Wolfgang Koenig, MD, FESC, FACC Wolfgang Koenig, MD, FESC, FACC Dept. of Internal Medicine II - Dept. of Internal Medicine II - Cardiology Cardiology University of Ulm Medical Center University of Ulm Medical Center Ulm, Germany Ulm, Germany RP, Lp-PLA RP, Lp-PLA 2 2 , and Other Serum Marke , and Other Serum Marke of Disease and Vulnerability of Disease and Vulnerability The 2 The 2 nd Vulnerable Patient Satellite Vulnerable Patient Satellite Symposium Symposium Towards a National Screening Program Towards a National Screening Program New Orleans, LA, March 6 New Orleans, LA, March 6 th th , 2004 , 2004
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Wolfgang Koenig, MD, FESC, FACC Dept. of Internal Medicine II - Cardiology University of Ulm Medical Center Ulm, Germany CRP, Lp-PLA 2, and Other Serum.
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Wolfgang Koenig, MD, FESC, FACCWolfgang Koenig, MD, FESC, FACCDept. of Internal Medicine II - CardiologyDept. of Internal Medicine II - Cardiology
University of Ulm Medical CenterUniversity of Ulm Medical CenterUlm, 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 Symposium Vulnerable Patient Satellite Symposium Towards a National Screening Program Towards a National Screening Program
New Orleans, LA, March 6New Orleans, LA, March 6thth, 2004, 2004
Pre-test Probability of CHD Event in 10 YrsPre-test Probability of CHD Event in 10 Yrs
Post
-test
Pro
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Eve
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Post
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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.)
CHD Risk Assessment in Asymptomatic CHD Risk Assessment in Asymptomatic Patients: Selective Use of Noninvasive TestingPatients: Selective Use of Noninvasive Testing
Modification of Probability Estimates of Modification of Probability Estimates of CHD by Non-invasive TestingCHD by Non-invasive Testing
Assessment by multivariable Assessment by multivariable statistical models: e.g. statistical models: e.g. Framingham Risk Score or Framingham Risk Score or PROCAM ScorePROCAM Score
Clear guidelines for high or low Clear guidelines for high or low risk subjects, but not so for risk subjects, but not so for those at intermediate riskthose at intermediate risk
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)
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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
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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 of RR of Cardiovascular Disease According to Levels of CRP and the Estimated10-Year Risk and According to CRP 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 performedClass 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 establishedClass III: Should not be performedClass III: Should not be performed
Class I: Should be performedClass I: Should be performedClass 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 establishedClass III: Should not be performedClass III: Should not be performed
AHA/CDC Recommendations for AHA/CDC Recommendations for Clinical and Public Health PracticeClinical and Public Health Practice
Of current inflammatory markers identified, Of current inflammatory markers identified, hs-CRP has hs-CRP has the analyte & assay characteristics most conducive to use the 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 for Other 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)
The Value of CRP in Cardiovascular The Value of CRP in Cardiovascular Risk Prediction: The Rotterdam Study Risk Prediction: The Rotterdam Study
Nested case-control study (157/500) within a population based Nested 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 risk Basic risk ** 0.642 (0.026)0.642 (0.026)Risk function 1 Risk function 1 †† 0.773 (0.021)0.773 (0.021) with CRPwith CRP 0.777 (0.021)0.777 (0.021)Risk function 2 Risk 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 + LVH based on the Framingham risk function + LVH
Van der Meer et al. Arch Intern Med 2003;163:1323-1328 Van 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 202000
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55
66
77
88
RR of CHD According to the Estimated 10-Yr RR 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 202000
11
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44
55
66
77
88
P=0.19P=0.19P=0.28P=0.28
P=0.02P=0.02
P=0.03P=0.03
P=0.14P=0.14
<1.0<1.01.0 – 3.01.0 – 3.0> 3.0> 3.0
CRP CRP mg/Lmg/L
18 18 32 32 35 50 5635 50 56
Population at risk Population at risk
809 914 650 526 536809 914 650 526 536
Framingham Estimate of 10-Year Risk (%)Framingham Estimate of 10-Year Risk (%)
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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)
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 curve AUC, Area under the curve
Risk of a First Coronary Event by Cox Risk of a First Coronary Event by Cox Model Without and With CRP for the FRS Model Without and With CRP for the FRS
With 3 and 5 Categories With 3 and 5 Categories
Koenig et al. Circulation (in press)Koenig et al. Circulation (in press)
Elevated CRP concentrations and an elevated TC/HDL-C ratio Elevated CRP concentrations and an elevated TC/HDL-C ratio were both independently related to incident CHD.were both independently related to incident CHD.
