Project Details
Projekt
A dysregulated Thrombopoiesis as driver of thromboinflammation in OSAS
Subject Area
Cardiology, Angiology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 541206655
OSAS is the most common respiratory sleep disorder characterized by recurrent pharyngeal collapse during sleep with intermittent episodes of hypoxia and apnea. OSAS is associated with an increased frequency of thromboinflammatory cardiovascular events such as acute myocardial infarction or venous thrombosis. It can also be viewed as an independent risk factor for the development of coronary heart disease. Continuous positive airway pressure therapy (CPAP) is the treatment of choice, but is not well tolerated in many patients and does not reliably protect against cardiovascular events. Pathophysiologically, repeated episodes of oxygen desaturation (intermittent hypoxia) and reoxygenation lead to oxidative stress. Given this, however, little is known about the underlying molecular mechanisms that lead to increased thromboischemic endpoints in OSAS. In preliminary experiments we found a pro-thromboinflammatory state in the bone marrow. We observed an increased interaction between megakaryocytes and neutrophils, which leads to an augmented release of young, reticular, thrombogenic blood platelets. This dysregulated platelet production in turn led to increased arterial thrombus formation in OSAS patients and a murine model of intermittent hypoxia. In summary, our preliminary data define OSAS as a chronic thromboinflammatory disease with increased platelet production as a driver of increased thromboischemic risk. In this project we want to (I) analyze the underlying mechanisms of neutrophil-dependent platelet production under OSAS in order to identify new therapeutic avenues to reduce the thrombotic risk. Furthermore, (II) we will characterize the role of OSAS/intermittent hypoxia in acute myocardial infarction. In this context, we will test various pharmacological approaches to inhibit neutrophil-dependent thrombopoiesis and improve outcome after acute infarction. In translational analyzes (III), we will investigate the influence of concomitant OSAS with elevated reticulated platelet counts in patients with ST-elevation myocardial infarction on cardiovascular events as well as infarct size and myocardial remodeling. Overall, the project will contribute to a better understanding of the underlying mechanisms of cardiovascular risk in OSAS and thereby identify new therapeutic approaches to improve patient care
DFG Programme
Research Grants
