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Risk prediction

 
A developing atherosclerosis is an underlying cause of CVD and it is well accepted that inflammation is implicated in the pathogenesis. Atherosclerosis develops gradually over many years and is already advanced and irreversible by the time of any tangible symptoms. Myocardial infarction (MI) and stroke often occur suddenly and before medical assistance is available. Hence, reliable biomarkers of a developing atherosclerosis are of great importance. Serum level of low-density lipoprotein (LDL) cholesterol is an important factor in the development of atherosclerosis, and still remains the primary target of therapy for the prevention of coronary heart disease (CHD). However, elevated serum level of LDL-cholesterol, even together with other risk factors, is a poor predictor of a future CHD event. CHD risk functions like Framingham (score includes gender, age, total cholesterol, HDL-cholesterol, cigarette smoking, blood pressure and diabetes) and PROCAM (score includes gender, age, cigarette smoking, blood pressure, history of diabetes, blood levels of LDL-cholesterol, HDL-cholesterol, sugar and triglycerides and heart attack history) seem to over or under estimate the risk of future CHD events in several populations. This imprecise estimation results in both over and under treatment. Sharper tools are indeed needed for risk assessment of CHD and biomarkers like myeloperoxidase (MPO), lipoprotein(a) (Lp(a)) and oxidized low-density lipoprotein (oxLDL) may prove to be useful complements to currently used risk scores.
 

 

Myeloperoxidase (MPO)

There is strong evidence that circulating markers of inflammation are closely associated with the development of subsequent cardiovascular events. MPO, an enzyme released from activated neutrophiles and monocytes as a result of inflammation, has in several studies been used as a marker for coronary artery disease (CAD). In a study by Ndrepepa and coworkers at the German Heart Center in Munich, Germany, MPO levels were not only found to be elevated in CAD patients, but also to be increased with the severity of CAD. Since MPO was also shown to have a stronger correlation to acute coronary syndromes (ACS) than CRP, the authors hypothesize that MPO may have a direct involvement in plaque destabilization. Baldus and colleagues at the University of Hamburg, Germany support this hypothesis and suggest that MPO might serve as both a marker and mediator of vascular inflammation in patients with acute coronary syndrome (ACS).

Oxidized LDL

LDL refers to a class of lipoproteins which main function is to transport cholesterol and triglycerides in the blood for use by various cells. Due to the high blood pressure, plasma constituents continuously seep into the intima of arteries and, at reasonable blood levels LDL particles can pass in and out of the vessel wall. In the blood, LDL particles may be protected from oxidation by blood antioxidants. In excess, LDL tends to get trapped in the matrix, by proteoglycans and other extracellular matrix constituents, where it is subjected to modifications. It has been suggested for more than 20 years that oxidation of lipoproteins is central in the initiation and progression of atherosclerosis, from the early stage conversion of monocytes/macrophages into lipid-laden foam cells and fatty streaks to the late-stage development of coronary artery stenosis, plaque instability, plaque rupture, coronary thrombosis and MI. The oxidative modification hypothesis is based on the concept that LDL in its native form is not atherogenic, and that oxidation of LDL lipids and ApoB-100 is central in the pathogenesis of vascular disease. Whereas native (unmodified) LDL lacks inflammatory properties, modified LDL particles are recognized by the body as foreign, which in turn triggers activation of the immune system and initiation of inflammation.

Lipoprotein (a)

Multiple risk factors usually contribute to the development of atherosclerosis. Hence, family history of premature or aggressive CVD is an important consideration. For example, circulating levels of Lp(a) are inherited and elevated levels have shown to be an independent risk marker for MI. Blood levels of Lp(a) are determined by polymorphism of the LPA gene, coding for the Apo(a) moiety of the Lp(a) particle. It has been shown that Apo(a) size, which depends of the number of kringle IV–type 2 (KIV-2) repeats, inversely correlates with circulating Lp(a) levels.

High levels of Lp(a) have been associated with heart disease since 1970s, but it has been difficult to detect whether Lp(a) actually plays a causative role. Recent findings, however, have provided support for a causal association of Lp(a) with coronary disease. In a publication, Kamstrup and coworkers at the Herlev Hospital, Denmark reported their observed associations of elevated levels of Lp(a) as well as the genetic variation raising the Lp(a) levels with MI risk. These findings were supported by the work of Clarke and colleagues at the University of Oxford, United Kingdom, who identified two LPA variants that were found to be strongly associated with increased Lp(a) levels, a reduced number of KIV-2 repeats, a small Lp(a) size and an increased risk for coronary disease. In an editorial to Kamstrup et al. Thanassoulis and O'Donnell, both affiliated to the National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA, correspond that “this is an important biological finding that elevates the status of Lp(a)”.

The Apo(a) moiety of the Lp(a) particle shares sequence homology with plasminogen, which in circulation is converted to its active form plasmin, an important enzyme that inhibits thrombus formation through fibrinolysis. Recent studies have shown that the plasminogen-like Apo(a) competes with plasminogen for binding to the plasminogen receipt and thus inhibits plasminogen activation and consequently the formation of plasmin. These properties of Apo(a) may explain the association of high Lp(a) concentrations with MI.