The addition of CRP to a prediction model of TC/HDL-C or the The addition of CRP to a prediction model of TC/HDL-C or the FRS resulted in a better fit of the model containing CRP and FRS resulted in a better fit of the model containing CRP and significantly improved prediction of incident CHD for TC/HDL-C significantly improved prediction of incident CHD for TC/HDL-C and the calculated FRS.and the calculated FRS.
The latter was particularly true for those at intermediate risk The latter was particularly true for those at intermediate risk (10-20% over 10 years).(10-20% over 10 years).
Thus, CRP measurement modulates coronary risk and may Thus, CRP measurement modulates coronary risk and may therefore modify the physician`s interpretation of the patient`s therefore modify the physician`s interpretation of the patient`s risk status.risk status.
However, these findings have to be replicated in other However, these findings have to be replicated in other populations.populations.
Koenig et al. Circulation (in press)Koenig et al. Circulation (in press)
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 inhibitor Anti-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
Adhesion Adhesion MoleculesMolecules
MonocyteMonocyte
PlaquePlaqueFormationFormation
PlaquePlaqueFormationFormationCytokinesCytokines
MacrophageMacrophageMacrophageMacrophage
Foam CellFoam CellFoam CellFoam Cell
Role of Lp-PLARole of Lp-PLA22 in Coronary Heart Disease in Coronary Heart Disease
West of Scotland Coronary West 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 or 4.5-6.0 elevated LDL levels (range 174-232 mg/dL or 4.5-6.0
mM)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 first time treatment with Pravastatin reduced risk of first time
heart attack (by 31%) and death (by 22%)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 @ -70ooC)C)
plasmaplasma
n=6,595n=6,595 4.9 years4.9 years
580 coronary 580 coronary events events
1,160 event free1,160 event free
(randomly selected, but (randomly selected, but age, smoking matched)age, smoking matched)
CasesCases
ControlsControls
Samples drawn Samples 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
CRP, Lp-PLACRP, Lp-PLA22 and CHD Risk: WOSCOPS and CHD Risk: WOSCOPS
univariateunivariate Inflam. markersInflam. markers All risk factorsAll risk factors
* 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: ARIC and Risk of CHD: ARIC
CHD HRs (95% CI) by Lp-PLACHD HRs (95% CI) by Lp-PLA2 2 TertilesTertilesLp-PLALp-PLA2 2 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 adjusted Also adjusted for smoking status, SBP, LDL-C, HDL-C, and diabetes; for smoking status, SBP, LDL-C, HDL-C, and diabetes; §§ Additionally adjusted for CRP Additionally 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: ARIC and Risk of CHD: ARIC
Weighted-Correlation Between Weighted-Correlation Between Lp-PLALp-PLA22 and Other Risk Factors: ARIC and Other Risk Factors: ARIC
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 0.00060.0006Ballantyne et al. Circulation 2004;109:837-842Ballantyne et al. Circulation 2004;109:837-842
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Association of Lp-PLA2 and hs-CRP with Incident Association 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)
CH
D H
azar
d R
atio
CH
D H
azar
d R
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Lp-PLALp-PLA22 µg/L µg/L
hs-CRP, mg/Lhs-CRP, mg/L
Lp-PLALp-PLA22 and Risk of CHD: ARIC and 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
Lp-PLALp-PLA2 2 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 the 934 men aged 45-64 years, participating in the
first MONICA survey 1984/85first MONICA survey 1984/85 Exclusion of prevalent CHD Exclusion of prevalent CHD Standardized assessment of cardiovascular risk Standardized assessment of cardiovascular risk
factors factors Lp-PLALp-PLA22 by diaDexus PLAC by diaDexus PLAC ™ test (enzyme ™ test (enzyme
immunoassay); immunoassay); CRP by a high-sensitivity CRP by a high-sensitivity immunoradiometric assay (Hutchinson et al. Clin immunoradiometric assay (Hutchinson et al. Clin Chem 2000)Chem 2000)
Endpoint determination according to the MONICA Endpoint 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 MONICA Aged 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 event Characteristic Men with event (n=97)(n=97) Men w/o event Men w/o event (n= 837)(n= 837) P-value P-value
C-reactive proteinC-reactive protein§ § (mg/L)(mg/L) 2.492.49 1.54 1.54 < 0.0001< 0.0001§§ geometric means calculated from the log-transformed distribution geometric means calculated from the log-transformed distribution
