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Wolfgang Koenig, MD, FESC, FACCWolfgang Koenig, MD, FESC, FACC
Dept. of Internal Medicine II - CardiologyDept. of Internal...
IdentityIdentity
Test PositiveTest Positive
Test NegativeTest Negative
0.50.5
0.40.4
0.30.3
0.20.2
0.10.1
0.00.0
0.05 0.1 ...
* ESR, erythrocyte sedimentation rate; PAI-1, plasminogen activator inhibitor-1; vWF, von Willebrand factor;* ESR, erythro...
KullerKuller MRFITMRFIT19961996 CHD deathCHD death
RidkerRidker PHSPHS 19971997 MIMI
RidkerRidker PHSPHS19971997 StrokeStr...
0.810.81<0.001<0.0012.32.32.02.01.61.61.41.41.01.0Risk-factor–adj. RRRisk-factor–adj. RR
0.810.81<0.001<0.0011.51.51.31.31...
00
55
1010
1515
2020
2525
0-10-1 2-42-4 5-95-9 ≥≥1010
<1.0<1.0
1.0-3.01.0-3.0
>3.>3.
00
CRP mg/LCRP mg/L
<1.0<1.0
1.0-3.01...
Class I: Should be performedClass I: Should be performed
Class II: Conflicting evidence/opinionClass II: Conflicting evide...
The Value of CRP in CardiovascularThe Value of CRP in Cardiovascular
Risk Prediction: The Rotterdam StudyRisk Prediction: ...
< 6 6-10 11-14 15-19< 6 6-10 11-14 15-19 ≥≥2020
00
11
22
33
44
55
66
77
88
RR of CHD According to the Estimated 10-YrRR of...
FactorFactor Events/nEvents/n HR (95%CI)HR (95%CI) P-valueP-value HR (95%CI)HR (95%CI) P-valueP-value
FRS 1FRS 1 <6<6 18/8...
MONICA Augsburg Cohort Study: SummaryMONICA Augsburg Cohort Study: Summary
 Elevated CRP concentrations and an elevated T...
* ESR, erythrocyte sedimentation rate; PAI-1, plasminogen activator inhibitor-1; vWF, von Willebrand factor;* ESR, erythro...
IL-18 and Risk of CHDIL-18 and Risk of CHD**: PRIME: PRIME
Combined EndpointCombined Endpoint Coronary Death and MICoronar...
 Lipoprotein-associated phospholipase ALipoprotein-associated phospholipase A22 (Lp-PLA(Lp-PLA22))
Platelet-activating fa...
Theory: Lp-PLATheory: Lp-PLA22 Promotes AtherogenesisPromotes Atherogenesis
 Generates lyso-PC during oxidation of LDLGen...
LumenLumen
IntimaIntima
MediaMedia
LDLLDL
OxidizedOxidized
LDLLDL
Lp-PLALp-PLA22
Lyso-PCLyso-PC
++
OxFAOxFA
AdhesionAdhesi...
West of Scotland CoronaryWest of Scotland Coronary
Prevention Study (WOSCOPS)Prevention Study (WOSCOPS)
WOSCOPS StudyWOSCO...
Lp-PLALp-PLA22 as a Novel Risk Factor in CHD:as a Novel Risk Factor in CHD:
WOSCOPSWOSCOPS
Baseline samplesBaseline sample...
CRP, Lp-PLACRP, Lp-PLA22 and CHD Risk: WOSCOPSand CHD Risk: WOSCOPS
univariateunivariate Inflam. markersInflam. markers Al...
Methods: Patient Population and AssaysMethods: Patient Population and Assays
 12,819 apparently healthy men and women fre...
Weighted-Adjusted* Means of Risk FactorsWeighted-Adjusted* Means of Risk Factors
Variable Cases (n=608) Noncases(n=740) P-...
22 (310-422(310-422 μμg/L)g/L) 33 (≥422(≥422 μμg/L)g/L)
Model 1Model 1††
1.26 (0.94-1.69)1.26 (0.94-1.69) 1.78 (1.33-2.38)...
Weighted-Correlation BetweenWeighted-Correlation Between
Lp-PLALp-PLA22 and Other Risk Factors: ARICand Other Risk Factors...
00
11
22
33
Association of Lp-PLA2 and hs-CRP with IncidentAssociation of Lp-PLA2 and hs-CRP with Incident
CHD in Patients...
Lp-PLALp-PLA22 and Risk of CHD:and Risk of CHD:
MONICA-Augsburg Cohort 1984-98MONICA-Augsburg Cohort 1984-98
 934 men age...
Age-adjusted Baseline Characteristics of 934 Men,Age-adjusted Baseline Characteristics of 934 Men,
Aged 45-64 Years Partic...
Correlation BetweenCorrelation Between Lp-PLALp-PLA22, CRP and, CRP and
Other Cardiovascular Risk Factors: MONICAOther Car...
MONICA: RR of CHD by a 1 SD IncreaseMONICA: RR of CHD by a 1 SD Increase
in CRP or Lp-PLAin CRP or Lp-PLA22 (separate mode...
MONICA: RR of CHD by a 1 SD IncreaseMONICA: RR of CHD by a 1 SD Increase
in Lp-PLAin Lp-PLA22 or CRP (same model)or CRP (s...
UnadjustedUnadjusted Adjusted for age MultivariableAdjusted for age Multivariable
DM, smokingDM, smoking adjustment*adjust...
Summary and ConclusionsSummary and Conclusions
 Lp-PLALp-PLA22 was the strongest predictor/biomarker of coronarywas the s...
BreakBreak
Diagnosing Risk: CRP and Lp-PLADiagnosing Risk: CRP and Lp-PLA22
Case-Control Study:Case-Control Study:
Population and Laboratory MethodsPopulation and Laboratory Methods
Patients withPat...
CADCAD patients (n=patients (n=312) Controls (n=312) Controls (n=479479))
Age (yrs)Age (yrs) 57.757.7 ±± 7.47.4 55.855.8±±...
Distribution of Lipid Variables, Markers ofDistribution of Lipid Variables, Markers of
Coagulation, Fibrinolysis and Infla...
CAD patients Controls P-value
Leukocytes [103
/µL]* 6.9±1.81 5.8±1.53 0.0001
C-reactive protein [mg/L]†
1.7 (0.7-3.8) 1.2 ...
VariablesVariables CasesCases P-valueP-value ControlsControls P-valueP-value
AgeAge -0.002-0.002 0.960.96 0.170.17 0.00010...
Odds Ratios (OR) of CAD Associated WithOdds Ratios (OR) of CAD Associated With
Lp-PLALp-PLA22 Levels After Various Adjustm...
Atherogenic Activities of Lyso-PCAtherogenic Activities of Lyso-PC
Endothelial cells
Promotes endothelial dysfunction, upr...
