►The role of lipoprotein-associated phospholipase A2 on cardiovascular disease risk assessment and plaque rupture: a clinical review Kota J. Reddy, MD, Manmeet Singh, MD, Joey R. Bangit, MD Richard R. Batsell, PhD
Journal of Clinical Lipidology (2009)
►Enhanced Expression of Lp-PLA2 and Lysophosphatidylcholine in Symptomatic Carotid Atherosclerotic Plaques Dallit Mannheim, Joerg Herrmann, Daniele Versari, Mario Gössl, Fredric B. Meyer, Joseph P. McConnell, Lilach O. Lerman and Amir Lerman
Background and Purpose—Circulating lipoprotein-associated phospholipase A2 (Lp-PLA2) has merged as a novel biomarker for cardiovascular diseases. However, the correlation between the plaque expression of Lp-PLA2 and plaque oxidative stress, inflammation, and stability as well as the clinical presentation remains poorly defined, especially for cerebrovascular disease. Therefore, this study was performed to test the hypothesis that Lp-PLA2 expression is higher in symptomatic than in symptomatic carotid plaques of patients undergoing carotid endarterectomy.
Methods—The expression of Lp-PLA2 in 167 carotid artery plaques was determined by immunoblotting and immunostaining. Plaque oxidative stress, inflammation, and stability were quantified by NAD(P)H oxidase p67phox and MMP-2 immunoblotting, oxidized LDL (oxLDL) immunoreactivity, macrophage and Sirius red collagen staining. Lysophosphatidylcholine 16:0 (lysoPC) concentration was measured in 55 plaques using liquid chromatography tandem mass spectrometry.
Results—Lp-PLA2 expression was significantly higher in plaques of symptomatic patients than asymptomatic patients (1.66 +/- 0.19 versus 1.14 +/- 0.10, P<0.05) and localized mainly to shoulder and necrotic lipid core areas in colocalization with oxLDL and macrophage content. Similarly, Lp-PLA2 expression was related to collagen content, which was lower in plaques from symptomatic patients than in plaques from asymptomatic patients (9.1 +/- 2.2 versus 18.5 +/- 1.7% of staining/field, P<0.001). LysoPC plaque concentration was significantly higher in plaques of symptomatic than asymptomatic patients (437.0 +/- 57.91 versus 228.84 +/- 37.00 mmol/L, P<0.05).
Conclusions—Symptomatic carotid artery plaques are characterized by increased levels of Lp-PLA2 and its product lysoPC in correlation with markers of tissue oxidative stress, inflammation, and instability. These findings strongly support a role for Lp-PLA2 in the pathophysiology and clinical presentation of cerebrovascular disease.
►Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) Study C.M Ballantyne, R.C Hoogeveen, H Bang ACC Current Journal Review (May 2004)
Study Question : Can lipoprotein-associated phospholipase A2 (Lp-PLA2), a proinflammatory enzyme associated primarily with LDL particles, be used to characterize coronary heart disease (CHD) risk?
Methods : The Atherosclerosis Risk in Communities (ARIC) study was performed in over 15,000 apparently healthy adults aged 45–64 years between 1987–1989, with three repeated exams until 1998. A prospective case cohort study was conducted in 1652 subjects in which cases with incident CHD were compared to a cohort random sample. Lp-PLA2 and C-reactive protein (CRP) (obtained at visit 2), traditional risk factors and risk for CHD events over a period of ≈6 years were examined in a proportional hazards model, stratified by LDL-C.
Results : Mean age was 58 years. Of the 608 CHD events, 41.6% were nonfatal myocardial infarctions (MIs), 9.5% silent MIs, 39% were revascularization procedures and 9.9% were fatal events with a mean time to events of 4.1 years. Lp-PLA2 and CRP levels were higher in the CHD cases than in the 740 controls. Both Lp-PLA2 and CRP were associated with incident CHD after adjustment for age, gender and race, with a hazard ratio of 1.78 for the highest tertile of Lp-PLA2 and 2.53 for the highest category of CRP vs. the lowest categories Lp-PLA2 correlated positively with LDL-C (r = 0.36) and negatively with HDL-C (r = −0.33) but not with CRP (r = −0.05). In a model adjusted for traditional risk factors including LDL-C, the association of Lp-PLA2 with CHD was attenuated and not statistically significant. For individuals with LDL-C below the median (130 mg/dL), Lp-PLA2 and CRP were both significantly and independently associated with CHD in fully adjusted models. For individuals with LDL-C <130 mg/dL, those with both Lp-PLA2 and CRP levels in the highest tertile were at the greatest risk for a CHD event. The combination of the high Lp-PLA2 (>422 μg/L) and CRP (>3 mg/L) increases the CHD risk by 2.95, 95% CI 1.47–5.94, p=0.002, whereas a high CRP and low-medium Lp-PLA2 or high Lp-PLA2 and low-medium CRP is not associated with an increased risk.
Conclusions : Both Lp-PLA2 and CRP may be complementary in identifying individuals at high CHD risk who have low LDL-C.