Koenig et al. (AHA 2003)Koenig et al. (AHA 2003)
Correlation Between Correlation Between Lp-PLALp-PLA22, CRP and , CRP and
Other Cardiovascular Risk Factors: MONICAOther Cardiovascular Risk Factors: MONICA
Additive Effect of CRP and Lp-PLAAdditive Effect of CRP and Lp-PLA22
in Coronary Risk Prediction: MONICAin Coronary Risk Prediction: MONICA Ha
zard
Rat
io (9
5% C
I)Ha
zard
Rat
io (9
5% C
I)
Koenig et al. (AHA 2003)Koenig et al. (AHA 2003)
Summary and ConclusionsSummary and Conclusions
Lp-PLALp-PLA22 was the strongest predictor/biomarker of coronary was the strongest predictor/biomarker of coronary events, and was independent of traditional and emerging risk events, and was independent of traditional and emerging risk factors, including CRP in hyperlipidemic individuals 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 independently were independently associated with incident associated with incident CHD in multivariable analysis including CRP 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 with based sample of initially healthy middle-aged men with moderately elevated total cholesterol levels during long-term moderately elevated total cholesterol levels during long-term FU of 14 years FU of 14 years (MONICA cohort)(MONICA cohort)
In addition to CRP, Lp-PLAIn addition to CRP, Lp-PLA22 appears to be a promising appears to be a promising marker of atherosclerotic complications and deserves further marker of atherosclerotic complications and deserves further studystudy
BreakBreak
Diagnosing Risk: CRP and Lp-PLADiagnosing Risk: CRP and Lp-PLA22
Case-Control Study: Case-Control Study: Population and Laboratory Methods Population and Laboratory Methods
Patients with Patients with clinicallyclinicallystable CAD stable CAD
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 with Demographic Characteristics of Patients with Coronary Artery Disease (CAD) and ControlsCoronary Artery Disease (CAD) and Controls
*mean *mean SD; SD; ††median and their interquartile ranges median and their interquartile ranges BMI = body mass indexBMI = body mass index Khuseyinova et al. (submitted)Khuseyinova et al. (submitted)
Distribution of Lipid Variables, Markers of Distribution of Lipid Variables, Markers of Coagulation, Fibrinolysis and Inflammation (I)Coagulation, Fibrinolysis and Inflammation (I)
CAD patients Controls P-value
Lp-PLA2 [ng/mL]* 296.1122.5 266.0109.8 <0.0001
Total cholesterol [mmol/L]* 5.051.06 5.270.85 0.0002
*mean *mean SD SD ††median and their interquartile ranges median and their interquartile ranges Khuseyinova et al. (submitted)Khuseyinova et al. (submitted)
*mean *mean SD SD ††median and their interquartile ranges median and their interquartile ranges Khuseyinova et al. (submitted)Khuseyinova et al. (submitted)
Distribution of Lipid Variables, Markers of Distribution of Lipid Variables, Markers of Coagulation, Fibrinolysis and Inflammation (II)Coagulation, Fibrinolysis and Inflammation (II)
Spearman Rank Correlation Coefficients Between Spearman Rank Correlation Coefficients Between Traditional Risk Factors, Lipid Variables, Systemic Traditional Risk Factors, Lipid Variables, Systemic
Inflammatory and Hemostatic Markers, and Lp-PLAInflammatory and Hemostatic Markers, and Lp-PLA22
No significant effect for No significant effect for BMI, smoking, lBMI, smoking, leukocytes, feukocytes, fibrinogen, ibrinogen, IL-6, IL-6, TNF-TNF-, , PAI-1 activity, sCD14, Apo A1, Apo A2, Apo C2, Apo C3, Apo E PAI-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 With Odds Ratios (OR) of CAD Associated With Lp-PLALp-PLA22 Levels After Various Adjustments Levels After Various Adjustments
Lp-PLALp-PLA22 Distr Distribution (ng/mL)ibution (ng/mL)
Model 2Model 2†† OR OR (95 % CI) (95 % CI) 11RefRef 0.91 0.91 (0.54-1.52)(0.54-1.52) 1.36 1.36 (0.84-2.21)(0.84-2.21) 1.72 1.72 (1.07-2.76)(1.07-2.76)
Model 3Model 3‡‡ OR OR (95 % CI) (95 % CI) 11RefRef 0.93 0.93 (0.55-1.56)(0.55-1.56) 1.40 1.40 (0.85-2.29)(0.85-2.29) 1.84 1.84 (1.12-2.99)(1.12-2.99)
Model 4Model 4§§ OR OR (95 % CI) (95 % CI) 11RefRef 1.03 1.03 (0.58-1.83)(0.58-1.83) 1.74 1.74 (1.01-3.01)(1.01-3.01) 2.04 2.04 (1.19-3.48)(1.19-3.48)
Model 5Model 5¶¶ OR OR (95 % CI) (95 % CI) 11RefRef 0.98 0.98 (0.55-1.76)(0.55-1.76) 1.65 1.65 (0.94-2.91)(0.94-2.91) 1.84 1.84 (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 cholesterol Model 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-DimerQ = quartileQ = quartile Khuseyinova et al. (submitted)Khuseyinova et al. (submitted)
Atherogenic Activities of Lyso-PCAtherogenic Activities of Lyso-PC