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Aeha2004 crp lppla2newtemplate

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Aeha2004 crp lppla2newtemplate

  1. 1. Wolfgang Koenig, MD, FESC, FACCWolfgang Koenig, MD, FESC, FACC Dept. of Internal Medicine II - CardiologyDept. of Internal Medicine II - Cardiology University of Ulm Medical CenterUniversity of Ulm Medical Center Ulm, GermanyUlm, Germany CRP, Lp-PLACRP, Lp-PLA22 , and Other Serum Markers, and Other Serum Markers of Disease and Vulnerabilityof Disease and Vulnerability The 2The 2ndnd Vulnerable Patient Satellite SymposiumVulnerable Patient Satellite Symposium Towards a National Screening ProgramTowards a National Screening Program New Orleans, LA, March 6New Orleans, LA, March 6thth , 2004, 2004
  2. 2. IdentityIdentity Test PositiveTest Positive Test NegativeTest Negative 0.50.5 0.40.4 0.30.3 0.20.2 0.10.1 0.00.0 0.05 0.1 0.15 0.20.05 0.1 0.15 0.2 Pre-test Probability of CHD Event in 10 YrsPre-test Probability of CHD Event in 10 Yrs Post-testProbabilityofCHDEventin10YrsPost-testProbabilityofCHDEventin10Yrs modified after Greenland et al. Circulation 2001;104:1863-1867modified after Greenland et al. Circulation 2001;104:1863-1867 Low-Risk Intermediate-Risk High-RiskLow-Risk Intermediate-Risk High-Risk (~35 % of Pts.) (~40% of Pts.) (~25% of Pts.)(~35 % of Pts.) (~40% of Pts.) (~25% of Pts.) <6 (10) % 6 (10) -19 % ≥ 20 %<6 (10) % 6 (10) -19 % ≥ 20 % over 10 yearsover 10 years CHD Risk Assessment in AsymptomaticCHD Risk Assessment in Asymptomatic Patients: Selective Use of Noninvasive TestingPatients: Selective Use of Noninvasive Testing Modification of Probability Estimates ofModification of Probability Estimates of CHD by Non-invasive TestingCHD by Non-invasive Testing  Assessment by multivariableAssessment by multivariable statistical models: e.g.statistical models: e.g. Framingham Risk Score orFramingham Risk Score or PROCAM ScorePROCAM Score  Clear guidelines for high or lowClear guidelines for high or low risk subjects, but not so forrisk subjects, but not so for those at intermediate riskthose at intermediate risk
  3. 3. * ESR, erythrocyte sedimentation rate; PAI-1, plasminogen activator inhibitor-1; vWF, von Willebrand factor;* ESR, erythrocyte sedimentation rate; PAI-1, plasminogen activator inhibitor-1; vWF, von Willebrand factor; CIC, circulating immune complexes; Lp-PLACIC, circulating immune complexes; Lp-PLA22 lipoprotein-associated phospholipase Alipoprotein-associated phospholipase A22 Acute Phase Reactants InvestigatedAcute Phase Reactants Investigated Prospectively in Epidemiological StudiesProspectively in Epidemiological Studies Non-ProteinNon-Protein MarkersMarkers Frequently StudiedFrequently Studied ProteinsProteins Infrequently StudiedInfrequently Studied ProteinsProteins LeukocytesLeukocytes C-reactive proteinC-reactive protein OrosomucoidOrosomucoid ESR*ESR* Serum amyloid ASerum amyloid A AlphaAlpha11-antitrypsin-antitrypsin Plasma viscosityPlasma viscosity FibrinogenFibrinogen HaptoglobinHaptoglobin AlbuminAlbumin CeruloplasminCeruloplasmin PlasminogenPlasminogen C3, C4C3, C4 PAI-1*PAI-1* IgA, G, M, and EIgA, G, M, and E vWF*vWF* Sialic acidSialic acid CytokinesCytokines (IL-6, 8, 10,(IL-6, 8, 10, 1818)) CIC*CIC* CAMsCAMs Lp (a)Lp (a) Lp-PLALp-PLA22**,, sPLAsPLA22-IIA-IIA mod. after Koenig & Rosenson. Sem Vasc Med 2002;2:417-24mod. after Koenig & Rosenson. Sem Vasc Med 2002;2:417-24
  4. 4. KullerKuller MRFITMRFIT19961996 CHD deathCHD death RidkerRidker PHSPHS 19971997 MIMI RidkerRidker PHSPHS19971997 StrokeStroke TracyTracy CHS/RHPPCHS/RHPP19971997 CHDCHD RidkerRidker PHSPHS1998,20011998,2001 PADPAD RidkerRidker WHSWHS 1998,2000,20021998,2000,2002 CVDCVD KoenigKoenig MONICAMONICA19991999 CHDCHD RoivainenRoivainen HELSINKIHELSINKI 20002000 CHDCHD MendallMendall CAERPHILLYCAERPHILLY 20002000 CHDCHD DaneshDanesh BRITAINBRITAIN 20002000 CHDCHD GusseklooGussekloo LEIDENLEIDEN 20012001 Fatal StrokeFatal Stroke LoweLowe SPEEDWELLSPEEDWELL 20012001 CHDCHD PackardPackard WOSCOPSWOSCOPS 20012001 CV EventsCV Events RidkerRidker AFCAPSAFCAPS 20012001 CV EventsCV Events RostRost FHSFHS 20012001 StrokeStroke PradhanPradhan WHIWHI 20022002 MI, CVD deathMI, CVD death AlbertAlbert PHSPHS 20022002 Sudden DeathSudden Death SakkinenSakkinen HHSHHS 20022002 MIMI 00 1.01.0 2.02.0 3.03.0 4.04.0 5.05.0 6.06.0 Relative Risk (upper versus lower quartile)Relative Risk (upper versus lower quartile) CRP as a Risk Factor for Future CVD –CRP as a Risk Factor for Future CVD – Results from Population-Based StudiesResults from Population-Based Studies
  5. 5. 0.810.81<0.001<0.0012.32.32.02.01.61.61.41.41.01.0Risk-factor–adj. RRRisk-factor–adj. RR 0.810.81<0.001<0.0011.51.51.31.31.11.10.90.91.01.0Risk-factor–adj. RRRisk-factor–adj. RR 0.730.73<0.001<0.0011.71.71.51.51.11.10.90.91.01.0Age-adjusted RRAge-adjusted RR 0.600.60<0.001<0.0012.22.21.81.81.31.31.01.01.01.0Crude RRCrude RR 55 (>153.9)(>153.9) 44 (>132.2-(>132.2- 153.9)153.9) 33 (>115.4-(>115.4- 132.2)132.2) 22 (>97.6(>97.6 -115.4)-115.4) 11 ((≤≤97.6)97.6) 0.740.74<0.001<0.0013.63.62.52.51.81.81.51.51.01.0Age-adjusted RRAge-adjusted RR 0.640.64<0.001<0.0014.54.53.23.22.32.31.81.81.01.0Crude RRCrude RR AreaArea underunder ROCROC CurveCurve P-P- ValueValue 55 (>4.19)(>4.19) 44 (>2.09-(>2.09- 4.19)4.19) 33 (>1.08-(>1.08- 2.09)2.09) 22 (>0.49-(>0.49- 1.08)1.08) 11 ((≤≤0.49)0.49) VariableVariable Quintile of CRP (mg/L)Quintile of CRP (mg/L) Quintile of LDL Cholesterol (mg/dL)Quintile of LDL Cholesterol (mg/dL) Ridker et al. N Engl J Med 2002;347:1557-1565Ridker et al. N Engl J Med 2002;347:1557-1565 Relative Risk (RR) of a First Cardiovascular Event,Relative Risk (RR) of a First Cardiovascular Event, According to CRP and LDL- C at Baseline (WHS)According to CRP and LDL- C at Baseline (WHS)
