Potential Biomakers for Predicting AAA Expansion

  Jes S. LindholtJes S. Lindholt

Vascular Research Unit, Viborg Hospital, Denmark

Amsterdam 2010

Amsterdam 2010

Background: why biomarkers ?

• 85-90% of screen-detected AAA 85-90% of screen-detected AAA is below 5½ cm in sizeis below 5½ cm in size

• Earlier AAA surgery produces Earlier AAA surgery produces more safe surgery + better QoLmore safe surgery + better QoL

• Only half benefit of surgery. Only half benefit of surgery. - more nuanced indication of - more nuanced indication of operationoperation

• Monitoring endovascular Monitoring endovascular excluded AAA for endoleakexcluded AAA for endoleak

• Monitoring pharmacological Monitoring pharmacological treatment to inhibit aneurysmal treatment to inhibit aneurysmal progressionprogression

33

The aim

to find potential present serological to find potential present serological biomarkers for expansion in the biomarkers for expansion in the literature of all publications from 1985 literature of all publications from 1985 to 2010 by conducting a systematic to 2010 by conducting a systematic review review

Urbonavicius S, Urbonaviciene G, Honoré B, Henneberg EW, Vorum H, Lindholt JS.Eur J Vasc Endovasc Surg. 2008 Sep;36(3):273-80;

44

924 hits

740 potentially relevant

titles

290 potentially relevant abstracts

51 included papers

Excluded due to irrelevant title

Excluded due to irrelevant abstract – mainly animals,

wall, case-controls and surrogate markers as size,

and volume

Excluded due to irrelevant content – mainly case-

controls, surrogate markers as size, and volume

PRISMA FLOW CHART

End-points

• Mean annual expansion rateMean annual expansion rate - Average growth rate - Average growth rate- Linear model of expansion - Linear model of expansion

• StatisticsStatistics- - Correlation analysis and Correlation analysis and

- multivariate regression analysis- multivariate regression analysis- - Above and below median of growth rate Above and below median of growth rate - Above and below interobserver variation - Above and below interobserver variation of the measurements of the measurements

• Prediction of surgeryPrediction of surgery - Survival analysis- Survival analysis- ROC curve analysis- ROC curve analysis

Degradation products: Elastin peptides (EP)

• N=79N=79• EP vs growth rate, 1st EP vs growth rate, 1st

year: year: r = 0.40 r = 0.40 (0.20-0.57)(0.20-0.57)

Lindholt et al. Eur J Vasc Endovasc Surg 1997;21:235-240Lindholt et al. Eur J Vasc Endovasc Surg 1997;21:235-240

Degradation products: elastin peptides (EP)

ROC Curve

Diagonal segments are produced by ties.

1 - Specificity

1,00,75,50,250,00

Se

nsi

tivity

1,00

,75

,50

,25

0,00

Source of the Curve

Reference Line

Last AAA-size (mm)

Multiple

SEP (ng/ml)

• ROC curve analysis: optimal sensitivity and specificity of 67% and 60% - similar to last AAA size

• Chichester Aneurysm Screening Programme

39 unoperated AAA > 6 cm: 12 ruptured later

• S-EP was significantly higher in AAA rupturing later

Lindholt et al. Eur J Vasc Endovasc Surg: 2001;21:546-550

ROC curve dataROC curve data SensitivitySensitivity SpecificitSpecificityy

Area under the Area under the curve curve (95%.C.I.)(95%.C.I.)

S-elastin peptides S-elastin peptides (ng/ml)(ng/ml)

67%67% 60%60% 0.68 (0.52-0.68 (0.52-0.85)0.85)

Last measured AAA-size Last measured AAA-size (mm)(mm)

58%58% 56%56% 0.67 (0.51-0.67 (0.51-0.82)0.82)

S-elastin peptides and S-elastin peptides and AAA-sizeAAA-size 83%83% 66%66% 0.74 (0.59-0.74 (0.59-

0.89)0.89)

Degradation products: Elastin peptides (EP)- limitations

• EP: an ELISA based EP: an ELISA based upon polyclonal upon polyclonal antibodies antibodies

• ””Poor” correlation Poor” correlation between generations of between generations of ELISAs: r=0.46ELISAs: r=0.46

• Standardized ELISA Standardized ELISA needed for clinical needed for clinical applicationapplication

•Lindholt et al. Int J Angio: 2001;21:546-50Lindholt et al. Int J Angio: 2001;21:546-50

ELISA2. S-elastin peptides (ng/ml)

500400300200100

EL

ISA

1.

