teleconferences fall 2009 1 copyright © 2009 by ascp notice of faculty disclosure in accordance...

TeleconferencTeleconferencesesFall 2009Fall 2009

2Copyright © 2009 by ASCP

Notice of Faculty DisclosureNotice of Faculty Disclosure

In accordance with ACCME guidelines, any individual in a position to influence and/or control the content of this ASCP CME activity has disclosed all relevant financial relationships within the past 12 months with commercial interests that provide products and/or services related to the content of this CME activity.

The individual below has responded that he has no relevant financial relationships with commercial interests to disclose:

Joseph P. McConnell PhD, DABCC

In accordance with ACCME guidelines, any individual in a position to influence and/or control the content of this ASCP CME activity has disclosed all relevant financial relationships within the past 12 months with commercial interests that provide products and/or services related to the content of this CME activity.

The individual below has responded that he has no relevant financial relationships with commercial interests to disclose:




Lipoprotein Associated Phospholipase A2A Novel Cardiovascular Risk Marker and a Potential

Therapeutic Target

Lipoprotein Associated Phospholipase A2A Novel Cardiovascular Risk Marker and a Potential

Therapeutic Target


The Mayo Clinic and Foundation

Health Diagnostic Laboratory, Inc.Richmond, Virginia

ASCP Teleconference: December 9, 2009


The Mayo Clinic and Foundation

Health Diagnostic Laboratory, Inc.Richmond, Virginia

ASCP Teleconference: December 9, 2009



Mayo Clinic

CardiovascularCardiovascularLaboratory MedicineLaboratory Medicine



ObjectivesObjectives

After attending this session, participants will be able to:

• Describe differences between Lp-PLA2 and other inflammatory biomarkers like C-reactive protein.

• Discuss the possible atherosclerotic mechanism of action of Lp-PLA2.

• Summarize primary and secondary cardiovascular (CV) prevention studies that have demonstrated associations between elevated Lp-PLA2, cardiovascular events, and stroke.

• Describe how Lp-PLA2 may become a future therapeutic target.

After attending this session, participants will be able to:

• Describe differences between Lp-PLA2 and other inflammatory biomarkers like C-reactive protein.

• Discuss the possible atherosclerotic mechanism of action of Lp-PLA2.

• Summarize primary and secondary cardiovascular (CV) prevention studies that have demonstrated associations between elevated Lp-PLA2, cardiovascular events, and stroke.

• Describe how Lp-PLA2 may become a future therapeutic target.



OutlineOutline

Novel Cardiovascular Biomarkers “risk markers”

Inflammation and atherosclerosis

Mechanisms by which Lp-PLA2 is Atherogenic

Studies linking elevated Lp-PLA2 to CV events

Is Lp-PLA2 present in atherosclerotic lesions? Vulnerable lesions?

Can Lp-PLA2 be a therapeutic target?

Lp-PLA2 measurement.



Ischemic Events in the U.S.Ischemic Events in the U.S.

1,500,000 heart attacks: 500,000 deaths

795,000 strokes: 150,000 deaths

Many individuals who experience an Many individuals who experience an Ischemic event will die as a result of that event.Ischemic event will die as a result of that event.

Several who have an event have no prior Several who have an event have no prior symptoms.symptoms.

Source: AHA Heart Disease and Stroke Statistics 2009 Update; Circulation, May 2009



Cardiovascular Risk Factors

There is a need for additional risk factors.

Although traditional risk factors produce reasonably accurate estimates of risk in a population, they predict only 50-60% of events in individual patients.

Additional risk factors would improve accuracy of decisions regarding preventative therapies

Rader DJ. NEJM. 2000;343:1179-82

monocytechemotaxis

Oxidized LDL

Native LDL

slow

rapid

ICAMVCAME-selectin

O2 radicals

GrowthFactors

Thrombin

smooth musclecell mitogenesis

Homocysteine

Tissue factorVWF

Vasoconstriction

TXA2

Platelet actv.