  6. 6. 00 55 1010 1515 2020 2525 0-10-1 2-42-4 5-95-9 ≥≥1010 <1.0<1.0 1.0-3.01.0-3.0 >3.>3. 00 CRP mg/LCRP mg/L <1.0<1.0 1.0-3.01.0-3.0 >3.0>3.0 CRP mg/LCRP mg/L 00 11 22 33 <130<130 130-160130-160 <160<160 MultivariableRelativeRiskMultivariableRelativeRisk MultivariableRelativeRiskMultivariableRelativeRisk Framingham Estimate of 10-Year Risk (%)Framingham Estimate of 10-Year Risk (%) LDL Cholesterol (mg/dL)LDL Cholesterol (mg/dL) RR of Cardiovascular Disease According to Levels ofRR of Cardiovascular Disease According to Levels of CRP and the Estimated10-Year Risk and According toCRP and the Estimated10-Year Risk and According to Levels of CRP and Categories of LDL-C (WHS)Levels of CRP and Categories of LDL-C (WHS) Ridker et al. N Engl J Med 2002;347:1557-1565Ridker et al. N Engl J Med 2002;347:1557-1565
  7. 7. Class I: Should be performedClass I: Should be performed Class II: Conflicting evidence/opinionClass II: Conflicting evidence/opinion a: Weight in favor of usefulness/efficacya: Weight in favor of usefulness/efficacy b: Usefulness/efficacy less well establishedb: Usefulness/efficacy less well established Class III: Should not be performedClass III: Should not be performed Class I: Should be performedClass I: Should be performed Class II: Conflicting evidence/opinionClass II: Conflicting evidence/opinion a: Weight in favor of usefulness/efficacya: Weight in favor of usefulness/efficacy b: Usefulness/efficacy less well establishedb: Usefulness/efficacy less well established Class III: Should not be performedClass III: Should not be performed AHA/CDC Recommendations forAHA/CDC Recommendations for Clinical and Public Health PracticeClinical and Public Health Practice  Of current inflammatory markers identified,Of current inflammatory markers identified, hs-CRP hashs-CRP has the analyte & assay characteristics most conducive to usethe analyte & assay characteristics most conducive to use in practicein practice (Class IIa, Level of Evidence B)(Class IIa, Level of Evidence B)  Other inflammatory markers should not be measured forOther inflammatory markers should not be measured for determination of CV risk in addition to hs-CRPdetermination of CV risk in addition to hs-CRP (Class III,(Class III, Level of Evidence C)Level of Evidence C) Laboratory TestsLaboratory Tests AHA/CDC Statement. Circulation 2003;107:499–511AHA/CDC Statement. Circulation 2003;107:499–511
  8. 8. The Value of CRP in CardiovascularThe Value of CRP in Cardiovascular Risk Prediction: The Rotterdam StudyRisk Prediction: The Rotterdam Study  Nested case-control study (157/500) within a population basedNested case-control study (157/500) within a population based cohort study of 7983 men and women >55 yearscohort study of 7983 men and women >55 years  Multivariable RR (Q4-Q1) for CRP 1.2 (95% CI, 0.6-2.2)Multivariable RR (Q4-Q1) for CRP 1.2 (95% CI, 0.6-2.2)  Assessment of Framingham Risk Score w/o and with CRPAssessment of Framingham Risk Score w/o and with CRP  Assessment of AUC by ROC analysisAssessment of AUC by ROC analysis VariableVariable AUC (SE)AUC (SE) Basic riskBasic risk ** 0.642 (0.026)0.642 (0.026) Risk function 1Risk function 1 †† 0.773 (0.021)0.773 (0.021) with CRPwith CRP 0.777 (0.021)0.777 (0.021) Risk function 2Risk function 2 ‡‡ 0.746 (0.021)0.746 (0.021) with CRPwith CRP 0.748 (0.021)0.748 (0.021) * Indicated by age, age squared, sex;* Indicated by age, age squared, sex; †† Indicated by age, age squared, sex, current smoking, BMI,Indicated by age, age squared, sex, current smoking, BMI, BP, DM, family hystory of early MI, TC, HDL;BP, DM, family hystory of early MI, TC, HDL; ‡‡ based on the Framingham risk function + LVHbased on the Framingham risk function + LVH Van der Meer et al. Arch Intern Med 2003;163:1323-1328Van der Meer et al. Arch Intern Med 2003;163:1323-1328
  9. 9. < 6 6-10 11-14 15-19< 6 6-10 11-14 15-19 ≥≥2020 00 11 22 33 44 55 66 77 88 RR of CHD According to the Estimated 10-YrRR of CHD According to the Estimated 10-Yr Risk Alone and in Combination With CRP:Risk Alone and in Combination With CRP: MONICA Augsburg CohortMONICA Augsburg Cohort < 6 6-10 11-14 15-19< 6 6-10 11-14 15-19 ≥≥2020 00 11 22 33 44 55 66 77 88 P=0.19P=0.19 P=0.28P=0.28 P=0.02P=0.02 P=0.03P=0.03 P=0.14P=0.14 <1.0<1.0 1.0 – 3.01.0 – 3.0 > 3.0> 3.0 CRPCRP mg/Lmg/L 1818 3232 35 50 5635 50 56 Population at riskPopulation at risk 809 914 650 526 536809 914 650 526 536 Framingham Estimate of 10-Year Risk (%)Framingham Estimate of 10-Year Risk (%) MultivariableRelativeRiskMultivariableRelativeRisk AIC 2776AIC 2776AIC 2789AIC 2789 (N=3,435 Men, 45-74 Yrs; 191 Events, FU 6.6 Yrs)(N=3,435 Men, 45-74 Yrs; 191 Events, FU 6.6 Yrs) Koenig et al. Circulation (in press)Koenig et al. Circulation (in press)