S-e

last

in p

ep

tide

s (n

g/m

l)

600

500

400

300

200

100

Compensatory disordered collagen: Procollagen-N-III-propeptide (NPIIIP)

• N=99• NPIIIP vs growth rate:

r=0.24 (0.02-0.44) • No potential for

predicting surgery

ROC Curve

Di agonal segments are produced by ties.

1 - Specifi city

1,00,75,50,250,00

Sen

siti

vity

1,00

,75

,50

,25

0,00

Source of the Curve

Ref erence Line

Multivar iate

predi ction

S-elastin-peptides

(ng/ ml)

I nitial size

(mm)

S-procollagen

(ng/ ml)

Lindholt et al. Eur J Vasc Endovasc Surg: 2001;21:235-240

BiomarkerBiomarker NN Relation between Relation between biomarkers and AAA biomarkers and AAA

progressionprogression

Author, yearAuthor, year

γγ--IFNIFNIL-1 βIL-1 βIL-6IL-6TNF-αTNF-α

5050 r=0.37r=0.37no associationno associationno associationno associationno associationno association

Juvonen J. et al., Juvonen J. et al., 19971997

IL-6IL-6 466466 no associationno association Jones et al. 2001Jones et al. 2001

IL-6IL-6TNF-TNF-ααCD40 ligandCD40 ligandEndothelin-1 Endothelin-1

178178 no associationno associationno associationno associationno associationno association

-/+ Median, P=0.01-/+ Median, P=0.01

Flondell-Sité D et al., 2010Flondell-Sité D et al., 2010

MIFMIFTGF-TGF-β1β1

112112 r=0.28r=0.28no associationno association

Pan JH et al., Pan JH et al., 20032003

OsteopontinOsteopontin 198198 r=0.24r=0.24 Golledge J et al., Golledge J et al., 20072007

OsteoprogeriOsteoprogerinn

146146 r=0.20r=0.20 Moran CS et al., Moran CS et al., 20052005

Inflammation: specific cytokines

BiomarkerBiomarker NN Relation between Relation between biomarkers and AAA biomarkers and AAA

progressionprogression

Author, yearAuthor, year

CRPCRP 545545 no associationno association Norman P. et al., Norman P. et al., 20042004

CRPCRP 151151 no associationno association Lindholt J et al., Lindholt J et al., 20012001

CRPCRP 3535 no associationno association Vega de Céniga M., Vega de Céniga M., 20092009

Inflammation acute phase reactants

1212

BiomarkerBiomarker NN Association between Association between biomarkers and AAA biomarkers and AAA

expansionexpansion

Author, yearAuthor, year

P-MMP-9P-MMP-9P-MMP-2P-MMP-2P-TIMP1+2P-TIMP1+2

3636 r=0.33r=0.33No associationNo associationNo associationNo association

Lindholt J. et al., Lindholt J. et al., 20002000

P-MMP9P-MMP9P-MMP2P-MMP2P-TIMP-1 P-TIMP-1

178178 No associationNo associationNo associationNo associationNo associationNo association

Flondell-Sité DFlondell-Sité D, 2010, 2010

P-MMP-9P-MMP-9P-TIMP1P-TIMP1aa11-antitrypsin-antitrypsin

464641414040

R=0.32R=0.32No associationNo associationNo associationNo association

Speelman L et al, Speelman L et al, 20102010

P-ElastaseP-ElastaseP-aP-a11-antitrypsin-antitrypsin

7979 r=0.30r=0.30No associationNo association

Lindholt J et al., Lindholt J et al., 20032003

aa11-antitrypsin-antitrypsin 3535 R=0.55R=0.55 Vega de Céniga M.,Vega de Céniga M., 2009 2009

Cystatin CCystatin C 142142 r= -0.24r= -0.24 Lindholt J. et al., Lindholt J. et al., 20012001

P-Plasmin (PAP)P-Plasmin (PAP) 7070 R=0.39R=0.39 Lindholt J. et al., Lindholt J. et al., 20012001