TXA212-HETEB-TBGP-selectin

Endothelium

EndothelinProstacyclinNitric oxidesoluble ICAMVCAM

Fibrinolysis

D-DimerPAI-IPlasminogen

Coagulation

FibrinogenPF 1+2TATTFPITPP

Lipids/Oxidation

LDL subclassesLp (a)F2 isoprostanesConj. dienes

Nutrition

HCYB12,B6FolateVit. C,E,Carotene

Inflamm.hsCRPantibodieschlamidiaCMV





NCEP: Emerging Risk FactorsNCEP: Emerging Risk Factors

Lipoprotein (a)HomocysteineProthrombotic factorsProinflammatory factorsImpaired fasting glucoseEvidence of subclinical atherosclerotic disease

Can have utility in selected individuals to guide intensity of risk reduction therapy.No guidelines for measurement



Cardiovascular Cardiovascular Risk Technology TeamTechnology Team

Cardiovascular Cardiovascular Health Clinic

Laboratory Cardiology Laboratory Cardiology Working GroupWorking Group



Proposed Markers of InflammationProposed Markers of Inflammation

Adhesion MoleculesICAM, VCAM, E-selectin, P-selectin

CytokinesIL-6, IL-1beta, TNF-alpha

Acute Phase reactantsC-reactive protein, Fibrinogen, Serum amyloid A

Matrix Metalloproteinases and OthersMMP-9, sCD-40 Ligand, myeloperoxidase

Adhesion MoleculesICAM, VCAM, E-selectin, P-selectin

CytokinesIL-6, IL-1beta, TNF-alpha

Acute Phase reactantsC-reactive protein, Fibrinogen, Serum amyloid A

Matrix Metalloproteinases and OthersMMP-9, sCD-40 Ligand, myeloperoxidase

Lp-PLA2



Different Inflammatory Markers: Different Inflammatory Markers: Different RolesDifferent Roles

Different Inflammatory Markers: Different Inflammatory Markers: Different RolesDifferent Roles

Adapted from: Rader D. N Engl J Med. 2000



Lp-PLA2 and CRP: Two Lp-PLA2 and CRP: Two Independent and Independent and DistinctDistinct Inflammatory MarkersInflammatory Markers

CRP Lp-PLA2

Marker of systemic Inflammation

Marker of vascular inflammation

Predominantly produced by liver in response to inflammatory reactions

Produced by macrophages

Specific role in CVD emerging

Cleaves oxidized phospholipids to produce bio-active products

Population distribution skewed to the right

Fairly Normal Population distribution

Acute phase protein with high biologic variability

Not an acute phase proteinMinimal biologic variability



Frequency of Lp-PLA2 in Men Frequency of Lp-PLA2 in Men and Womenand Women

N = 56

02

468

1012

1416

100 150 200 250 300 350 400 450 500

[Lp-PLA2] (ng/mL)

Freq

uenc

y Mean = 266

Median = 255

0

2

4

6

8

10

12

14

16

100 150 200 250 300 350 400 450 500

[Lp-PLA2] (ng/mL)

Freq

uenc

y Mean = 227

Median = 204

Men: N = 56Men: N = 56 Women: N = 56Women: N = 56



*Wolfert RL, et al. Circulation. 2004.

Biological Variability of Lp-PLA2Biological Variability of Lp-PLA2

Blood from 43 healthy adults each

drawn 7 times over 4 weeks

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Lp-PLA2* CRP LDL HDL TG

10.0%

42.6%

7.4%4.7%

22.8%

Intra-Individual CV's

Additive Risk for Incident CHD for LDL <130 by Additive Risk for Incident CHD for LDL <130 by Lp-PLALp-PLA22 and hsCRP Tertiles and hsCRP Tertiles

Adjusted for demographics, current smoking status, blood pressure, diabetes, and HDL