  10. 10. FactorFactor Events/nEvents/n HR (95%CI)HR (95%CI) P-valueP-value HR (95%CI)HR (95%CI) P-valueP-value FRS 1FRS 1 <6<6 18/80918/809 Ref.Ref. Ref.Ref. (%)(%) 6-196-19 117/2090117/2090 2.81 (1.71-4.62)2.81 (1.71-4.62) 2.39 (1.45-3.94)2.39 (1.45-3.94) ≥≥2020 56/53656/536 6.19 (3.64-10.54)6.19 (3.64-10.54) <0.0001<0.0001 4.85 (2.82-8.33)4.85 (2.82-8.33) <0.0001<0.0001 AICAIC 28162816 27972797 ∆∆AIC 19AIC 19 AUCAUC 0.7130.713 0.7400.740 0.00770.0077 FRS 2FRS 2 <6<6 18/80918/809 Ref.Ref. Ref.Ref. (%)(%) 6-106-10 32/91432/914 1.63 (0.91-2.90)1.63 (0.91-2.90) 1.46 (0.82-2.61)1.46 (0.82-2.61) 11-1411-14 35/65035/650 2.70 (1.53-4.77)2.70 (1.53-4.77) 2.35 (1.32-4.16)2.35 (1.32-4.16) 15-1915-19 50/52650/526 5.61 (3.27-9.62)5.61 (3.27-9.62) 4.50 (2.59-7.80)4.50 (2.59-7.80) ≥≥2020 56/53656/536 6.21 (3.65-10.57)6.21 (3.65-10.57) <0.0001<0.0001 5.01 (2.91-8.62)5.01 (2.91-8.62) <0.0002<0.0002 AICAIC 27892789 27762776 ∆∆AIC 13AIC 13 AUCAUC 0.7350.735 0.7500.750 0.01630.0163 AIC, Akaike’s Information Criterion; ΔAIC, AIC (model without CRP) – AIC (model with CRP);AIC, Akaike’s Information Criterion; ΔAIC, AIC (model without CRP) – AIC (model with CRP); AUC, Area under the curveAUC, Area under the curve Risk of a First Coronary Event by CoxRisk of a First Coronary Event by Cox Model Without and With CRP for the FRSModel Without and With CRP for the FRS With 3 and 5 CategoriesWith 3 and 5 Categories Koenig et al. Circulation (in press)Koenig et al. Circulation (in press)
  11. 11. MONICA Augsburg Cohort Study: SummaryMONICA Augsburg Cohort Study: Summary  Elevated CRP concentrations and an elevated TC/HDL-CElevated CRP concentrations and an elevated TC/HDL-C ratio were both independently related to incident CHD.ratio were both independently related to incident CHD.  The addition of CRP to a prediction model of TC/HDL-C orThe addition of CRP to a prediction model of TC/HDL-C or the FRS resulted in a better fit of the model containingthe FRS resulted in a better fit of the model containing CRP and significantly improved prediction of incident CHDCRP and significantly improved prediction of incident CHD for TC/HDL-C and the calculated FRS.for TC/HDL-C and the calculated FRS.  The latter was particularly true for those at intermediateThe latter was particularly true for those at intermediate risk (10-20% over 10 years).risk (10-20% over 10 years).  Thus, CRP measurement modulates coronary risk andThus, CRP measurement modulates coronary risk and may therefore modify the physician`s interpretation of themay therefore modify the physician`s interpretation of the patient`s risk status.patient`s risk status.  However, these findings have to be replicated in otherHowever, these findings have to be replicated in other populations.populations. Koenig et al. Circulation (in press)Koenig et al. Circulation (in press)
  12. 12. * ESR, erythrocyte sedimentation rate; PAI-1, plasminogen activator inhibitor-1; vWF, von Willebrand factor;* ESR, erythrocyte sedimentation rate; PAI-1, plasminogen activator inhibitor-1; vWF, von Willebrand factor; CIC, circulating immune complexes; Lp-PLACIC, circulating immune complexes; Lp-PLA22 lipoprotein-associated phospholipase Alipoprotein-associated phospholipase A22 Acute Phase Reactants InvestigatedAcute Phase Reactants Investigated Prospectively in Epidemiological StudiesProspectively in Epidemiological Studies Non-ProteinNon-Protein MarkersMarkers Frequently StudiedFrequently Studied ProteinsProteins Infrequently StudiedInfrequently Studied ProteinsProteins LeukocytesLeukocytes C-reactive proteinC-reactive protein OrosomucoidOrosomucoid ESR*ESR* Serum amyloid ASerum amyloid A AlphaAlpha11-antitrypsin-antitrypsin Plasma viscosityPlasma viscosity FibrinogenFibrinogen HaptoglobinHaptoglobin AlbuminAlbumin CeruloplasminCeruloplasmin PlasminogenPlasminogen C3, C4C3, C4 PAI-1*PAI-1* IgA, G, M, and EIgA, G, M, and E vWF*vWF* Sialic acidSialic acid CytokinesCytokines (IL-6, 8, 10,(IL-6, 8, 10, 1818)) CIC*CIC* CAMsCAMs Lp (a)Lp (a) Lp-PLALp-PLA22**,, sPLAsPLA22-IIA-IIA mod. after Koenig & Rosenson. Sem Vasc Med 2002;2:417-24mod. after Koenig & Rosenson. Sem Vasc Med 2002;2:417-24
  13. 13. IL-18 and Risk of CHDIL-18 and Risk of CHD**: PRIME: PRIME Combined EndpointCombined Endpoint Coronary Death and MICoronary Death and MI <160 160-235 >235<160 160-235 >235 <160 160-235 >235<160 160-235 >235 [pg/mL][pg/mL] [pg/mL][pg/mL] RelativeRisk(95%CI)RelativeRisk(95%CI) RelativeRisk(95%CI)RelativeRisk(95%CI) 33 22 11 00 33 22 11 00 FF FF FF FF BB BB BB BB Blankenberg et al. Circulation 2003;108:2453-2459Blankenberg et al. Circulation 2003;108:2453-2459 * In tertiles of IL-18* In tertiles of IL-18
  14. 14.  Lipoprotein-associated phospholipase ALipoprotein-associated phospholipase A22 (Lp-PLA(Lp-PLA22)) Platelet-activating factor acetylhydrolasePlatelet-activating factor acetylhydrolase 50kDa, Ca-insensitive lipase50kDa, Ca-insensitive lipase Produced predominantly by macrophages/Produced predominantly by macrophages/ monocytes, T-cells, and mast cellsmonocytes, T-cells, and mast cells Not responsive to IL-1, IL-6, TNF-Not responsive to IL-1, IL-6, TNF-αα  Secretory phospholipase ASecretory phospholipase A22 (sPLA(sPLA22)) 14 kDa, Ca-dependent lipase14 kDa, Ca-dependent lipase Produced by arterial wall SMC and macrophagesProduced by arterial wall SMC and macrophages Increased by cytokines IL-1, IL-6, TNF-Increased by cytokines IL-1, IL-6, TNF-αα Phospholipases APhospholipases A22 and Atherosclerosisand Atherosclerosis
  15. 15. Theory: Lp-PLATheory: Lp-PLA22 Promotes AtherogenesisPromotes Atherogenesis  Generates lyso-PC during oxidation of LDLGenerates lyso-PC during oxidation of LDL  Lp-PLALp-PLA22-dependent oxFFA are also bioactive-dependent oxFFA are also bioactive human monocyte chemoattractantshuman monocyte chemoattractants  Anti-atherosclerotic effect of inhibitorAnti-atherosclerotic effect of inhibitor demonstrated in WHHL rabbitdemonstrated in WHHL rabbit  Plasma levels correlate with CHD in patients?Plasma levels correlate with CHD in patients?
