stressors. Relevance: Cardiomyopathy and heart failure are severe and potentially life-limiting side effects of cancer therapy. Improved understanding of the roles and molecular mechanisms of intrinsic Flt3-action in the heart is mandatory to anticipate potential cardiotoxic effects and to allow for early monitoring and interdisciplinary management of patients on Flt3-targeting therapy. Furthermore, the characterization of molecular targets of cancer therapy and their roles in the heart will help guide future cancer drug design and lead to the identification of novel therapeutic targets for the treatment of cardiomyopathy and heart failure in general. Role of the hematopoietic growth factor "Flt3-ligand" in post-myocardial infarction remodeling Research Project | 1 Project MembersNo Description available Myokardiale Stammzellen Research Project | 1 Project MembersNo Description available 1 1 OverviewResearch Publications Projects & Collaborations
Projects & Collaborations 4 foundShow per page10 10 20 50 Targeted correction of plasma sodium levels in hospitalized patients with hyponatremia: a randomized, controlled, parallel-group trial with blinded outcome-assessment - The Hyponatremia Intervention Trial (HIT trial) Research Project | 6 Project MembersHyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. It can be caused by the underlying disease, prescribed drugs, or aspecific stimuli such as nausea and pain. Hyponatremia may be life-threatening if it develops acutely and causes cerebral edema with neurological symptoms. The treatment of acute symptomatic hyponatremia is therefore straight forward and implies the administration of hypertonic saline to treat cerebral edema. In contrast, the rationale for treatment of chronic hyponatremia - the most prevalent subtype - is less evident. There are no intervention studies to show that correcting chronic hyponatremia improves outcomes.Importantly, there is increasing data showing an association between chronic hyponatremia and complications such as falls or attention deficit, as well as increased risk of fractures and osteoporosis. It has also been reported that hyponatremia is associated with a poorer prognosis of cardiac, hepatic, kidney and pulmonary diseases as well as the overall outcome of ICU patients resulting in a significant association with an increased mortality and readmission risk. However, it is unclear whether these are merely associations or indicate causality: despite several retrospective analyses showing improvement of readmission and mortality rates, as well as some small uncontrolled studies reporting reduction of adverse events with plasma sodium correction, there is a complete lack of randomized clinical trials investigating whether correction of hyponatremia counteracts the increased risk of readmission and mortality. Thus, there is clinical equipoise on whether chronic hyponatremia should be treated or not. Therefore, the aim of this intervention study is to determine the benefits and harms of a targeted correction of plasma sodium concentration on the combined endpoint 30-day mortality and rehospitalization rate. Patients will be randomly assigned to targeted correction of plasma sodium concentration or standard care alone. Study Design: Pragmatic randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center study with blinded outcome assessment.Patients: Hospitalized patients with chronic hypotonic hyponatremia <130mmol/l. Patients requiring acute treatment with 3% saline infusion due to severe symptomatic hyponatremia, patients on dialysis, patients with acute liver failure, encephalopathic complications of liver failure or hepatorenal syndrome will be excluded. Intervention: Targeted correction of plasma sodium concentrationComparison: Current standard careOutcome measures: The primary objective is to investigate whether targeted correction of hyponatremia compared to standard care alone reduces the combined risk of death or rehospitalization within 30 days. Secondary objectives will include: Short- (30 days) and longterm (1 year) risk of death and rehospitalization; other clinical outcomes (neurocognition, quality of life, falls, fractures, length of hospital stay); Safety of the intervention; Exploratory analysis of biomarkers for hyponatremia. Main statistical hypothesis and sample size calculation:The intervention is superior to standard care by reducing the patients risk of death or re-hospitalization within 30 days from 23% to 18%. 