P-tPAP-tPAP-uPAP-uPA

7070 r=0.37r=0.37No associationNo association

Lindholt J. et al., Lindholt J. et al., 20032003

ChymaseChymase 115115 r=0.24 r=0.24 Sun J et al., Sun J et al., 20102010

Matrix degradation: Involved proteases and their inhibitors

1313

BiomarkerBiomarker NN Correlation between Correlation between biomarkers and AAA biomarkers and AAA

expansionexpansion

Author, yearAuthor, year

Activated protein Activated protein C-protein C C-protein C inhibitor (APC-PCI)inhibitor (APC-PCI)

232232 No associationNo association Kölbel TKölbel T. et al., . et al., 20082008

APC-PCIAPC-PCIserpine-1serpine-1tPa-serpine-1tPa-serpine-1

178178 No associationNo associationNo associationNo associationNo associationNo association

Flondell-Sité D, Flondell-Sité D, 20102010

ThioredoxinThioredoxin 7878 R=0.25R=0.25 Martinez-Pinna R et al, Martinez-Pinna R et al, 20102010

Intraluminal thrombus

BiomarkerBiomarker NN Relation between Relation between biomarkers and AAA biomarkers and AAA

progressionprogression

Author, yearAuthor, year

T-CholesterolT-Cholesterol 17431743 no associationno association Brady AR et al, 2004Brady AR et al, 2004

T-cholesterolT-cholesterolHdlHdlLdLLdLTriglycerideTriglyceride

230230 no associationno associationno associationno associationno associationno associationno associationno association

Schlösser FJ et al., 2008Schlösser FJ et al., 2008

TriglycerideTriglycerideT-cholesterolT-cholesterolLdLLdLAb-OxLdLAb-OxLdLLipoprotein (a)Lipoprotein (a)

117117 no associationno associationno associationno associationno associationno associationno associationno associationno associationno association

Lindholt J. et al., Lindholt J. et al., 20012001

Lipoprotein (a)Lipoprotein (a) 3535 no associationno association Vega de Céniga M., 2009Vega de Céniga M., 2009

T-cholesterolT-cholesterolLdLLdL

451451 no associationno associationno associationno association

Ferguson CD, 2010Ferguson CD, 2010

Triggering factorsLipids

BiomarkerBiomarker NN Relation between Relation between biomarkers and AAA biomarkers and AAA

progressionprogression

Author, yearAuthor, year

S-CotinineS-Cotinine 4343 significant correlationsignificant correlation MacSweeney et al., MacSweeney et al., 19941994

S-CotinineS-CotinineHomocysteineHomocysteine

122122 r=0.24r=0.24no correlationno correlation

Lindholt J. et al., Lindholt J. et al., 20032003

HomocysteineHomocysteine 108108 r=0.28r=0.28 Halazun KJ et al., Halazun KJ et al., 20072007

C. pneumoniaeC. pneumoniae infectioninfection

110110 IgA r=0.28IgA r=0.28IgG r=0.45IgG r=0.45

Lindholt J. et al., Lindholt J. et al., 20012001

C. pneumoniaeC. pneumoniae serologyserology

6868 IgA , p = 0.046IgA , p = 0.046 Falkensammer B. et al., Falkensammer B. et al., 20072007

C. pneumoniaeC. pneumoniae serologyserology

259259 IgA: no associationIgA: no associationIgG: no associationIgG: no association

Karlsson L et al., 2009Karlsson L et al., 2009

Triggering factorsSmoking, Homocysteine and Ig-C.pneumoniae

Conclusions

• Several potential serological predictors Several potential serological predictors • Few with clinical potential: Few with clinical potential: - - Elastin peptidesElastin peptides – (standardized ELISA needed) – (standardized ELISA needed) - - Plasmin or tPAPlasmin or tPA – the common proteolytic – the common proteolytic

activator activator - - MMP9 ?MMP9 ? - -

γ-Interferon?γ-Interferon?- - Ig-Ig-CPCP by ELISA ? by ELISA ?

• Multivariate approachMultivariate approach• Confirmation in larger cohortesConfirmation in larger cohortes• International collaboration neededInternational collaboration needed• New methodologies in the huntNew methodologies in the hunt