Perspective : The findings are similar to those in WOSCOPS, a study limited to men with severe hypercholesterolemia. Lp-PLA2 is an enzyme responsible for the hydrolysis of oxidized phospholipids and can lead to increased vascular inflammation and expression of adhesion molecules. Lp-PLA2 would appear to be most useful in risk-stratifying the intermediate-risk patient, particularly those with an LDL-C <130 mg/dL, the cohort that is most difficult to assess regarding lipid-lowering treatment. MR
►Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Kolodgie FD, Burke AP, Skorija KS, et al. Arterioscler Thromb Vasc Biol. (2006)
Objective— Although lipoprotein-associatedphospholipaseA2 (Lp-PLA2) has received recent attention as a biomarker ofinflammation and risk for acute coronary events, its relativeexpression in coronary plaque phenotypes, including unstablelesions, has not been established.
Methods and Results— Coronary segments (n=30) were prospectivelycollected from 25 sudden coronary death patients for immunolocalizationof Lp-PLA2. Lesion morphologies were classified as pathologicintimal thickening, fibroatheromas, thin-cap fibroatheromas(fibrous cap thicknesses <65 µm), and rupture. Theexpression of Lp-PLA2 was detected using a specific monoclonalantibody. Apoptosis was identified by DNA end-labeling usingterminal deoxynucleotidyl transferase (TdT). Lp-PLA2 stainingin early plaques was absent or minimally detected. In contrast,thin-cap fibroatheromas and ruptured plaques showed intenseLp-PLA2 expression within necrotic cores and surrounding macrophagesincluding those in the fibrous cap. The degree of macrophageapoptosis was greater in thin-cap fibroatheroma and rupturescompared with less advanced plaques with additional double labelingstudies showing Lp-PLA2 present in apoptotic cells in regionsof high macrophage density.
Conclusions— Lp-PLA2 is strongly expressed within thenecrotic core and surrounding macrophages of vulnerable andruptured plaques, with relatively weak staining in less advancedlesions. These findings together with the association of Lp-PLA2in apoptotic macrophages suggest a potential role in promotingplaque instability.
The expression of lipoprotein-associatedphospholipase A2 (Lp-PLA2)was assessed in early through late, unstable coronary plaquesfrom sudden death victims. Lp-PLA2 was mostly present in plaqueruptures and thin-cap fibroatheromas in necrotic cores and surroundingareas of apoptotic macrophages. The present study suggests Lp-PLA2may be an important biomarker for plaque instability.
► Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality : collaborative analysis of 32 prospective studies Lancet 2010
Background Lipoprotein-associated phospholipase A2 (Lp-PLA2), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA2 mass and activity with risk of coronary hoeart disease, stroke, and mortality under different circumstances.
Methods With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA2 or other risk factor. The primary outcome was coronary heart disease.
Findings Lp-PLA2 activity and mass were associated with each other (r=0·51, 95% CI 0·47–0·56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA2 activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1·10 (95% CI 1·05–1·16) with Lp-PLA2 activity and 1·11 (1·07–1·16) with Lp-PLA2 mass for coronary heart disease; 1·08 (0·97–1·20) and 1·14 (1·02–1·27) for ischaemic stroke; 1·16 (1·09–1·24) and 1·13 (1·05–1·22) for vascular mortality; and 1·10 (1·04–1·17) and 1·10 (1·03–1·18) for
non-vascular mortality, respectively. RRs with Lp-PLA2 did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA2 mass. Adjusted RRs for coronary heart disease were 1·10 (1·02–1·18) with non-HDL cholesterol and 1·10 (1·00–1·21) with systolic blood pressure.
Interpretation Lp-PLA2 activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA2 mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids.
Funding UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.
Discoveries & Breakthroughs Inside Science - August 2009
Blood Test Predicts Stroke
The Discoveries & Breakthroughs “Inside Science” segment featuring Dr. Richard Karas and the PLAC Test has been posted to the DBIS website. It includes a film segment on the PLAC Test and uncovering hidden risk for heart disease and ischemic stroke. It positions the PLAC Test as a great tool to help identify people at an increased risk that are not caught by traditional risk assessment.
Physician's Weekly - August 2009
Markers of Arterial Inflammation
by Dr. Bradley Bale
The article titled, “Markers of Arterial Inflammation” contributed by Dr. Bradley Bale appears in the August 31 edition of Physician’s Weekly. A news partner of Pri-Med, the publication reaches over 200,000 practicing clinicians and is also available online at www.physweekly.com. The article that discusses hs-CRP and Lp-PLA2 as key markers of arterial inflammation, but highlights and focuses on the clinical validity of Lp-PLA2 to a very important audience for diaDexus.
WomenOf.com - August 2009
Coronary Heart Disease and Ischemic Stroke Predicted
by Dr. Leonard Moss
Dr. Moss recently published an article in WomenOf.com, an online women's magazine that delivers usable information to women on topics ranging from career-business, health, family, style and travel to entertainment with 500,000 unique visitors per month. In his article, Dr. Moss positions the PLAC Test as an FDA-cleared test that detects hidden risk for coronary heart disease and ischemic stroke.
