COMMENTARY: Biomarkers for cardiovascular risk assessment

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Recent research demonstrates the growing role inflammatory markers play in heart disease. Results from the JUPITER study, issued at the recent American Heart Association Annual Meeting and published in the New England Journal of Medicine, demonstrate that patients with normal cholesterol but high levels of high-sensitivity C-reactive protein (hs-CRP), can lower their risk of suffering a heart attack or stroke with statin therapy. 1 This study is further evidence that assessing only traditional risk factors in patients, such as cholesterol testing, may lead to a large number of patients at risk for heart disease going undiagnosed.

Research into inflammatory biomarkers has opened a new era in the assessment of risk in patients with cardiovascular disease (CVD). Of the dozens of candidate biomarkers, there are two that have accumulated sufficient published evidence to support their utility in clinical practice: the aforementioned high-sensitivity C-reactive protein (hs-CRP) and lipoprotein-associated phospholipase A 2 (Lp-PLA 2).

Clinical Review of Lp-PLA 2

Lp-PLA2 is produced predominantly by macrophages and is strongly associated with rupture-prone plaque. Because it is produced by macrophages in atherosclerotic lesions in the arterial intima, it is a more vascular-specific marker than hs-CRP or other acute phase reactant inflammatory markers, many of which are produced in the liver.1 Lp-PLA 2 is potentially linked to the causal pathway of plaque inflammation, instability and eventual rupture, is found at high levels in thin fibrous cap atheroma and can be lowered by lipid-modifying medications (statins, fibrates, niacin, ezetimibe and omega-3 fish oil).

An elevated Lp-PLA 2 result may indicate a need for more aggressive therapy, including treatment to lower low-density lipoprotein cholesterol (LDL-C) goals. Lipid-lowering therapies, including statins, are proven to reduce cardiovascular events regardless of baseline LDL-C levels. In multiple clinical studies, Lp-PLA 2 has been shown to be a predictor of unstable plaque, myocardial infarction (MI) and ischemic stroke.2 Since low-density lipoprotein has proven not to be a reliable predictor of stroke, the Lp-PLA 2 test addresses this unmet clinical need.

Lp-PLA2 resides mainly on and travels with LDL particles in plasma via apolipoprotein B binding, although it is also associated with high-density lipoprotein (HDL) particles, lipoprotein (a), and remnant lipoproteins. Lp-PLA 2 is highly upregulated in atherosclerotic plaque, and through hydrolysis of oxidized LDL, this enzyme generates two pro-inflammatory mediators, lysophosphatidylcholine and non-esterified oxidized fatty acid. In pre-clinical animal studies, inhibition of the enzyme attenuates the inflammatory process and slows atherosclerotic disease progression. A Phase II study sponsored by GlaxoSmithKline showed that a direct Lp-PLA 2 inhibitor (darapladib), in addition to standard of care treatment, prevented expansion of the necrotic core, a region within coronary plaque associated with a high risk of rupture.3

The Lp-PLA 2 Difference

Numerous peer-reviewed publications have confirmed that elevated plasma levels of Lp-PLA 2, measured using the PLAC Test, are independently associated with risk of coronary heart disease (CHD) and ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) study showed that in individuals with normal LDL, elevated Lp-PLA 2 levels were strongly associated with heart disease and ischemic stroke, independent of traditional risk factors and hs-CRP.4,5 Elevated levels of both inflammatory markers conferred an even higher risk of MI and stroke. Individuals with elevated Lp-PLA 2 and hs-CRP levels had greater than a four-fold increase in risk for heart attacks, and more than an 11-fold increase in risk for ischemic stroke. Additionally, increased levels of Lp-PLA 2 doubled the risk of ischemic stroke at every level of systolic blood pressure, while individuals with the highest levels of Lp-PLA 2 and elevated blood pressure had nearly a seven-fold increase in risk of suffering an ischemic stroke.6 In the KAROLA study, high-risk patients followed for four to six years showed a significantly lower incidence of cardiovascular events if their Lp-PLA 2 levels were <223 ng/mL.7

Acknowledging the limitations of traditional risk factors to precisely assess cardiovascular risk across the general population, the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III)