Review
Biomarkers of premature atherosclerosis

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C-reactive protein (CRP) is an acute phase protein and a biochemical marker with important prognostic value for cardiovascular events. Interleukins IL-1 and IL-6 are implicated in the pathogenesis of atherosclerosis and are associated with CRP. Apolipoproteins ApoA-I and ApoB are the main lipid metabolic markers implicated in the development and progression of atherosclerosis. Fibrinogen has also been proposed to be a major independent risk factor for cardiovascular events. Because premature atherosclerosis precedes the development of cardiovascular disease, identification of the associated biomarkers is of great importance. However, further studies will be needed to determine whether or not these markers are useful predictors of future cardiovascular events. Here, we review the roles of specific biomarkers that have been implicated in premature atherosclerosis.

Introduction

Cardiovascular disease (CVD) accounts for approximately 50% of all deaths worldwide and is the leading cause of death in western countries 1, 2. The main pathophysiological mechanism leading to CVD is the development of atherosclerosis (see Glossary), in which inflammation has an important role.

Circulating inflammatory markers might be associated with disease activity and parallel the transition from stable lesions to vulnerable plaques. Recent studies have shown that known markers are associated with the pathogenesis and progression of atherosclerosis 3, 4. Interestingly, along with C-reactive protein (CRP), other markers have been associated with progression of atherosclerosis. Biochemical markers such as fibrinogen, apolipoproteins and interleukins have a crucial role in all steps of the atherosclerotic process and have a great relevance in risk stratification 3, 4. So, there is an increasing need to identify an ideal biomarker that will be able to facilitate the clinical diagnosis of CVD. The ideal biomarker should have the following characteristics: highly sensitive, specific, reliable, accessible, standardized, cost effective and easily interpretable by clinicians. Here, we focus on the presentation and evaluation of the most promising biomarkers used in risk assessment of premature atherosclerosis because this could be a first step in preventing cardiovascular disease.

Section snippets

Pathophysiology of atherosclerosis

Atherosclerosis is a disease of large- and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation and the build-up of lipids, cholesterol, calcium and cellular debris within the intima of the vessel wall. These are all factors implicated in plaque formation, vascular remodelling, acute and chronic luminal obstruction, abnormalities of blood flow and diminished oxygen supply to target organs. The initial lesion in atherosclerosis begins in childhood

Biochemical markers

The combination of carefully identifying risk factors and biomarkers is expected to lead to more accurate risk stratification and treatment selection. However, in a large proportion of patients, the traditional cardiovascular risk factors do not provide information on the presence of atherosclerosis and other specific factors such as inflammation need to be considered [32].

Experimental models to study the use of inflammatory, lipid metabolic and thrombotic markers in premature atherosclerosis

A number of experimental animal models for studying the use of inflammatory and other biomarkers in atherogenesis have been developed during the last few years. For example, a widely used model is the ApoE knockout mouse, in which decreased expression of ApoE results in accelerated premature atherosclerosis, especially when fed with a high-fat diet [78]. Genetically modified animal models have also been developed to overexpress specific proteins (e.g. GTP-cyclohydrolase I [79] and others).

Concluding remarks

Understanding the processes that have crucial roles in the pathogenesis of atherosclerosis, such as inflammation, thrombosis and oxidative stress, is important for the development of potential therapeutic approaches. It is necessary for a useful marker to be easily accessed in daily clinical practice. Such a marker should also be well standardized, accurate, have good sensitivity, and be specific, predictive, cost effective, available and suitable for widespread application. The effectiveness

Glossary

Adhesion molecules
proteins located on the cell surface involved in cell adhesion interactions with other cells or with the extracellular matrix (typically via transmembrane receptors).
Atheromatous caps
the fibrous caps surrounding atheromatous plaques.
Atherosclerosis
a disease of the arterial wall, mainly the result of a chronic inflammatory response and the contribution of macrophages, white blood cells and lipids, resulting in the formation of multiple plaques within the arteries.
Chemokines
a

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