  16. 16. LumenLumen IntimaIntima MediaMedia LDLLDL OxidizedOxidized LDLLDL Lp-PLALp-PLA22 Lyso-PCLyso-PC ++ OxFAOxFA AdhesionAdhesion MoleculesMolecules MonocyteMonocyte PlaquePlaque FormationFormationCytokinesCytokines MacrophageMacrophage Foam CellFoam Cell Role of Lp-PLARole of Lp-PLA22 in Coronary Heart Diseasein Coronary Heart Disease
  17. 17. West of Scotland CoronaryWest of Scotland Coronary Prevention Study (WOSCOPS)Prevention Study (WOSCOPS) WOSCOPS StudyWOSCOPS Study DesignDesign  randomized, double blind, placebo controlled trialrandomized, double blind, placebo controlled trial  6,595 men, aged 45 to 656,595 men, aged 45 to 65  elevated LDL levels (range 174-232 mg/dL orelevated LDL levels (range 174-232 mg/dL or 4.5-6.0 mM)4.5-6.0 mM)  no previous myocardial infarction (MI)no previous myocardial infarction (MI)  mean follow-up of 5 yearsmean follow-up of 5 years Study ResultsStudy Results  treatment with Pravastatin reduced risk of firsttreatment with Pravastatin reduced risk of first time heart attack (by 31%) and death (by 22%)time heart attack (by 31%) and death (by 22%) Packard et al. N Engl J Med 2000;343:1148-1155Packard et al. N Engl J Med 2000;343:1148-1155
  18. 18. Lp-PLALp-PLA22 as a Novel Risk Factor in CHD:as a Novel Risk Factor in CHD: WOSCOPSWOSCOPS Baseline samplesBaseline samples (stored @ -70(stored @ -70oo C)C) plasmaplasma n=6,595n=6,595 4.9 years4.9 years 580 coronary580 coronary eventsevents 1,160 event free1,160 event free (randomly selected, but(randomly selected, but age, smoking matched)age, smoking matched) CasesCases ControlsControls Samples drawnSamples drawn from freezerfrom freezer Packard et al. N Engl J Med 2000;343:1148-1155Packard et al. N Engl J Med 2000;343:1148-1155
  19. 19. CRP, Lp-PLACRP, Lp-PLA22 and CHD Risk: WOSCOPSand CHD Risk: WOSCOPS univariateunivariate Inflam. markersInflam. markers All risk factorsAll risk factors Relative Risk (confidence interval)Relative Risk (confidence interval) ModelModel 11 22 33 CRPCRP 1.27 (1.141.27 (1.14 --1.42)1.42) 1.21 (1.061.21 (1.06 --1.39)1.39) 1.13 (0.981.13 (0.98 -- 1.29)1.29) WCCWCC 1.22 (1.091.22 (1.09 --1.37)1.37) 1.15 (1.021.15 (1.02 --1.31)1.31) 1.10 (0.971.10 (0.97 -- 1.25)1.25) FibrinogenFibrinogen 1.19 (1.071.19 (1.07 --1.31)1.31) 1.04 (0.921.04 (0.92--1.17)1.17) 1.02 (0.901.02 (0.90 -- 1.15)1.15) LpLp--PLAPLA22 1.20 (1.081.20 (1.08 --1.34)1.34) 1.19 (1.071.19 (1.07 --1.33)1.33) 1.18 (1.051.18 (1.05 -- 1.33)1.33) Packard et al. N Engl J Med 2000;343:1148-1155Packard et al. N Engl J Med 2000;343:1148-1155
  20. 20. Methods: Patient Population and AssaysMethods: Patient Population and Assays  12,819 apparently healthy men and women free of CHD at ARIC visit 2  608 individuals with incident CHD between visit 2 and visit 4 (6- to 8-year follow-up), with 740 controls from a cohort random sample  Lp-PLA2 : diaDexus PLAC™ test (Dada et al. Expert Re Mol Diagn 2002), dual monoclonal Ab immunoassay standardized to recombinant Lp-PLA2  hs-CRP: Denka Seiken asssay, which has been validated to Dade Behring method (Roberts et al. Clin Chem 2001) Lp-PLALp-PLA22 and Risk of CHD: ARICand Risk of CHD: ARIC Ballantyne et al. Circulation 2004;109:837-842Ballantyne et al. Circulation 2004;109:837-842
  21. 21. Weighted-Adjusted* Means of Risk FactorsWeighted-Adjusted* Means of Risk Factors Variable Cases (n=608) Noncases(n=740) P-value DM 28.7 15.1 <0.001 BMI 28.7 28.1 0.014 TC 219.7 207.2 <0.001 TG 144.8 124.5 <0.001 HDL-C 45.6 51.2 <0.001 LDL-C 145.1 131.2 <0.001 SBP 127.5 121.6 <0.001 DBP 73.1 72.6 0.350 Lp-PLA2 404 373 <0.001 hs-CRP 4.05 3.04 <0.001 * Adjusted for age, sex, and race* Adjusted for age, sex, and race Ballantyne et al. Circulation 2004;109:837-842Ballantyne et al. Circulation 2004;109:837-842 Lp-PLALp-PLA22 and Risk of CHD: ARICand Risk of CHD: ARIC
  22. 22. 22 (310-422(310-422 μμg/L)g/L) 33 (≥422(≥422 μμg/L)g/L) Model 1Model 1†† 1.26 (0.94-1.69)1.26 (0.94-1.69) 1.78 (1.33-2.38)1.78 (1.33-2.38) Model 2Model 2‡‡ 1.02 (0.73-1.43)1.02 (0.73-1.43) 1.16 (0.82-1.65)1.16 (0.82-1.65) Model 2Model 2‡‡ , LDL-C<130 mg/dL, LDL-C<130 mg/dL 1.83 (1.11-3.00)1.83 (1.11-3.00) 1.99 (1.17-3.38)1.99 (1.17-3.38) Model 3Model 3§§ 1.00 (0.71-1.41)1.00 (0.71-1.41) 1.15 (0.81-1.63)1.15 (0.81-1.63) Model 3Model 3§§ , LDL-C<130 mg/dL, LDL-C<130 mg/dL 1.83 (1.10-3.05)1.83 (1.10-3.05) 2.08 (1.20-3.62)2.08 (1.20-3.62) CHD HRs (95% CI) by Lp-PLACHD HRs (95% CI) by Lp-PLA22 TertilesTertiles Lp-PLALp-PLA22 Tertiles *Tertiles * *Lowest tertile (<310µg/L) is reference;*Lowest tertile (<310µg/L) is reference; †† Adjusted for age, sex, and race;Adjusted for age, sex, and race; ‡‡ Also adjustedAlso adjusted for smoking status, SBP, LDL-C, HDL-C, and diabetes;for smoking status, SBP, LDL-C, HDL-C, and diabetes; §§ Additionally adjusted for CRPAdditionally adjusted for CRP Ballantyne et al. Circulation 2004;109:837-842Ballantyne et al. Circulation 2004;109:837-842 Lp-PLALp-PLA22 and Risk of CHD: ARICand Risk of CHD: ARIC
  23. 23. Weighted-Correlation BetweenWeighted-Correlation Between Lp-PLALp-PLA22 and Other Risk Factors: ARICand Other Risk Factors: ARIC Pearson CorrelationPearson Correlation Risk FactorRisk Factor CoefficientCoefficient P-ValueP-Value Total cholesterolTotal cholesterol 0.230.23 <0.0001<0.0001 LDL-CLDL-C 0.360.36 <0.0001<0.0001 HDL-CHDL-C - 0.33- 0.33 <0.0001<0.0001 SBPSBP 0.040.04 NSNS DBPDBP - 0.01- 0.01 NSNS hs-CRPhs-CRP - 0.05- 0.05 NSNS BMIBMI - 0.02- 0.02 NSNS TriglyceridesTriglycerides 0.130.13 0.00060.0006 Ballantyne et al. Circulation 2004;109:837-842Ballantyne et al. Circulation 2004;109:837-842
