Atherosclerosis is a leading cause of cardiovascular complications worldwide, often leading to ischemic heart disease and stroke, peripheral artery disease and myocardial infarction. Atherosclerosis is a systemic disease affecting the cardiovascular system. It is characterized by formation of plaques in the arterial wall containing retained lipids, inflammatory cells, apoptotic cells and increased extracellular matrix (ECM) protein formation. Over time, the plaque hardens which narrows the arteries and restricts blood flow. The biological composition of the plaque determines the risk of plaque rupture. Acute plaque rupture can cause local thrombosis which leads to partial- or total occlusion of the affected artery. If this happens in one of the two major arteries supplying blood to the heart, the result is often a heart attack. Conversely, when plaque rupture happens in the arteries leading to the brain it can cause a stroke. Atherosclerosis in the coronary artery leads to coronary artery/heart disease (CAD/CHD), which is one of the most common cardiovascular diseases caused by limited blood supply to the heart.

How many suffer from atherosclerosis?
Atherosclerosis is a very common and asymptomatic condition: it is therefore difficult to accurately determine incidence. However, as mentioned above, atherosclerosis can lead to major cardiovascular events. In the Western world, more than 370.000 people die every year from CAD/CHD, and approximately 800.000 people suffer from stroke annually, resulting in more than 140.000 deaths. Additionally, 735.000 Americans have a heart attack, and it is estimated that 75% of myocardial infarctions happens due to plaque rupture. Atherosclerosis therefore constitutes a major health concern.

How is atherosclerosis diagnosed?
Atherosclerosis is commonly assessed by computed tomography angiography. Cardiac magnetic resonance imaging is also frequently being implemented in diagnosis and risk assessment of plaque rupture. Atherosclerosis can also be assessed invasively by angiography but is not recommended as a screening tool. Blood-based biomarkers are also implemented in diagnosis, such as C-reactive protein (CRP), lipids and lipoproteins.

How is atherosclerosis treated?
The best treatment for atherosclerosis is to treat risk factors, especially elevated LDL, blood pressure and diabetes. Exercise and healthy dietary habits are also important to reduce risk. Statins are the main treatment options for lowering LDL levels. To control blood pressure multiple drug classes are implemented, most commonly including angiotensin-converting enzyme (ACEs) inhibitors and angiotensin II receptor blockers (ARBs). Clinical treatment of atherosclerosis includes bypass surgery and insertion of stents.

The currently applied detection tools for atherosclerotic plaques rely on imaging techniques or blood-based biomarkers. Evaluating plaque presence by imaging can be difficult due to spatial distribution of the plaque throughout the circulatory system. Furthermore, imaging-based techniques do not provide insight in plaque composition, a critical component for plaque stability. Blood-based biomarkers measuring lipids and cholesterol are also flawed because atherosclerosis is not only caused by lipid accumulation. The currently applied biomarkers are therefore imprecise and only portray part of the underlying factors of the condition.

ECM proteins constitute a significant proportion of the atherosclerotic plaque. During normal tissue homeostasis the balance between formation and degradation is finely balanced. Disruption of this balance can lead to an unstable plaque. Accurately quantifying ECM changes in atherosclerotic plaques could therefore add incremental value to the panel of established biomarkers and assessment techniques, potentially improving the prognostic power.

The Protein FingerprintTM Technology is based on biomarkers that are the combination of specific ECM proteins and specific proteases generating degradation or formation fragments. As inflammation is an intrinsic feature of atherosclerosis  these protease-mediated fragments are released in high abundance from the plaque. These fragments can be targeted by specific ELISAs and thus serve as surrogate markers of tissue remodeling in the atherosclerotic plaque. Targeting propeptides cleaved  off during ECM protein maturation will reflect protein formation, whilst targeting protease mediated fragmentation will reflect protein degradation

The endothelial cells of the arteries rest upon a specific zone of the ECM called the basement membrane. The vascular basement membrane is a thin, sheet-like structure mainly composed of type IV collagen and laminin. In healthy tissue the formation of these ECM proteins is kept in check by an accompanying degradation by matrix metalloproteinases (MMPs). In atherosclerosis, MMP activity is increased which accelerates degradation of the basement membrane, ultimately destabilizing the plaque. Collagen type I is found in high abundance in atherosclerotic plaques. Evaluating circulatory protein fragments of basement membrane and type I collagen degradation could therefore provide unique insight in plaque remodelling.

Protein FingerprintTM biomarkers of laminin (LG1M), type I (C1M) and type IV (C4M) collagen degradation have shown to be associated with adverse events in atherosclerotic patients, potentially linked to a higher risk of plaque rupture due to the dysregulated protein turnover in the plaque.

Other ECM components are also regulated differentially during plaque remodeling. These include type III, VI and VIII collagens, and biglycan, fibromodulin, decorin, elastin, fibronectin and agrin. These ECM proteins constitute therefore interesting biomarker targets which are measurable by the Protein FingerprintTM Technology.

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