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Biomarkers for cardiovascular risk assessment.

Research into inflammatory biomarkers has opened up 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: high-sensitivity C-reactive protein (hs-CRP) and lipoprotein-associated phospholipase [A.sub.2] ([Lp-PLA.sub.2]).

Clinical review of [Lp-PLA.sub.2]

[Lp-PLA.sub.2] 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.sub.2] is potentially linked to the causal pathway of plaque inflammation, instability, and eventual rupture; 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.sub.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.sub.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, measuring levels of [Lp-PLA.sub.2] addresses this unmet clinical need.

[Lp-PLA.sub.2] resides mainly on and travels with LDL particles in plasma via apolipoprotein B binding, although it is also associated with high-density lipoprotein, or HDL, particles, lipoprotein (a), and remnant lipoproteins. [Lp-PLA.sub.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.sub.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.sub.2] difference

Numerous peer-reviewed publications have confirmed that elevated plasma levels of [Lp-PLA.sub.2] are independently associated with risk of coronary heart disease (CHD) and ischemic stroke. The Atherosclerosis Risk in Communities, or ARIC, study showed that in individuals with normal LDL, elevated [Lp-PLA.sub.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.sub.2] and hs-CRP levels had greater than a fourfold increase in risk for heart attacks, and more than an elevenfold increase in risk for ischemic stroke. Additionally, increased levels of [Lp-PLA.sub.2] doubled the risk of ischemic stroke at every level of systolic blood pressure, while individuals with the highest levels of [Lp-PLA.sub.2] and elevated blood pressure had nearly a sevenfold 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.sub.2] levels were <223 ng/mL.(7)

Lab measurement of [Lp-PLA.sub.2]

Testing for [Lp-PLA.sub.2] in the laboratory is available in an ELISA test format or as an automated format. Two highly specific monoclonal antibodies are used in the assay, and it is calibrated to a well-characterized recombinant [Lp-PLA.sub.2] standard to increase the accuracy of the test. The automated assay employs immunoturbidimetric technology and can be run on the Hitachi, Roche Modular P and Olympus analyzers. Additional applications are in development. The [Lp-PLA.sub.2] protein in serum is generally .stable (i.e., the protein itself does not degrade), but it is highly recommended that the serum and plasma samples be collected and stored according to the Recommended Specimen Collection and Storage procedures.

Acknowledging the limitations of traditional risk factors to precisely assess cardiovascular risk across the general population, the National Cholesterol Education Program Adult Treatment Panel, or NCEP ATP III, report recognized the potential of inflammatory markers to help refine cardiovascular risk assessment. As [Lp-PLA.sub.2] evaluates vascular inflammation specifically, persons with elevated levels of [Lp-PLA.sub.2] could potentially 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-PLA.sub.2] 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-PLA.sub.2] 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-PLA.sub.2] should be used as an adjunct to traditional risk-factor assessment. They suggested that elevated [Lp-PLA.sub.2] levels would justify more aggressive risk-reducing strategies, including treatment to lower LDL-C goals.

In summary, a substantial body of evidence supports [Lp-PLA.sub.2] 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. As such, [Lp-PLA.sub.2] should be used as an adjunct in persons assessed to be at moderate or high cardiovascular risk by traditional risk factor assessment, to help refine absolute risk status and identify the individuals who would most benefit from intensification of lifestyle modification and lipid lowering therapies.

Note: This article is followed by another article, "Cancer biomarkers--a good start," that is also part of the Continuing Education test.


(1.) McConnell JP, Hoefner DA. Lipoprotein-associated phospholipase [A.sub.2]. J Clin Lab Med. 2006;26:679-697.

(2.) Garza CA, et al. Association between lipoprotein-associated phospholipase [A.sub.2] and cardiovascular disease: a systemic review. Mayo Clin Proc. 2007;82(2):159-165.

(3.) Serruys PW, et al. Darapladib: effects of the direct lipoprotein-associated phospholipase [A.sub.2] inhibitor darapladib on human coronary atherosclerotic plaque. Circulation. 2008;118:1172-1182.

(4.) Ballantyne CM, Hoogeveen RC, Band H, Coresh J. Folsom AR, Heiss G, Sharrett AR. Lipoprotein-associated phospholipase [A.sub.2], high-sensitivity C-reactive protein, and risk for incident heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004;109:837-842.

(5.) Ballantyne CM, et al. Lipoprotein-associated phospholipase [A.sub.2], high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Arch Intern Med. 2005;165:2479-2484.

(6.) Gorelick PB. Lipoprotein-associated phospholipase [A.sub.2] and risk of stroke. Am. J Cardiol. 2008: 101 [suppl]:34F-40F.

(7.) Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoprotein-associated phospholipase [A.sub.2], predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function and hemodynamic stress (KAROLA). Arterioscler Thomb Vasc Biol. 2006;26:1586-1593.

(8.) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.

(9.) National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol education Program (NCEP) Expert Panel on detection, evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421 11-30-11-31.

(10.) Pearson TA, Mensah GA, Alexander RW, Anderson JL, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511.

(11.) Smith SC, Allen J,, Blair SN, Bonow RO, Brass LM, Fonarow GC, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation. 2006;113:2363-2372.

(12.) Brilakis ES, McConnell JP, Lennon RJ, Elesber AA, Meyer JG, Berger PB. Association of lipoprotein-associated phospholipase [A.sub.2] levels with coronary artery disease risk factors, angiographic coronary artery disease, and major adverse events at follow-up. Eur Heart J. 2005;26:137-144.

(13.) Davidson MH, Corson MA, Alberts MJ, et al. Consensus Panel Recommendation for Incorporating Lipoprotein-Associated Phospholipase [A.sub.2] Testing Into Cardiovascular Disease Risk Assessment Guidelines. Am. J Cardiol. 2008: 101 [suppl]:51F-57F.


To earn CEUs, see test on page 22, or at under the CE Tests tab. The May 2009 test covers both articles in this section.


Upon completion of this article, the reader will be able to:

1. Identify inflammatory biomarkers related to cardiovascular disease.

2. Correlate [Lp-PLA.sub.2] with atherosclerotic plaque.

3. Identify laboratory methods for measuring [Lp-PLA.sub.2].

4. Describe genetic changes of cells resulting in tumors.

5. Identify biomarker factors useful to guide cancer treatment.

By Robert L. Wolfert, PhD

Robert L Wolfert, PhD, is executive vice president and chief scientific officer at diaDexus Inc. in South San Francisco. For more information, please visit,
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Author:Wolfert, Robert L.
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:May 1, 2009
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