2050 patients are required to detect an effect that is relevant for patients, clinicians and policy makers, i.e. an absolute reduction of 5% of the primary outcome (combined mortality and rehospitalization rate) with a statistical power of 80% (two-sided significance level 5%). With an assumed drop-out rate of 10 %, 2278 patients should be recruited.Importance: This study will influence future hyponatremia management on a national and international level regardless of its outcome:If the intervention results in a significant reduction of mortality and rehospitalization rate, hyponatremia awareness and its consecutive treatment during hospitalization will change substantially.If the intervention shows no effect on mortality and rehospitalization rate, hyponatremia will be recognized more as a marker of severity of the disease and not as its cause. Current treatment guidelines will be adapted. Regulators of cardiac progenitor cells: focus on cancer drug targets Research Project | 2 Project MembersIncreased apoptosis and premature senescence of cardiac progenitor cells (CPCs) result in impaired cardiac adaptation and enhanced susceptibility of anthracycline-exposed hearts to stressors. This may apply to targeted cancer drugs as well, given their targets are expressed in the heart and involved in the regulation of cardiac homeostasis. Fms-like tyrosine kinase 3 (Flt3) is an important drug target for solid tumor and acute myeloid leukemia treatment. We recently demonstrated that Flt3 is expressed on cardiomyocytes and CPCs, and that its activation protects against apoptosis and improves post-myocardial infarction remodeling and function in mice. Further preliminary data support the hypothesis that Flt3-signaling participates in the regulation of CPCs. In this study, we will test the hypothesis that disruption of Flt3-signaling disturbs CPC homeostasis and function and facilitates cardiac disease. We will (i) characterize the role and mechanisms of Flt3-signaling in the maintenance of the cardiac cellular homeostasis and determine the functional consequences of its disruption in the mouse heart, (ii) identify roles and molecular mechanisms of Flt3 signaling in the regulation of quiescence and in vitro proliferation and differentiation capacities of CPCs, and (iii) determine whether disruption of intrinsic Flt3 signaling facilitates cardiac disease in response to additional stressors. Relevance: Cardiomyopathy and heart failure are severe and potentially life-limiting side effects of cancer therapy. Improved understanding of the roles and molecular mechanisms of intrinsic Flt3-action in the heart is mandatory to anticipate potential cardiotoxic effects and to allow for early monitoring and interdisciplinary management of patients on Flt3-targeting therapy. Furthermore, the characterization of molecular targets of cancer therapy and their roles in the heart will help guide future cancer drug design and lead to the identification of novel therapeutic targets for the treatment of cardiomyopathy and heart failure in general. Role of the hematopoietic growth factor "Flt3-ligand" in post-myocardial infarction remodeling Research Project | 1 Project MembersNo Description available Myokardiale Stammzellen Research Project | 1 Project MembersNo Description available 1 1
Targeted correction of plasma sodium levels in hospitalized patients with hyponatremia: a randomized, controlled, parallel-group trial with blinded outcome-assessment - The Hyponatremia Intervention Trial (HIT trial) Research Project | 6 Project MembersHyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. It can be caused by the underlying disease, prescribed drugs, or aspecific stimuli such as nausea and pain. Hyponatremia may be life-threatening if it develops acutely and causes cerebral edema with neurological symptoms. The treatment of acute symptomatic hyponatremia is therefore straight forward and implies the administration of hypertonic saline to treat cerebral edema. In contrast, the rationale for treatment of chronic hyponatremia - the most prevalent subtype - is less evident. There are no intervention studies to show that correcting chronic hyponatremia improves outcomes.Importantly, there is increasing data showing an association between chronic hyponatremia and complications such as falls or attention deficit, as well as increased risk of fractures and osteoporosis. It has also been reported that hyponatremia is associated with a poorer prognosis of cardiac, hepatic, kidney and pulmonary diseases as well as the overall outcome of ICU patients resulting in a significant association with an increased mortality and readmission risk. However, it is unclear whether these are merely associations or indicate causality: despite several retrospective analyses showing improvement of readmission and mortality rates, as well as some small uncontrolled studies reporting reduction of adverse events with plasma sodium correction, there is a complete lack of randomized clinical trials investigating whether correction of hyponatremia counteracts the increased risk of readmission and mortality. Thus, there is clinical equipoise on whether