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Lp-PLA 2 Lipoprotein-associated phospholipase A 2

Lp-PLA 2 Lipoprotein-associated phospholipase A 2. Closing the Diagnostic Gap in Cardiovascular Risk Assessment. The role of Lp-PLA 2 in risk assessment of cardiovascular disease. Hubert Scharnagl Clinical Institute of Medical and Chemical Laboratory Diagnostics

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Lp-PLA 2 Lipoprotein-associated phospholipase A 2

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  1. Lp-PLA2Lipoprotein-associated phospholipase A2 Closing the Diagnostic Gap in Cardiovascular Risk Assessment

  2. The role of Lp-PLA2 in risk assessment of cardiovascular disease Hubert Scharnagl Clinical Institute of Medical and Chemical Laboratory Diagnostics Medical University of Graz, Austria

  3. Prevalence of Conventional Risk Factors in 87,869 Patients with Established CHD 4 riskfactors (0.9%) 3 riskfactors (8.9%) 0 riskfactor 19.4% 62.4%had 0 to 1 conventional risk factor 2 riskfactors (27.8%) 1 riskfactor (43%) 4 Conventional Risk Factors: Hypertension, Smoking, Hypercholesterolemia, Diabetes KhotUM et al., JAMA 2003

  4. Lp-PLA2Lipoprotein-associated Phospholipase A2 • Ca2+ - independent phospholipaseA2 • 45-kDa proteinwith 441 amino acids • Synthesized by inflammatory cells: monocyte-derived macrophages, T-lymphocytes, mast cells • Lp-PLA2 in circulationbindswithhighaffinityto lipoproteins, primarily to low density lipoproteins (LDL) • Lp-PLA2 catalyzes the hydrolysis of platelet-activating factor (PAF) • Lp-PLA2 is involved in hydrolysis of oxidized phospholipids associated with lipoproteins

  5. The Role of Lp-PLA2 in the Formation ofVulnerable Plaques LUMEN oxLDL INTIMA MEDIA

  6. The Role of Lp-PLA2 in the Formation ofVulnerable Plaques LUMEN Adhesion molecules oxLDL Lp-PLA2 INTIMA Lyso-PC oxFA MEDIA

  7. The Role of Lp-PLA2 in the Formation ofVulnerable Plaques LUMEN Monocytes Plaque formation Cytokines Adhesion molecules oxLDL Lp-PLA2 Foam cell INTIMA Macrophage Macrophages Lyso-PC oxFA MEDIA

  8. The Role of Lp-PLA2 in the Formation ofVulnerable Plaques LUMEN Monocytes Plaque formation Cytokines Adhesion molecules oxLDL Lp-PLA2 Foamcell INTIMA Macrophages Lyso-PC oxFA oxFA andLyso-PC stimulategrowthofplaque  ongoing inflammation within the cap causes plaque instability MEDIA

  9. Contrasting Histopathological Characteristics of a Stable versus Ruptured Plaque Lumen Lumen Lp-PLA2 Lp-PLA2 Thin Fibrous Cap Thick Fibrous Cap Lipid Pool Lipid Pool • Stable Plaque • Low Lp-PLA2 content (dark staining) • May have significant stenosis • Thick fibrous cap / high collagen content • Small lipid pool • Few inflammatory cells • Ruptured Plaque • High Lp-PLA2 content (dark staining) • May have minimal stenosis • Thin fibrous cap / low collagen content • Large lipid pool • Many inflammatory cells Corson MA, Davidson MH, Jones PH. Am J Card Suppl 2008.

  10. Lp-PLA2: a Marker of Plaque Stability and Vulnerability Lp-PLA2… • is a markerofvascularinflammation • is expressed in higherconcentrationsin rupture-prone and ruptured plaques • is an importantmarkerandmediator of plaqueprogressionand vulnerability

  11. Plaque Rupture:Thrombosis versusStenosis Acute Myocardial Infarction Sudden Cardiac Death 68% 76% 70 80 70 60 60 50 50 40 Proportion (%) of AMIs Proportion (%) of Sudden Cardiac Deaths 40 30 24% 30 18% 20 14% 20 10 10 0 0 > 70% 50% - 70% Severe Luminal Narrowing < 50% Plaque Rupture Lesion % Stenosis Falk E, et al. Circulation 1995. Kolodgie F, et al. ATVB 2006.

  12. Substantial Body of Evidence… …supports Lp-PLA2as a cardiovascular risk marker that provides new information, over and above traditional risk factors. 100+ Papers in peer-review journals and Conference abstracts 125,000+ Patients Studied