Ballantyne et al., Circulation 2004

0

1

2

3

4

5

hsCRPtop

hsCRPbottom

Lp-PLA2 bottom

Lp-PLA2 top

4.2

1.2

1.4

1.0

RiskRatios

(95% CI 1.7-10.3, p=0.001)





Additive Risk for Incident Ischemic Additive Risk for Incident Ischemic Stroke Stroke by Lp-PLAby Lp-PLA22 and hsCRP Tertiles and hsCRP Tertiles

Adjusted for demographics, current smoking status, blood pressure, diabetes, LDL and HDL

Ballantyne et al. (Scientific Sessions of the AHA, November, 2004)Ballantyne et al. (Scientific Sessions of the AHA, November, 2004)

0

2

4

6

8

10

12

hsCRPtop

hsCRPbottom

Lp-PLA2 bottom

Lp-PLA2 top

11.4

5.85.5

1.0

RiskRatios

(95% CI 3.1–41.4, p<0.001)



Lipoprotein Associated Lipoprotein Associated Phospholipase A2 (Lp-PLA2)Phospholipase A2 (Lp-PLA2)

AKA: Platelet-activating factor acetylhydrolase

50kDa, Ca-insensitive lipase

Produced predominantly by macrophages

> 80% bound to LDL

Not responsive to IL-1, IL-6, TNF-alpha.

Hydrolyzes oxidized phospholipids



Lp-PLA2 and LDL OxidationLp-PLA2 and LDL Oxidation

Phosphatidylcholine (PC)Phosphatidylcholine (PC)

Oxidatively-Modified PCOxidatively-Modified PC

Lyso-PCLyso-PCOxidized Fatty AcidOxidized Fatty Acid

OxidationOxidation

Lp-PLA2

++Putative Inflammatory Mediators



Pro-Atherogenic Activities of Pro-Atherogenic Activities of Lysophosphatidylcholine (Lyso-Lysophosphatidylcholine (Lyso-PC)PC)

Lyso-PC

Expression of adhesion molecules

Inhibition of endothelial derived nitric oxide

Upregulation of cytokines and CD40 ligand

Migration of vascular smooth muscle cells

Stimulation of macrophage proliferation

Induction of MCP-1

Chemoattractant for macrophage and T-cells1. Dada N, et al. Expert Rev Mol Diagn. 2002;2(1):89-94.

2. Quinn MT, et al. Proc Natl Acad Sci USA. 1988;85:2805-2809..

3. MacPhee CH, et al. Biochem J. 1999;338:479-487.4. Carpenter KL, et al. FEBS Lett. 2001;505:357-363



LUMEN

MEDIA

INTIMA

Oxidized LDL

Lyso-PCOxFA

Lp-PLA2

Adhesion Molecules

CytokinesAtheroma

Foam Cell

Monocytes

• Macrophage

The Role of Lp-PLA2 in CVD





When arterial blood touches the When arterial blood touches the necrotic lipid pool – it clots…necrotic lipid pool – it clots…

Lipid core

Lumen

Fibrous cap

•May have significant stenosis• Thick fibrous cap / high collagen content• Small lipid pool• Few inflammatory cells• Low Lp-PLA2 content

Lumen

Stable Plaque Unstable Plaque•May have minimal stenosis• Thin fibrous cap / low collagen content• Large lipid pool• Active inflammatory cells•High Lp-PLA2 content



Lp-PLA2 in the atherosclerotic lesionLp-PLA2 in the atherosclerotic lesion

Kolodgie et.al, ATVB 2006;26:2523-29



West of Scotland Coronary West of Scotland Coronary Prevention Study (WOSCOPS): NEJM, Prevention Study (WOSCOPS): NEJM,

Oct. 2000Oct. 2000

Hypercholesterolemic subjects

6,595 men, aged 45 to 65

mean follow-up of 5 year

580 coronary events

1160 event free controlsMatched for age and smoking status



Inflammatory Markers in Ischemia Inflammatory Markers in Ischemia (WOSCOPS)(WOSCOPS)

