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Stress as a modifier of atherosclerosis - Novel mechanistic insights and therapeutic avenues -

Periodic Reporting for period 2 - STRATO (Stress as a modifier of atherosclerosis - Novel mechanistic insights and therapeutic avenues -)

Reporting period: 2019-08-01 to 2021-01-31

Atherosclerosis is a chronic disease of the arterial vessel wall and a major cause of death in the EU and worldwide. The ultimate complication of atherosclerosis is the rupture of an atherosclerotic plaque with subsequent thrombosis causing a sudden partial or complete occlusion of the vessel. This results in emergencies, such as acute coronary syndrome (ACS, including myocardial infarction) and stroke. Plaque progression and destabilization, which humans experience as ACS, can be triggered by several conditions, among them mental stress (both acute and chronic). Yet, the effect of mental stress on plaque progression is poorly understood although a number of clinical and epidemiological studies linked social stressors to increased occurrence of cardiovascular diseases. Compared to chronic stress, acute mental stress is far more common and associated with an even greater incidence of cardiovascular events. In this project, our overall objective is to fill the gap in knowledge on how acute mental stress rapidly promotes plaque destabilization and to identify novel therapeutic measures to reduce acute mental stress related morbidity and mortality.
The overarching aim of our proposal is to fill the gap in knowledge on how acute mental stress rapidly promotes plaque destabilization and to identify novel therapeutic measures based on new mechanistic understanding to reduce acute mental stress related morbidity and mortality. To achieve this goal, the project plan was separated into four distinct objectives partly building on each other.
In the last 18 months, we gained detailed insight into how acute mental stress influences plaque inflammation. We were able to prove that acute mental stress promotes the expansion of inflammatory plaque leukocytes through increased influx of these cells into plaques in a mouse model of atherosclerosis. Mechanistically, we were able to connect the acute mental stress response to plaque endothelial cell activation which provides first insights into how acute mental stress is directly linked to progression of atherosclerosis. In ongoing experiments, we investigate potential intervention strategies to dampen stress-induced leukocyte recruitment.
Upon completion, this project will provide an extensive, unequaled view on how acute mental stress aggravates atherosclerosis resulting in myocardial infarction and stroke. By unravelling new mechanisms, we aim to gain ground-breaking insight into disease mechanisms to provide the basis for future pharmaceutical treatment to reduce the burden of stress-induced mortality and morbidity.
overview of the main objectives