  13. Elevated Lp-PLA2is Associated with a Doubling of Risk 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 RED = Lp-PLA2 Activity Packard (WOSCOPS), N Engl J Med 2000 – CHD Blake (WHS), J Am Coll Cardiol 2001 – CHD Blankenberg (AtheroGENE), J Lipid Res 2003 - CAD Ballantyne (ARIC), Circulation 2004 - CHD LDL < 130 Winkler, J Clin Endocrinology and Metabolism 2004 – CHD Oei (Rotterdam), Circulation 2005 – CHDBrilakis (Mayo Heart), Eur Heart J 2005 – CHD Ballantyne (ARIC), Arch Intern Med 2005 – Stroke Oei (Rotterdam), Circulation 2005 – Stroke Winkler (LURIC), Circulation 2005 – CHD Khuseyinova (HELICOR), Atherosclerosis 2005 – CHD Koenig (KAROLA), Arterioscler Thromb Vasc Biol 2005 – CVD May (Intermountain Heart), Am Heart J - CHD Jenny (CHS), AHA-EPI Abstract 2006 – MI Elkind (NOMAS), Arch Intern Med 2006 – Stroke O’Donoghue (PROVE IT), Circulation 2006 – CVD Corsetti (THROMBO), Clinical Chemistry 2006 - CHD Gerber (Olmsted County), ATVB 2006 - Death S/P MI Oldgren (GUSTO / FRISC), Eur Heart J 2007 - Acute ACS Sabatine (PEACE), AHA-Scientific Sessions 2006 - CVD Persson (Malmo), Arterioscler Thromb Vasc Biol 2007 - CVD Mockel (NOBIS-II), Clin Res Cardiol 2007 – CVD Hatoum (Nurse’s Health Study), Circ Suppl 2007 – MI Daniels (Rancho Bernardo), JACC 2008 – CHD Robins (VA-HIT), ATVB 2008 - CVD Lp-PLA2 mass Lp-PLA2 activity Corson MA, Davidson MH, Jones PH. Am J Card Suppl 2008

  14. ARIC Study: Lp-PLA2 Increases Risk of Ischemic Stroke at All Levels of Blood Pressure Risk Ratios for Ischemic Stroke Based on Lp-PLA2 Level and SBP 6.8*** 6.8*** Risk Ratio 3.5** 3.5** 2.3* 2.3* High Lp-PLA2 (above median) 3.5 3.5 2.1 2.1 Low Lp-PLA2 (below median) 1.0 1.0 LDL-C in stroke cases = 136 mg/dL LDL-C in non-cases = 132 mg/dL » No significant difference Tertile of Systolic Blood Pressure *p=0.03, **p<0.005, ***p<0.0001 vs. Lp-PLA2 below median Gorelick PM. Am J Cardiol Supplement 2008

  15. The Lp-PLA2 Studies Collaboration Lp-PLA2and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies 32 prospective studies 79,036 subjects 474,976 person-years at risk 17,346 incident vascular and non-vascular outcomes The Lp-PLA2 Studies Collaboration, Lancet 2010

  16. Lp-PLA2 Studies CollaborationLancet 2010 • Key Findings • Lp-PLA2 mass and activity are associated with CVD risk similar in magnitude to two well established risk markers: non-HDL-Cand systolic blood pressure. • Lp-PLA2 levels provide CVD risk assessment independentfrom other biomarkers The Lp-PLA2 Studies Collaboration: Lancet 2010; 375: 1536–44.

  17. Lp-PLA2 Activity Primary Prevention Studies

  18. Lp-PLA2 ActivitySecondary Prevention Studies

  19. Lipid Lowering Medications Shown to Reduce CV Events also Lower Lp-PLA2 Feno- Fibrate1,4 Average Statin1-4 Omega 3FA + Statin6 Niacin + Statin5 Ezetimibe1 Statin Statin Reduction in Lp-PLA2 Omega 3 FA added Niacin added 4. Muhlestein JB, et al. JACC. 2006 5. Kuvin J, et al. Am J Cardiol. 2006 6. Schalwitz R, et al. ATVB Annual Mtg2007 1. SaougosVG, et al. ATVB 2007 2. Albert M, et al. Atherosclerosis 2005 3. Schaefer EJ, et al. Am J Cardiol. 2005

  20. Effect of changes in levels of Lp-PLA2 activity on CVD outcomes: LIPID study CVD death, MI, stroke, UAP, revascularization 2.0 0.5 1.0 Adjusted for age, gender, stroke, diabetes, smoker, hypertension, total-c, HDL-c, prior ACS, revascularisation, SBP, atrial fibrillation, eGFR, BMI, dyspnoea, angina, WBC, PVD, aspirin, fasting glucose, triglycerides, ApoB, ApoA1, and change in LDL-c White HD et al., J Am Heart Assoc 2013

  21. LIPID Study: Results • Reduction in Lp-PLA2 is a significant predictor of CHD events even after adjustment for • treatment • 23 baseline risk factors • 7 other new biomarkers (i.e. NTproBNP, troponin I, Lp-PLA2) • reduction in LDL-cholesterol • Change in Lp-PLA2 may account for a substantial proportion of Pravastatin effect in reducing CHD events White HD et al., J Am Heart Assoc 2013

  22. Expert Consensus Panel Recommendation for Use of Lp-PLA2 Testing Lp-PLA2 TESTING Elevated Low Assess CV Risk Low CV Risk0-1 risk factors ModerateCV Risk2+ risk factors High CV RiskCHD, or CHD RiskEquivalent Very HighCV Risk Lp-PLA2 TESTING Test Lp-PLA2 Elevated Low Treat to LDL goal LDL-C Goal< 160 mg/dL < 4.0 mmol/L LDL-C Goal< 130 mg/dL < 3.3 mmol/L LDL-C Goal< 100 mg/dL < 2.5 mmol/L LDL-C Goal< 70 mg/dL < 1.8 mmol/L Davidson MH, et al. Am J Card Suppl 2008

  23. Summary • Lp-PLA2 is a specific marker for vascular inflammation and is a circulating measure of the progression of rupture-prone plaque • Elevated Lp-PLA2 plasma levels and activity correlate with a doubling of risk for cardiovascular disease • Lp-PLA2 levels can be used to identify patients who require more aggressive treatment, including lipid-lowering therapy • Lp-PLA2 – risk factor and therapeutical target ?

  24. Thank you for your attention

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