CP1009715-53NEJM 343(16):1148, 2000

Ris

k ra

tio

Ris

k ra

tio

White-Cell CountWhite-Cell Count(x10(x10-3-3/mm/mm33))

<1.80<1.80 6.01-6.906.01-6.90 >8.10>8.105.21-6.005.21-6.00 6.91-8.106.91-8.10

Lipoprotein-AssociatedLipoprotein-AssociatedPhospholipase APhospholipase A22 (mg/L) (mg/L)

<1.80<1.80 2.08-2.362.08-2.36 >2.72>2.721.81-2.071.81-2.07 2.37-2.722.37-2.72

C-ReactiveC-ReactiveProtein (mg/L)Protein (mg/L)

3.03.0

2.02.0

1.01.0

0.50.5<0.76<0.76 1.45-2.521.45-2.52

1.45-2.521.45-2.52 2.53-4.592.53-4.59>4.59>4.59

UnivariateOther Inflamm. markersAge, BP, Lipids



Elevated Lp-PLA2 is Consistently Associated with Increased Risk for Cardiovascular DiseaseElevated Lp-PLA2 is Consistently Associated with Increased Risk for Cardiovascular Disease

Packard (WOSCOPS) - CHD 2000

Blake (WHS) - CHD 2001

Blankenberg (AtheroGENE) - CAD 2003

Ballantyne (ARIC) – CHD LDL < 130 2004

Winkler - CHD 2004

Oei (ROTTERDAM) - CHD 2005

Brilakis (Mayo Heart) - CHD 2005

Ballantyne (ARIC) - Stroke 2005

Oei (ROTTERDAM) - Stroke 2005

Winkler (LURIC) - CHD 2005

Khuseyinova (HELICOR) - CHD 2005

Koenig (KAROLA) - CVD 2005

Yang – Endothelial dysfunction 2006

Intermountain Heart - CHD 2006

Caslake (PROSPER) - CVD 2006

Jenny (CHS) - MI 2006

Daniels (Rancho Bernardo) - CHD 2006

Elkind (NOMAS) – Stroke 2006

O’Donoghue (PROVE IT) - CVD 2006

Corsetti (THROMBO) - CHD 2006

Gerber (Olmsted Cty) – Death S/P MI

2006

Sabatine (PEACE) - CVD 2006 0.5 4.51 1.5 2 2.5 3 3.5 4



Lp-PLA2: Relation to Angiographic Lp-PLA2: Relation to Angiographic CAD and Cardiovascular EventsCAD and Cardiovascular Events

None

Mild1V

2V

3V

46% patients have none or mild coronary occlusion54% patients have significant occlusion (>50% stenosis))

Vessel Disease

504 patients with coronary angiography

Brilakis, McConnell et.al, European Heart Journal, Jan. 2005Brilakis, McConnell et.al, European Heart Journal, Jan. 2005



Lp-PLA2 and Angiographic Coronary Lp-PLA2 and Angiographic Coronary Disease Univariate AnalysisDisease Univariate Analysis

200

210

220

230

240

250

260

270

Nodisease

Mild 1V 2V 3V

Lp-PLA2 (P = 0.02)



Multivariate Logistic Regression Multivariate Logistic Regression AnalysisAnalysis

After adjusting for age, gender, smoking history, hypertension, cholesterol, HDL cholesterol, and triglyceride, Lp-PLA2 was no longer was no longer independently predictive of angiographic CAD.

CRP was not predictive of CAD in either the univariate or multivariate model.



Lp-PLA2 and Clinical Lp-PLA2 and Clinical OutcomesOutcomes

Median Follow-up was 4 years

58 cardiovascular events occurred in 49 of 466 contacted patients (11%)

cardiac death in 6 myocardial infarction in 14 coronary revascularization in 28 stroke in 10

Clinical, lipid, and inflammatory (CRP and fibrinogen) variables were assessed.



