Aeha2004 crp lppla2newtemplate

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

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

* 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

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

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)

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
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

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

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

< 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 (%)
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)

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

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.

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

 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

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?

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

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

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

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)

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

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

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)
, 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

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

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
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

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)

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

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

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

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

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)

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

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 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)

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)

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)

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)

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)

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)
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§§
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¶¶
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)

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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