chronic hyponatremia should be treated or not. Therefore, the aim of this intervention study is to determine the benefits and harms of a targeted correction of plasma sodium concentration on the combined endpoint 30-day mortality and rehospitalization rate. Patients will be randomly assigned to targeted correction of plasma sodium concentration or standard care alone. Study Design: Pragmatic randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center study with blinded outcome assessment.Patients: Hospitalized patients with chronic hypotonic hyponatremia <130mmol/l. Patients requiring acute treatment with 3% saline infusion due to severe symptomatic hyponatremia, patients on dialysis, patients with acute liver failure, encephalopathic complications of liver failure or hepatorenal syndrome will be excluded. Intervention: Targeted correction of plasma sodium concentrationComparison: Current standard careOutcome measures: The primary objective is to investigate whether targeted correction of hyponatremia compared to standard care alone reduces the combined risk of death or rehospitalization within 30 days. Secondary objectives will include: Short- (30 days) and longterm (1 year) risk of death and rehospitalization; other clinical outcomes (neurocognition, quality of life, falls, fractures, length of hospital stay); Safety of the intervention; Exploratory analysis of biomarkers for hyponatremia. Main statistical hypothesis and sample size calculation:The intervention is superior to standard care by reducing the patients risk of death or re-hospitalization within 30 days from 23% to 18%. 2050 patients are required to detect an effect that is relevant for patients, clinicians and policy makers, i.e. an absolute reduction of 5% of the primary outcome (combined mortality and rehospitalization rate) with a statistical power of 80% (two-sided significance level 5%). With an assumed drop-out rate of 10 %, 2278 patients should be recruited.Importance: This study will influence future hyponatremia management on a national and international level regardless of its outcome:If the intervention results in a significant reduction of mortality and rehospitalization rate, hyponatremia awareness and its consecutive treatment during hospitalization will change substantially.If the intervention shows no effect on mortality and rehospitalization rate, hyponatremia will be recognized more as a marker of severity of the disease and not as its cause. Current treatment guidelines will be adapted.
Regulators of cardiac progenitor cells: focus on cancer drug targets Research Project | 2 Project MembersIncreased apoptosis and premature senescence of cardiac progenitor cells (CPCs) result in impaired cardiac adaptation and enhanced susceptibility of anthracycline-exposed hearts to stressors. This may apply to targeted cancer drugs as well, given their targets are expressed in the heart and involved in the regulation of cardiac homeostasis. Fms-like tyrosine kinase 3 (Flt3) is an important drug target for solid tumor and acute myeloid leukemia treatment. We recently demonstrated that Flt3 is expressed on cardiomyocytes and CPCs, and that its activation protects against apoptosis and improves post-myocardial infarction remodeling and function in mice. Further preliminary data support the hypothesis that Flt3-signaling participates in the regulation of CPCs. In this study, we will test the hypothesis that disruption of Flt3-signaling disturbs CPC homeostasis and function and facilitates cardiac disease. We will (i) characterize the role and mechanisms of Flt3-signaling in the maintenance of the cardiac cellular homeostasis and determine the functional consequences of its disruption in the mouse heart, (ii) identify roles and molecular mechanisms of Flt3 signaling in the regulation of quiescence and in vitro proliferation and differentiation capacities of CPCs, and (iii) determine whether disruption of intrinsic Flt3 signaling facilitates cardiac disease in response to additional stressors. Relevance: Cardiomyopathy and heart failure are severe and potentially life-limiting side effects of cancer therapy. Improved understanding of the roles and molecular mechanisms of intrinsic Flt3-action in the heart is mandatory to anticipate potential cardiotoxic effects and to allow for early monitoring and interdisciplinary management of patients on Flt3-targeting therapy. Furthermore, the characterization of molecular targets of cancer therapy and their roles in the heart will help guide future cancer drug design and lead to the identification of novel therapeutic targets for the treatment of cardiomyopathy and heart failure in general.
Role of the hematopoietic growth factor "Flt3-ligand" in post-myocardial infarction remodeling Research Project | 1 Project MembersNo Description available