  24. 24. 00 11 22 33 Association of Lp-PLA2 and hs-CRP with IncidentAssociation of Lp-PLA2 and hs-CRP with Incident CHD in Patients with Low LDL-C (<130mg/dL)CHD in Patients with Low LDL-C (<130mg/dL) CHDHazardRatioCHDHazardRatio Lp-PLALp-PLA22 µg/Lµg/L hs-CRP, mg/Lhs-CRP, mg/L Lp-PLALp-PLA22 and Risk of CHD: ARICand Risk of CHD: ARIC Ballantyne et al. Circulation 2004;109:837-842Ballantyne et al. Circulation 2004;109:837-842 95% CI 1.47 - 5.94,95% CI 1.47 - 5.94, P=0.002P=0.002 High (≥ 422)High (≥ 422) Low-Med (< 422)Low-Med (< 422) High (>3) Low-Med (≤3)High (>3) Low-Med (≤3) 2.952.95 1.14 1.001.14 1.00 0.990.99
  25. 25. Lp-PLALp-PLA22 and Risk of CHD:and Risk of CHD: MONICA-Augsburg Cohort 1984-98MONICA-Augsburg Cohort 1984-98  934 men aged 45-64 years, participating in the934 men aged 45-64 years, participating in the first MONICA survey 1984/85first MONICA survey 1984/85  Exclusion of prevalent CHDExclusion of prevalent CHD  Standardized assessment of cardiovascular riskStandardized assessment of cardiovascular risk factorsfactors  Lp-PLALp-PLA22 by diaDexus PLACby diaDexus PLAC ™ test (enzyme™ test (enzyme immunoassay);immunoassay); CRP by a high-sensitivityCRP by a high-sensitivity immunoradiometric assay (Hutchinson et al. Clinimmunoradiometric assay (Hutchinson et al. Clin Chem 2000)Chem 2000)  Endpoint determination according to the MONICAEndpoint determination according to the MONICA protocol (fatal and non-fatal MI and SCD)protocol (fatal and non-fatal MI and SCD) Koenig et al. (AHA 2003)Koenig et al. (AHA 2003)
  26. 26. Age-adjusted Baseline Characteristics of 934 Men,Age-adjusted Baseline Characteristics of 934 Men, Aged 45-64 Years Participating in the MONICAAged 45-64 Years Participating in the MONICA Augsburg Survey 1984/85 With Follow-up 1998Augsburg Survey 1984/85 With Follow-up 1998 Characteristic Men with eventCharacteristic Men with event (n=97)(n=97) Men w/o eventMen w/o event (n= 837)(n= 837) P-valueP-value BMI (kg/mBMI (kg/m22 )) 27.627.6 27.627.6 n.s.n.s. Total cholesterol (mg/dl)Total cholesterol (mg/dl) 259.6259.6 243.3243.3 0.0010.001 HDL cholesterol (mg/dl)HDL cholesterol (mg/dl) 46.846.8 51.851.8 0.00370.0037 TC/HDL-RatioTC/HDL-Ratio§§ 5.665.66 4.834.83 < 0.0001< 0.0001 Systolic BP (mmHg)Systolic BP (mmHg) 139.0139.0 136.6136.6 n.s.n.s. Diastolic BP (mmHg)Diastolic BP (mmHg) 84.984.9 84.584.5 n.s.n.s. Regular smoker %Regular smoker % 53.953.9 28.028.0 <0.0001<0.0001 Physical activity %Physical activity % 25.725.7 35.635.6 0.050.05 Diabetes %Diabetes % 8.48.4 3.13.1 0.00960.0096 Education (<12 years) %Education (<12 years) % 74.274.2 73.773.7 n.s.n.s. Lp-PLALp-PLA 22 (ng/ml)(ng/ml) 292.3292.3 263.4263.4 0.00130.0013 C-reactive proteinC-reactive protein§§ (mg/L)(mg/L) 2.492.49 1.541.54 < 0.0001< 0.0001 §§ geometric means calculated from the log-transformed distributiongeometric means calculated from the log-transformed distribution Koenig et al. (AHA 2003)Koenig et al. (AHA 2003)
  27. 27. Correlation BetweenCorrelation Between Lp-PLALp-PLA22, CRP and, CRP and Other Cardiovascular Risk Factors: MONICAOther Cardiovascular Risk Factors: MONICA Risk factor Spearman correlation coefficient (P-value)Risk factor Spearman correlation coefficient (P-value) Lp-PLALp-PLA22 CRPCRP AgeAge 0.13 (<0.0001)0.13 (<0.0001) 0.15 (<0.0001)0.15 (<0.0001) Total-CTotal-C 0.300.30 (<0.0001)(<0.0001) 0.07 (0.03)0.07 (0.03) HDL-CHDL-C 0.11 (0.0006)0.11 (0.0006) -0.15 (<0.0001)-0.15 (<0.0001) TC/HDL-CTC/HDL-C 0.07 (0.04)0.07 (0.04) 0.16 (<0.0001)0.16 (<0.0001) Systolic BPSystolic BP 0.03 (0.40)0.03 (0.40) 0.11 (0.0013)0.11 (0.0013) BMIBMI -0.04 (0.24)-0.04 (0.24) 0.21 (<0.0001)0.21 (<0.0001) CRPCRP 0.07 (0.04)0.07 (0.04) 1.01.0 Koenig et al. (AHA 2003)Koenig et al. (AHA 2003)
  28. 28. MONICA: RR of CHD by a 1 SD IncreaseMONICA: RR of CHD by a 1 SD Increase in CRP or Lp-PLAin CRP or Lp-PLA22 (separate models)(separate models) ModelModel RR (95% CI)RR (95% CI) P-valueP-value CRP onlyCRP only UnadjustedUnadjusted 1.57 (1.30-1.90)1.57 (1.30-1.90) 0.00010.0001 Adjusted for age, DM, smokingAdjusted for age, DM, smoking 1.32 (1.07-1.62)1.32 (1.07-1.62) 0.0080.008 Multivariable adjustment*Multivariable adjustment* 1.28 (1.03-1.60)1.28 (1.03-1.60) <0.03<0.03 Lp-PLALp-PLA22 onlyonly UnadjustedUnadjusted 1.37 (1.16-1.62)1.37 (1.16-1.62) 0.00020.0002 Adjusted for age, DM, smokingAdjusted for age, DM, smoking 1.26 (1.05-1.54)1.26 (1.05-1.54) 0.010.01 Multivariable adjustment*Multivariable adjustment* 1.23 (1.02-1.47)1.23 (1.02-1.47) 0.030.03 *Age, systolic BP, TC/HDL-ratio, physical activity, BMI, smoking, DM, alcohol*Age, systolic BP, TC/HDL-ratio, physical activity, BMI, smoking, DM, alcohol intake, educationintake, education Koenig et al. (AHA 2003)Koenig et al. (AHA 2003)