Hazard Ratio Associated with Hazard Ratio Associated with Markers of Inflammation (per 1 SD)Markers of Inflammation (per 1 SD)

1.32 (1.00-1.75)P = 0.05

1.09 (0.78-1.51)

P = 0.6241.32 (1.06-1.63)

P = 0.012

Brilakis et al., EHJ 2005

1.41 (1.14-1.74)

P = 0.002

1.36 (1.06-1.75)

P = 0.015

1.33 (1.08-1.64)

P = 0.006

Single analyte

Lp-PLA2 + CRP + Fibrinogen

Fibrinogen

CRPLp-PLA2

Adjusted for Clinical (age, gender, smoking, HTN) and lipid (total and HDL cholesterol, Lp(a), and triglycerides) variables

All Cause Death/AMI/Revasc/Stroke



HR For events in 425 non-AMI: HR For events in 425 non-AMI: MultivariateMultivariate

Variable HR 95% CIAge 1.3 0.96 - 1.88Male Gender 1.2 0.62 - 2.49Hypertension 1.3 0.74 - 2.30Smoking 1.2 0.68 - 2.23LDL cholesterol 1.0 0.69 - 1.45HDL cholesterol 0.83 0.61 - 1.13Log triglyceride 0.97 0.70 - 1.34Log CRP 1.1 0.73 - 1.55Log HCY 1.2 0.92 - 1.59LDL size 1.9 0.72 - 1.37Fibrinogen 1.6 1.16 - 2.29Lp-PLA2 1.3 1.05 - 1.57



HR For Angiographic CAD: HR For Angiographic CAD: MultivariateMultivariate

Variable HR 95% CI P-Value

Age 1.05 1.03 - 1.07 <0.0001Male Gender 4.03 2.46 – 6.60 <0.0001Hypertension 1.60 1.06 - 2.42 0.026Smoking 1.45 0.95 - 2.22 0.087Total cholesterol 1.01 1.004 - 1.016 0.001HDL cholesterol 0.96 0.94 - 0.98 0.0002Log triglyceride 0.84 0.52 - 1.37 0.481Log CRP 1.06 0.87 - 1.30 0.532Fibrinogen 1.16 0.95 - 1.42 0.154Lp-PLA2 0.91 0.71 - 1.17 0.466Lp(a) cholesterol (per 5 mg/dL) 1.56 1.15 - 2.11 0.004



Atherosclerosis Burden vs.Atherosclerosis Burden vs.Vulnerable PlaqueVulnerable Plaque

Risk markers for atherosclerotic buildup and plaque formation may be different than those which predict events.

This needs to be studied in more detail, but may provide insight into most appropriate measures in given clinical situations.



Other Published Mayo StudiesOther Published Mayo Studies

Lp-PLA2 in Peripheral Arterial Disease Lp-PLA2 and Endothelial Dysfunction Lp-PLA2 and Cardiac Allograft Vasculopathy in Heart Transplant

Patients Production of Lp-PLA2 and LPC in coronary arteries and

presence in carotid plaques Lp-PLA2 prognosis after MI Lp-PLA2 recommended clinical cut-points Effect of Pioglitizone and Glipizide on Lp-PLA2

Importance of Lp-PLA2 distribution on Lipoproteins

Lp-PLA2 in Peripheral Arterial Disease Lp-PLA2 and Endothelial Dysfunction Lp-PLA2 and Cardiac Allograft Vasculopathy in Heart Transplant

Patients Production of Lp-PLA2 and LPC in coronary arteries and

presence in carotid plaques Lp-PLA2 prognosis after MI Lp-PLA2 recommended clinical cut-points Effect of Pioglitizone and Glipizide on Lp-PLA2

Importance of Lp-PLA2 distribution on Lipoproteins



Production of Lp-PLA2 and LysoPC Production of Lp-PLA2 and LysoPC across the coronary circulationacross the coronary circulation