WebMD Blog - August 2009
Markers of Cardiovascular Risk - PLAC Test
by Michael Richman, MD, FACS
Dr Michael Richman contrinutes an article to the "Cholesterol Management 101" section of the WebMD Blog in which he discusses the benefits of the PLAC Test.
Cardiovascular Business - July 2009
New Cardiac Biomarkers Target Plaque, Protein & Patelets
by C.P. Kaiser
While well-established cardiovascular biomarkers still play a major role in clinical practice, many more biomarkers are vying for clinical attention. Four biomarkers are discussed in detail.
ADVANCE for Administrators of the Laboratory - July 2009
Arterial Inflammation Biomarkers. Which should your lab offer for routine testing? by Bradley Field Bale, MD
Dr. Bradley Bale contributed an article to ADVANCE for Administraotors of the Laboratory discussing the benefits of Arterial Inflammation Biomarkers. Of the four markers he describes, Lp-PLA2 is mentioned and directly linked to the evolution of atherosclerosis.
SeniorJournal.com - May 20, 2009
New Protection from Coronary Heart Disease is Avoiding Plaque Rupture with PLAC Test by Dr. Paul Ziajka
Dr. Ziajka recently contributed an article to the Health & Medicine for Senior Citizens section of SeniorJournal.com. He discussed the importance of testing for rupture-prone plaque in senior citizens with the PLAC Test and included a brief animation of how rupture-prone plaque is created.
KFDX 3 News - May 15, 2009
Dr. Michael Wegner, Director of Medical Affairs for diaDexus, visited Bowie Memorial Hospital to discuss the advances in the detection of rupture-prone plaque. Bowie Memorial Hospital is currently the only facility in the Texoma area with the capability to offer PLAC Test for Lp-PLA2.
Prevention - May 2009
Healthy Power Pairs by Danielle Kosecki
PLAC Test + hsCRP. These tests measure Lp-PLA2 and CRP levels, two important markers of the kind of inflammation caused by the accumulation of plaque in your ateries - a big predictor of heart disease. When doctors added the results of these screenings to their usual assessment of risk factors (blood pressure, cholesterol, etc.) they ended up reclassifying 39% of intermediate-risk patients - including 11% who were in need of more serious treatment - reports a new study published in the journal Stroke. Many of these patients may now be candidates for statins.
Senior Observer - April 20, 2009
Paul Ziaika, MD, director of the Florida Lipid Institute in Winter Park, FL is one of the first doctos in Winter Park to use a new FDA-approved test that helps identify hidden risk for heart attack and stroke for his patients. It's called the PLAC Test.
The Doctors - March 20, 2009
"The Doctors," a nationally syndicated televison program, aired a segment about women's heart health in their 40’s which highlighted the PLAC Test, a new tool physicians are using to detect hidden risk of heart disease and ischemic stroke. The show’s physician explains the atherosclerotic process highlighting how Lp-PLA2 builds up in the artery walls and can cause a plaque rupture that can lead to a blood clot. The results of one woman's blood work were revealed on the show finding that she was at high risk of suffering a heart attack or stroke.
Woman’s World - March 16, 2009
Ask your doctor for this test! By Amy Capetta
PLAC Test Patient Francis Thornberry’s experience with test is featured in the “Medical Breakthroughs” section.
Univision.com - February 26, 2009
El riesgo de ataque al corazón By Paola Ortiz
Dr. Bradley Bale provides commentary about identifying and reducing risk for suffering a heart attack including use of the PLAC Test.
Forbes.com - February 2, 2009
How to Avoid a Heart Attack By Rebecca Ruiz Dr. Howard Weintraub provides commentary for this article, which features Retired NFL player Dave O’Brien’s experience with the PLAC Test.
Figure - February 2009
Take this heart health test By Linda Wasmer
The PLAC Test is featured on the health news page of the magazine; readers are encouraged to ask their doctors about the PLAC Test.
HealthDay - January 8, 2009
Inflammation Markers May Help Predict Stroke Risk By Ed Edelson
Dr. Nambi and Dr. Philip Gorelick provide commentary for this article focusing on a recent study published in the journal STROKE that demonstrated the value of testing for Lp-PLA2, in addition to traditional risk factors, to best determine one’s risk for stroke.
Saturday Evening Post - January 2009
Are You as Healthy as You Think? The PLAC Test is featured in the Medical Update section.
Only a Game - December 5, 2008
Former NFL Players Check their Heart Health Coverage features sound bites from Dr. Archie Roberts and PLAC Test patient Dave O’Brien who discuss the test and how it is used at cardiovascular screening events held by the Living Heart Foundation.
SeniorJournal.com - October 29, 2008
PLAC Test to Get Tested on Defensive Line for Heart Attack, Stroke of NFL Retirees By Tucker Sutherland
The article discusses the PLAC Test and its use at Living Heart Foundation events geared for retired NFL players. PLAC Test patient Dave O’Brien and Dr. Archie Roberts are quoted in the piece.