  29. 29. MONICA: RR of CHD by a 1 SD IncreaseMONICA: RR of CHD by a 1 SD Increase in Lp-PLAin Lp-PLA22 or CRP (same model)or CRP (same model) ModelModel RR (95% CI)RR (95% CI) P-valueP-value UnadjustedUnadjusted CRPCRP Lp-PLALp-PLA22 1.55 (1.28-1.89)1.55 (1.28-1.89) 1.35 (1.14-1.60)1.35 (1.14-1.60) <0.0001<0.0001 0.0060.006 Adjusted for age, DM, smokingAdjusted for age, DM, smoking CRPCRP Lp-PLALp-PLA22 1.31 (1.07-1.62)1.31 (1.07-1.62) 1.25 (1.04-1.50)1.25 (1.04-1.50) 0.010.01 <0.02<0.02 Multivariable adjustment*Multivariable adjustment* CRPCRP Lp-PLALp-PLA22 1.27 (1.01-1.59)1.27 (1.01-1.59) 1.21 (1.01-1.45)1.21 (1.01-1.45) 0.040.04 0.040.04 *Age, systolic BP, TC/HDL-ratio, physical activity, BMI, smoking, DM, alcohol*Age, systolic BP, TC/HDL-ratio, physical activity, BMI, smoking, DM, alcohol intake, educationintake, education Koenig et al. (AHA 2003)Koenig et al. (AHA 2003)
  30. 30. UnadjustedUnadjusted Adjusted for age MultivariableAdjusted for age Multivariable DM, smokingDM, smoking adjustment*adjustment* *Age, systolic BP, TC/HDL-ratio, physical activity, BMI,*Age, systolic BP, TC/HDL-ratio, physical activity, BMI, smoking, DM, alcohol intake, educationsmoking, DM, alcohol intake, education 00 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 4.04.0 6.06.0 Ref.Ref. Ref.Ref. Ref.Ref. CRP ≤ 3 mg/LCRP ≤ 3 mg/L Lp-PLALp-PLA22 < 290.8 ng/mL< 290.8 ng/mL N=447N=447 CRP > 3 mg/LCRP > 3 mg/L Lp-PLALp-PLA22 < 290.8 ng/mL< 290.8 ng/mL N=176N=176 CRP ≤ 3 mg/LCRP ≤ 3 mg/L Lp-PLALp-PLA22 ≥ 290.8 ng/mL≥ 290.8 ng/mL N=203N=203 CRP > 3 mg/LCRP > 3 mg/L Lp-PLALp-PLA22 ≥ 290.8 ng/mL≥ 290.8 ng/mL N=108N=108 Additive Effect of CRP and Lp-PLAAdditive Effect of CRP and Lp-PLA22 in Coronary Risk Prediction: MONICAin Coronary Risk Prediction: MONICA HazardRatio(95%CI)HazardRatio(95%CI) Koenig et al. (AHA 2003)Koenig et al. (AHA 2003)
  31. 31. Summary and ConclusionsSummary and Conclusions  Lp-PLALp-PLA22 was the strongest predictor/biomarker of coronarywas the strongest predictor/biomarker of coronary events, and was independent of traditional and emergingevents, and was independent of traditional and emerging risk factors, including CRP in hyperlipidemic individualsrisk factors, including CRP in hyperlipidemic individuals (WOSCOPS)(WOSCOPS)  In particular, in individuals with low LDL-C (<130 mg/dL),In particular, in individuals with low LDL-C (<130 mg/dL), levels of Lp-PLAlevels of Lp-PLA22 were independentlywere independentlyassociated withassociated with incident CHD in multivariable analysis including CRPincident CHD in multivariable analysis including CRP (ARIC)(ARIC)  Lp-PLALp-PLA22 was predictive of coronary events in a population-was predictive of coronary events in a population- based sample of initially healthy middle-aged men withbased sample of initially healthy middle-aged men with moderately elevated total cholesterol levels during long-moderately elevated total cholesterol levels during long- term FU of 14 yearsterm FU of 14 years (MONICA cohort)(MONICA cohort)  In addition to CRP, Lp-PLAIn addition to CRP, Lp-PLA22 appears to be a promisingappears to be a promising marker of atherosclerotic complications and deservesmarker of atherosclerotic complications and deserves further studyfurther study
  32. 32. BreakBreak Diagnosing Risk: CRP and Lp-PLADiagnosing Risk: CRP and Lp-PLA22
  33. 33. Case-Control Study:Case-Control Study: Population and Laboratory MethodsPopulation and Laboratory Methods Patients withPatients with clinicallyclinically stable CADstable CAD aged 40-68 yearsaged 40-68 years (n=312)(n=312) Age- and gender-Age- and gender- matchedmatched voluntary bloodvoluntary blood donorsdonors (n=479)(n=479) Lp-PLALp-PLA22 plasma levels - ELISA,plasma levels - ELISA, diaDexus Inc.diaDexus Inc. Inflammatory markersInflammatory markers Hemostatic markersHemostatic markers Complete lipid profileComplete lipid profile Khuseyinova et al. (unpublished data)Khuseyinova et al. (unpublished data)
  34. 34. CADCAD patients (n=patients (n=312) Controls (n=312) Controls (n=479479)) Age (yrs)Age (yrs) 57.757.7 ±± 7.47.4 55.855.8±±7.27.2 Male (%)Male (%) 85.685.6 74.974.9 Family status married (%)Family status married (%) 85.985.9 83.983.9 School education <10 yr (%)School education <10 yr (%) 69.269.2 58.558.5 Daily alcohol consumption (%)Daily alcohol consumption (%) 29.529.5 28.528.5 Smoked pack yearsSmoked pack years 20.320.3 10.810.8 Current smokerCurrent smoker 9.69.6 14.214.2 BMI (kg/mBMI (kg/m22 )) 27.327.3 ±± 3.63.6 26.326.3±±3.23.2 History of high blood pressure (%)History of high blood pressure (%) 57.757.7 20.520.5 History of diabetes (%)History of diabetes (%) 13.513.5 2.72.7 History of hyperlipidemia (%)History of hyperlipidemia (%) 67.367.3 20.920.9 Lp-PLALp-PLA22 (ng/mL)*(ng/mL)* 296.1296.1±±122.5122.5 266.0266.0±±109.8109.8 C-reactive protein (mg/L)C-reactive protein (mg/L)†† 1.7 (0.7-3.8)1.7 (0.7-3.8) 1.2 (0.5-2.6)1.2 (0.5-2.6) Demographic Characteristics of Patients withDemographic Characteristics of Patients with Coronary Artery Disease (CAD) and ControlsCoronary Artery Disease (CAD) and Controls *mean*mean ±± SD;SD; †† median and their interquartile rangesmedian and their interquartile ranges BMI = body mass indexBMI = body mass index Khuseyinova et al. (submitted)Khuseyinova et al. (submitted)