Coronary sinusCoronary sinus

CoronaryCoronaryOstiumOstium

==MyocardialMyocardialProductionProduction

CS levels - aorta levelsCS levels - aorta levels X CBFX CBF

Coronary gradientCoronary gradient



Coronary atherosclerosisCoronary atherosclerosisNo atherosclerosisNo atherosclerosis

Lp-PLALp-PLA22 net netproductionproduction

(ng/min)(ng/min)

-1,000

-500

0

500

1,000

1,500

-40

-20

0

20

40

60

CRP netCRP netproductionproduction

((g/min)g/min)

Lp-PLALp-PLA22CRPCRP

P=NSP=NSP<0.01P<0.01

Lp-PLALp-PLA2 2 Enters the Coronary Circulation Enters the Coronary Circulation When Coronary Atherosclerosis (by IVUS) When Coronary Atherosclerosis (by IVUS) is Presentis Present

Lavi S, McConnell JP, Rihal CS, Prasad A, Mathew V, Lerman LO, Lerman A. Local Production of Lp-PLA2 and LysoPC in the Coronary Circulation: Association With Early Coronary Atherosclerosis and Endothelial Dysfunction in Humans. Circulation 2007



Myocardial Production of Lp-PLA2 Myocardial Production of Lp-PLA2 and LysoPCand LysoPC

15 patients with and 15 patients without early atherosclerosis by angiography and or IVUS

Lavi, McConnell, Lerman, et.al. Circulation 2007

-4000 -2000 0 2000

-60

-35

-10

15

40rs -0.5, p=0.005

lysoPC production ng/min

% C

AD

0 10 20 30 40 50 60

-5000

-2500

0

2500

5000

7500

r=0.46, p=0.01

Atheroma volume (%)

Lp

-PL

A 2 n

et

pro

du

cti

onng

/min



Measurement of Lp-PLA2Measurement of Lp-PLA2

FDA approved microtiter plate ELISARequires batch samplingReported to be automatableNot easily adapted in a routine clinical

laboratoryAutomated immunoturbidimetric method

has been developed and now has been approved by the FDA

FDA approved microtiter plate ELISARequires batch samplingReported to be automatableNot easily adapted in a routine clinical

laboratoryAutomated immunoturbidimetric method

has been developed and now has been approved by the FDA



Automated immunoturbidimetric Automated immunoturbidimetric method for Lp-PLA2 (Auto-PLAC)method for Lp-PLA2 (Auto-PLAC)Automated immunoturbidimetric Automated immunoturbidimetric method for Lp-PLA2 (Auto-PLAC)method for Lp-PLA2 (Auto-PLAC)

Performed on multiple automated chemistry analyzers (Roche, Hitachi 912, etc.)

Improved performance characteristicsPrecision, Linearity, Recovery

Correlation: Gen 3 ELISA to Auto=PLAC (y = 1.1609x +12.11, R2 = 0.5363, (n = 452)

Sample and Reagent Stability Issues exist that we are working on in collaboration with diaDexus

Performed on multiple automated chemistry analyzers (Roche, Hitachi 912, etc.)

Improved performance characteristicsPrecision, Linearity, Recovery

Correlation: Gen 3 ELISA to Auto=PLAC (y = 1.1609x +12.11, R2 = 0.5363, (n = 452)

Sample and Reagent Stability Issues exist that we are working on in collaboration with diaDexus



Lp-PLA2 activity assaysLp-PLA2 activity assays

Some commercially available methods and home brews

Currently no FDA approved methodsAs methods are developed issues to be addressed

will beStandardizationWhat is the most appropriate substrate?

Platelet activating factor

Oxidized phosphatidylcholineInfluence/interference form other

phospholipases

Some commercially available methods and home brews

Currently no FDA approved methodsAs methods are developed issues to be addressed

will beStandardizationWhat is the most appropriate substrate?

Platelet activating factor

Oxidized phosphatidylcholineInfluence/interference form other

phospholipases



Therapeutic Reduction of Lp-PLA2Therapeutic Reduction of Lp-PLA2


If so, will reduction reliably predict outcome?


