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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

STROKE RISK PREDICTION IN ATHEROSCLEROSIS MEASURING CIRCULATING COMPLEMENT SYSTEM PROTEINS

Awarded: NOK 2.9 mill.

Stroke is a major public health burden, causing 5.5 annual deaths worldwide and is responsible for an overwhelming percentage of patients living with disabilities. Recent treatment and risk factor management improve patient survival after stroke, but pose a serious problem in the growing number of people living with permanent disability, cognitive impairment and loss of productivity. This is especially important in view of the increase in strokes in young adults. As such, in addition to advances in acute stroke, there is a critical need for improvements in primary and secondary prevention to truly reduce the global impact of stroke. About 25% of all strokes are dependent on atherosclerosis, which consists of fat deposits that line the vessel walls leading to the formation of atherosclerotic plaques. Plaque can become vulnerable and subject to erosion which causes thromboembolic complications and leads to ischemic stroke. Available diagnostic procedures cannot detect vulnerable plaques at risk of stroke, making clinical detection of vulnerable atherosclerotic plaques a priority to improve the diagnosis and classification of atherosclerotic patients and to conduct treatment. The central hypothesis in STATEMENT is that the complement system through its inflammatory reactions actively participates in the erosion of atherosclerotic plaque, and that its protein level in blood can be markers of cardiovascular risk and stroke. This hypothesis is formulated in our previous study which reports that complement proteins are most likely present in the atherosclerotic plaques, and secondly the change in blood levels that reflects a vulnerable plaque morphology. In STATEMENT, we envisage validating the use of pre-identified complement proteins as circulating biomarkers for plaque instability, with a clear prognostic value for stroke. This will offer new tools for patient diagnosis, stratification and monitoring based on sensitive detection of circulating levels of complement proteins that inform about plaque morphological development. The use of circulating biomarkers for plaque vulnerability can be integrated into new imaging strategies, which are still far from being common techniques in clinical practice, to predict the strength of strokes in atherosclerotic patients. Furthermore, circulating biomarkers will offer a widely used cost-effective tool, a critical point in performing longitudinal assessments of patients to monitor the temporal development of atherosclerotic lesions, which have important implications for detecting disease mechanisms, predicting plaque disturbance, preventing stroke and improving treatment, and reduce the burden of disease for those who will continue to suffer from stroke. The start of the project was originally set for 1 April 2020. Then the corona pandemic started, and we had to postpone many of the planned sub-projects. Our most important partners are in Milan, and Milan was the epicenter of Europe at that time. Traveling between Oslo and Milan was not possible. We planned that we would first travel to Milan for training, and then the researchers in Milan would come to Oslo and perform the experiments. However, all plans for the experiment could be made, and equipment and reagents were purchased to start as soon as the pandemic situation is under control. A realistic extension of the project will be at least one year, which is applied for separately. Since the previous report, 2 materials have now been collected from patients with stroke. The first material deals with late consequences of stroke including a number of inflammatory markers (cytokines) that will be related to functional examination of patients. The analyzes have been completed and data processing and article writing remain (assumed to be completed on 1 April 2022. The other material is a large biobank where patient data is characterized, but where the analyzes remain. These are special analyzes of complement activation with emphasis on lectin activation done at us and by Professor Peter Garred, as described in the minutes. The analyzes are expected to be completed and the article written by 1 August 2022. The last project is an experimental mouse study that was completely planned right before the Corona arrived. Now we take it up again, first with a week in February in Milan to learn the technique, and then 3 weeks in May where a specialist comes to Oslo to perform the experiments with us. These experiments are performed on knock-out mice for complement factor C3 and TRL-co-factor CD14. It is a large project that will require the whole of 2022 for analysis of the data; and writing of the work is planned to be completed before the project ends in 2023. Together, these three major projects will shed new light on the cause of tissue damage in stroke and lay the foundation for new treatment.

Stroke is the third cause of death and the first cause of long-term disability worldwide. Atherosclerosis lead to the formation of atherosclerotic plaques which cause vessel narrowing (stenosis). More than stenosis, plaque vulnerability raises the risk of stroke, but there is no reliable and standard tool to detect vulnerable plaques. Thus a clear-cut clinical definition of vulnerable plaques is needed for diagnosis, classification and clinical decision making. The progress of the atherosclerotic lesion is driven by the inflammatory response which include the complement system. We have proposed that the lectin pathway (LP) of complement activation is associated with vulnerability of atherosclerotic lesions, thus LP proteins may be markers for cardiovascular risk. In view of supporting the use of a given biomarker as well as developing targeting strategies, the mechanisms underpinning the LP vascular damage need clarification. It is now acknowledged that the LP is a hub of different vascular events driving inflammation and damage. These events include interactions with macrophages, neutrophils, lymphocytes and platelets, contributing to the atherosclerotic lesion. The STATEMENT project will consist of a retrospective study, using the clinical material already available, as well as in vitro models to identify complement biomarkers and their mechanisms of action within the plaque. STATEMENT will also include a prospective study, setting a multicenter observational study, for final biomarker clinical use validation. STATEMENT specifically aims as primary objective at validating the pre-identified complement proteins as prognostic markers for stroke occurrence; and as secondary objective at defining the mechanisms of complement LP protein action in the atherosclerotic plaque. STATEMENT final goal is to offer a tool to identify patients with at-risk plaques, helping clinical decision-making, improving stroke prevention and ameliorating its neurological consequences.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering