COMMENTARY: Biomarkers for cardiovascular risk assessment

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 A2 (Lp-PLA2).

Clinical Review of Lp-PLA2

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-PLA2 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-PLA2 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-PLA2 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-PLA2 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-PLA2 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-PLA2 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-PLA2 Difference

Numerous peer-reviewed publications have confirmed that elevated plasma levels of Lp-PLA2, 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-PLA2 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-PLA2 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-PLA2 doubled the risk of ischemic stroke at every level of systolic blood pressure, while individuals with the highest levels of Lp-PLA2 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-PLA2 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) report recognized the potential of inflammatory markers to help refine cardiovascular risk assessment. Currently, the PLAC Test (diaDexus) is the only blood test cleared by the FDA to aid in assessing risk for both CHD and ischemic stroke associated with atherosclerosis. But these types of specific vascular inflammation markers could help identify persons with elevated levels of Lp-PLA2, who would then be classified into a higher risk category, prompting the need to further intensify lifestyle and medication therapy in direct proportion to the degree of determined risk.8-11

The current literature has reported that the central 90th percentile of Lp-PLA2 levels range from 120 to 342 ng/mL for women and 131 to 376 ng/mL for men.12 Recently, using data from all currently published Lp-PLA2 studies, an independent consensus panel of cardiologists, neurologists and laboratorians endorsed a cut point of >200 ng/mL to identify patients at higher risk for CHD/CVD.13

The same consensus panel recommended, consistent with the ATP III guidelines, that Lp-PLA2 should be used as an adjunct to traditional risk factor assessment. They suggested that elevated Lp-PLA2 levels would justify more aggressive risk-reducing strategies, including treatment to lower LDL-C goals.

Bottom Line

In summary, a substantial body of evidence supports Lp-PLA2 as a cardiovascular risk marker that provides new information, over and above traditional risk factors, to help identify individuals at increased risk of suffering a heart attack or stroke. The level of the enzyme in the bloodstream is related to the progression of instability of the atherosclerotic plaque, and the likelihood for plaque rupture and a resulting thrombotic event. Persons assessed to be at moderate or high cardiovascular risk by traditional risk factor assessment, could benefit from knowing their Lp-PLA2 levels intensification of lifestyle modification and lipid lowering therapies.

Dr. Speck is a cardiologist and medical director of the Swedish Heart & Vascular Institute's Center for Cardiovascular Wellness in Seattle, Wash.

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