  35. 35. Distribution of Lipid Variables, Markers ofDistribution of Lipid Variables, Markers of Coagulation, Fibrinolysis and Inflammation (I)Coagulation, Fibrinolysis and Inflammation (I) CAD patients Controls P-value Lp-PLA2 [ng/mL]* 296.1±122.5 266.0±109.8 <0.0001 Total cholesterol [mmol/L]* 5.05±1.06 5.27±0.85 0.0002 HDL cholesterol [mmol/L]* 1.09±0.27 1.33±0.34 0.0001 LDL cholesterol [mmol/L]* 3.10±0.75 3.19±0.79 0.11 Apolipoprotein A1 [mg/dL]* 129±21.5 145±23.0 0.0001 Apolipoprotein A2 [mg/dL]* 45±7.7 49±15.6 0.0001 Apolipoprotein B [mg/dL]* 107±27.5 103±23.6 0.09 Apolipoprotein C2 [mg/dL]* 4.4±2.75 4.1±2.94 0.10 Apolipoprotein C3 [mg/dL]* 15.6±6.66 14.8±4.21 0.11 Apolipoprotein E [mg/dL]* 9.4±4.92 9.0±2.58 0.91 Lipoprotein (a) [mg/dL] † 14.8 (5.4-47.1) 9.7 (3.5-25.3) <0.0001 *mean*mean ±± SDSD †† median and their interquartile rangesmedian and their interquartile ranges Khuseyinova et al. (submitted)Khuseyinova et al. (submitted)
  36. 36. CAD patients Controls P-value Leukocytes [103 /µL]* 6.9±1.81 5.8±1.53 0.0001 C-reactive protein [mg/L]† 1.7 (0.7-3.8) 1.2 (0.5-2.6) 0.0001 Serum amyloid A [mg/L]† 3.1 (1.9-4.9) 2.6 (1.7-4.1) 0.002 Interleukin-6 [pg/mL]† 2.20 (1.53-3.95) 1.34 (0.92-2.04) 0.0001 TNF-α [pg/mL]† 256 (202-359) 184 (130-262) 0.0001 sICAM-1 [ng/mL]* 518±166 488±141 0.009 Fibrinogen [g/L]* 2.82±0.63 2.52±0.61 0.0001 Plasma viscosity [m Pa•s]* 1.22±0.07 1.19±0.05 0.0001 Plasminogen [%]* 113.6±17.4 114.1±16.8 0.43 PAI-1 activity [U/mL]† 11.8 (7.4-19.3) 8.2 (4.1-13.7) 0.0001 D-Dimers [ng/mL]† 11.2 (0-28.9) 2.8 (0-15.1) <0.001 Von Willebrand factor [activity %]† 144 (110-181) 134 (99-162) 0.0001 sCD14 [µg/mL]† 4.07 (3.36-4.81) 4.06 (3.38-4.84) 0.51 *mean*mean ±± SDSD †† median and their interquartile rangesmedian and their interquartile ranges Khuseyinova et al. (submitted)Khuseyinova et al. (submitted) Distribution of Lipid Variables, Markers ofDistribution of Lipid Variables, Markers of Coagulation, Fibrinolysis and Inflammation (II)Coagulation, Fibrinolysis and Inflammation (II)
  37. 37. VariablesVariables CasesCases P-valueP-value ControlsControls P-valueP-value AgeAge -0.002-0.002 0.960.96 0.170.17 0.00010.0001 TCTC 0.290.29 <0.0001<0.0001 0.100.10 0.030.03 HDL-CHDL-C -0.15-0.15 0.0080.008 -0.05-0.05 0.240.24 LDL-CLDL-C 0.330.33 <0.0001<0.0001 0.140.14 0.0020.002 Apo BApo B 0.270.27 <0.0001<0.0001 0.100.10 0.030.03 CRP (log)CRP (log) 0.130.13 0.020.02 0.050.05 0.310.31 ICAM-1ICAM-1 0.150.15 0.0090.009 0.0450.045 0.330.33 Plasma viscosityPlasma viscosity 0.140.14 0.010.01 0.060.06 0.200.20 D-Dimer (log)D-Dimer (log) 0.110.11 0.050.05 -0.07-0.07 0.110.11 vWFvWF 0.080.08 0.120.12 0.180.18 <0.0001<0.0001 PlasminogenPlasminogen -0.11-0.11 0.040.04 -0.04-0.04 0.350.35 Spearman Rank Correlation Coefficients BetweenSpearman Rank Correlation Coefficients Between Traditional Risk Factors, Lipid Variables, SystemicTraditional Risk Factors, Lipid Variables, Systemic Inflammatory and Hemostatic Markers, and Lp-PLAInflammatory and Hemostatic Markers, and Lp-PLA22 No significant effect forNo significant effect for BMI, smoking, lBMI, smoking, leukocytes, feukocytes, fibrinogen,ibrinogen, IL-6,IL-6, TNF-TNF-αα,, PAI-1 activity, sCD14, Apo A1, Apo A2, Apo C2, Apo C3, Apo EPAI-1 activity, sCD14, Apo A1, Apo A2, Apo C2, Apo C3, Apo E Khuseyinova et al. (submitted)Khuseyinova et al. (submitted)
  38. 38. Odds Ratios (OR) of CAD Associated WithOdds Ratios (OR) of CAD Associated With Lp-PLALp-PLA22 Levels After Various AdjustmentsLevels After Various Adjustments Lp-PLALp-PLA22 DistrDistribution (ng/mL)ibution (ng/mL) Q1Q1 Q2Q2 ((≤≤188.2) (>188.2-249.2 )188.2) (>188.2-249.2 ) Q3Q3 (>249.2-323.5 )(>249.2-323.5 ) Q4Q4 (>323.5 )(>323.5 ) Model 1* ORModel 1* OR (95 % CI)(95 % CI) 11RefRef 0.980.98 (0.63-1.52)(0.63-1.52) 1.231.23 (0.80-1.88)(0.80-1.88) 1.611.61 (1.07-2.44)(1.07-2.44) Model 2Model 2†† OROR (95 % CI)(95 % CI) 11RefRef 0.910.91 (0.54-1.52)(0.54-1.52) 1.361.36 (0.84-2.21)(0.84-2.21) 1.721.72 (1.07-2.76)(1.07-2.76) Model 3Model 3‡‡ OROR (95 % CI)(95 % CI) 11RefRef 0.930.93 (0.55-1.56)(0.55-1.56) 1.401.40 (0.85-2.29)(0.85-2.29) 1.841.84 (1.12-2.99)(1.12-2.99) Model 4Model 4§§ OROR (95 % CI)(95 % CI) 11RefRef 1.031.03 (0.58-1.83)(0.58-1.83) 1.741.74 (1.01-3.01)(1.01-3.01) 2.042.04 (1.19-3.48)(1.19-3.48) Model 5Model 5¶¶ OROR (95 % CI)(95 % CI) 11RefRef 0.980.98 (0.55-1.76)(0.55-1.76) 1.651.65 (0.94-2.91)(0.94-2.91) 1.841.84 (1.05-3.12)(1.05-3.12) ** Adjustment for age and gender (matching variables)Adjustment for age and gender (matching variables) †† Adjustment for matching variables and for BMI, smoking status, alcohol intake, school education years,Adjustment for matching variables and for BMI, smoking status, alcohol intake, school education years, hypertension, diabeteshypertension, diabetes ‡‡ Model 2 and additional adjustment for TC and HDL cholesterolModel 2 and additional adjustment for TC and HDL cholesterol § Model 3 and additional adjustment for statin intake§ Model 3 and additional adjustment for statin intake ¶ Additionally adjusted for CRP, fibrinogen, vWF, sICAM-1, plasma viscosity, plasminogen, D-Dimer¶ Additionally adjusted for CRP, fibrinogen, vWF, sICAM-1, plasma viscosity, plasminogen, D-Dimer Q = quartileQ = quartile Khuseyinova et al. (submitted)Khuseyinova et al. (submitted)
  39. 39. Atherogenic Activities of Lyso-PCAtherogenic Activities of Lyso-PC Endothelial cells Promotes endothelial dysfunction, upregulates adhesion molecules Monocytes Chemoattractant, stimulates cytokine production Macrophages Stimulates proliferation, inhibits migration, cytotoxic T-lymphocytes Chemoattractant, upregulates cytokine & CD40 ligand expression Smooth muscle cells Cytotoxic, upregulates growth factor expression

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