If so, will reduction reliably predict outcome?

Lipid Lowering Medications Shown to Reduce CV Events Lipid Lowering Medications Shown to Reduce CV Events also Lower Lp-PLAalso Lower Lp-PLA22

Perc

en

t re

du

cti

on

in

Lp

-PLA

2

3. Muhlestein JB, et al. Am H Journal. 2006;48:396-401.4. Kuvin J, et al. Am J Cardiol. 2006.

5. Schalwitz R, et al. ATVB Annual Mtg abstract 2007.1. Albert M, et al. Atherosclerosis 2005;182:193-198.

2. Schaefer EJ, et al. Am J Cardiol. 2005;95:1025-1032.

Niaspan Omacor

Average Statin1,2,3 Fenofib.3 added to added to

statin4 statin5

-29% -29%

-53%

-46%

-60%

-50%

-40%

-30%

-20%

-10%

0%

Statin

Niacin AddedTo Statin

Statin

Omacor AddedTo Statin





Glaxo SmithKline

Have developed specific Lp-PLA2 inhibitors (Azetidinones)

Orally active compounds which specifically inhibit Lp-PLA2: Darapladib is now in Phase II clinical trials

NO

S

N

O

OCl

SB-222657; Ki = 40 nM



Effects of Darapladib on Human Coronary Atherosclerotic Plaque


330 patients with CAD

Treated with darapladib or placebo for 12 months

Lp-PLA2 activity was decreased by 59% in the darapladib group

LDL cholesterol was not different in placebo vs. treatment groups.

330 patients with CAD

Treated with darapladib or placebo for 12 months

Lp-PLA2 activity was decreased by 59% in the darapladib group

LDL cholesterol was not different in placebo vs. treatment groups.





Primary end points Coronary atheroma deformability by IVUS Reduction in CRP

There was no significant difference in plaque deformability (P=0.22) or CRP (P=0.35) between groups

One of at least 3 secondary endpoints (necrotic core size) was improved (discussion focused on this)

The safety profile was good although mean systolic blood pressure was higher in the darapladib group

Primary end points Coronary atheroma deformability by IVUS Reduction in CRP

There was no significant difference in plaque deformability (P=0.22) or CRP (P=0.35) between groups

One of at least 3 secondary endpoints (necrotic core size) was improved (discussion focused on this)

The safety profile was good although mean systolic blood pressure was higher in the darapladib group



Lp-PLA2 ConclusionsLp-PLA2 ConclusionsLp-PLA2 ConclusionsLp-PLA2 Conclusions

Lp-PLA2 has emerged recently as an independent biomarker of cardiovascular risk and events.

Lp-PLA2 is a measure of vascular, not systemic inflammation.

Lp-PLA2 is not an acute phase reactant.

It’s biologic variability is similar to lipid measures.

There are some analytical issues to overcome.

Lp-PLA2 has emerged recently as an independent biomarker of cardiovascular risk and events.

Lp-PLA2 is a measure of vascular, not systemic inflammation.

Lp-PLA2 is not an acute phase reactant.

It’s biologic variability is similar to lipid measures.

There are some analytical issues to overcome.



ConclusionsConclusionsConclusionsConclusions

Lp-PLA2 is a biomarker that may be used as a specific therapeutic target, but further studies are necessary

Utility of Lp-PLA2 or other novel biomarkers for clinical purposes or to assess pharmacologic response to therapeutic agents must be viewed in light of our understanding (or lack of understanding) of mechanism of action and our ability to determine if altering biomarker concentration reliably predicts outcomes.

Lp-PLA2 is a biomarker that may be used as a specific therapeutic target, but further studies are necessary

Utility of Lp-PLA2 or other novel biomarkers for clinical purposes or to assess pharmacologic response to therapeutic agents must be viewed in light of our understanding (or lack of understanding) of mechanism of action and our ability to determine if altering biomarker concentration reliably predicts outcomes.

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