5th Symposium Vulnerable Plaque Org5th Symposium Vulnerable Plaque OrgMarch 29th, 2003March 29th, 2003

ChicagoChicago

Vulnerable (Thrombogenic) BloodVulnerable (Thrombogenic) Blood

Juan Jose BadimonJuan Jose BadimonCardiovascular Biology Research LaboratoryCardiovascular Biology Research Laboratory

Cardiovascular InstituteCardiovascular InstituteMount Sinai School of MedicineMount Sinai School of Medicine

New York, NYNew York, NY

3rd Symposium Vulnerable Plaque Org3rd Symposium Vulnerable Plaque OrgMarch 16th, 2002March 16th, 2002

AtlantaAtlanta

VulnerableVulnerable VulnerableVulnerable VulnerableVulnerable PlaquePlaque Blood Blood PatientPatient++ = =

Juan Jose BadimonJuan Jose BadimonCardiovascular Biology Research LaboratoryCardiovascular Biology Research Laboratory

Cardiovascular InstituteCardiovascular InstituteMount Sinai School of MedicineMount Sinai School of Medicine

New York, NYNew York, NY

ATHEROTHROMBOTICATHEROTHROMBOTIC DISEASE DISEASE

ACSACS and Stenotic Severity and Stenotic Severity

Falk E et al; Circulation 1995Falk E et al; Circulation 1995

CULPRIT LESION VS. DIFUSE DISEASECULPRIT LESION VS. DIFUSE DISEASE

One single culprit lesion but multiple One single culprit lesion but multiple plaque ruptures in the same patient plaque ruptures in the same patient 11. . The difuse disease may be responsible The difuse disease may be responsible for the widespread coronary for the widespread coronary inflammation observed in UAinflammation observed in UA221 1 Rioufol G. Circ.2002;106:804-808 Rioufol G. Circ.2002;106:804-808 22 Buffon A, NEJM Buffon A, NEJM 2002;347:5-122002;347:5-12

Multiple complex coronary Multiple complex coronary plaques in AMI patients. plaques in AMI patients. Goldstein JA NEJM 2000;343:915Goldstein JA NEJM 2000;343:915

Systemic therapies more effective than local interventions in the Systemic therapies more effective than local interventions in the long-rangelong-rangeIs there a role for PCI’s in plaque stabilization?. Probably no.Is there a role for PCI’s in plaque stabilization?. Probably no.

AtherothrombosisAtherothrombosis Complicated MechanismsComplicated Mechanisms

Plaque DisruptionPlaque Disruption BloodBlood ThrombogenicityThrombogenicityLocationLocation VulnerableVulnerable Non-Vulnerable Non-Vulnerable

CoronariesCoronaries ++++++ +/- +/- ++ ++CarotidsCarotids +/-+/- ++ ++ +/- +/-Thoracic AortaThoracic Aorta ++ - - + +PeripheralPeripheral - - - - +++ +++

Suggested Predominant MechanismSuggested Predominant Mechanism

Vulnerable (High-risk) PlaqueVulnerable (High-risk) Plaque++Vulnerable (High-Risk) BloodVulnerable (High-Risk) Blood

==High-RiskHigh-Risk (Vulnerable) (Vulnerable) PatientPatient

Plaque - Blood - PatientPlaque - Blood - Patient

W Kannel Am J Cardiol 1996; 77:6BW Kannel Am J Cardiol 1996; 77:6B

Association of Cardiovascular Risk FactorsAssociation of Cardiovascular Risk Factors

Family/Genes Family/Genes Gender Gender Age (menopause)Age (menopause)DietDietInflammation Inflammation HypertensionHypertensionObesityObesitySedentarismSedentarismothersothers

SmokingSmokingCathecholaminesCathecholaminesFibrinogenFibrinogenLp(a)/HomocysteinLp(a)/HomocysteinFactor V LeidenFactor V LeidenPlatelet polymorph.Platelet polymorph.HypercoagulabilityHypercoagulabilityHypofibrinolysisHypofibrinolysisGenetic Protein Genetic Protein deficienciesdeficiencies

DiabetesHyperlipidemiaApoptosis?Shear rateStressDepression ? cRP?

ATHEROGENESISATHEROGENESIS THROMBOSISTHROMBOSIS

Risk Factor and AtherothrombosisRisk Factor and Atherothrombosis

00

40004000

80008000

1200012000

1600016000

SIMVASTATINSIMVASTATIN PRAVASTATINPRAVASTATIN

p<0.05p<0.05p<0.05p<0.05

Thr

ombu

s For

mat

ion

Thr

ombu

s For

mat

ion

(( mm

22 /mm

/mm

))

Pre treatmentPre treatment Post treatmentPost treatment

LIPID LOWERING and BLOOD THROMBOGENICITYLIPID LOWERING and BLOOD THROMBOGENICITY

251±51251±51 176±44176±44 Total CHOTotal CHO 246+39246+39 202+41202+41165±99165±99 151±83151±83 LDL-CHOLDL-CHO 141+56141+56 123±65123±65

Rauch U et al. Atherosclerosis 2000; 153: 181-89Rauch U et al. Atherosclerosis 2000; 153: 181-89

Effect of 2-year statin on Vessel WallEffect of 2-year statin on Vessel Wall

Corti R, Badimon JJ et al. Circulation 2002 106:2884-87Corti R, Badimon JJ et al. Circulation 2002 106:2884-87

BLOODBLOOD ARTERIAL WALLARTERIAL WALL

ACUTE CORONARY EVENTS

PLASMA LIPIDSPLASMA LIPIDS

plaque vulnerability

plaque progression

endothelial dysfunction

platelet reactivity

macrophages

hyper-coagulability

thrombus formation

STATINSSTATINS

plaque disruption

“ “ Vulnerable /Hyper-reactive” BloodVulnerable /Hyper-reactive” BloodSeveral risk factors correlate with hyperreactive blood. These Several risk factors correlate with hyperreactive blood. These factors modulate the severity of the event after plaque disruptionfactors modulate the severity of the event after plaque disruption

““Classic”Classic”Diabetes Smoking HyperlipidemiaInflammation/ Apoptosis/ Infection? CathecholaminesFibrinogen Lp(a) HomocysteinemiaFactor V Leiden Platelet polymorph Shear rate Genetic Protein deficiencies (AT III, Prot C or S)Hypercoagulable state (FVII, F1.2, FPA)Hypofibrinolytic state (PAI-1, t-PA, u-PA)

““Not so-classic”Not so-classic”DepressionDepression Circulating TF activityCirculating TF activity Stress Stress

Inflammation Thrombosis Atherosclerosis

Apoptosis Tissue factor micro-particles

Aggregated Platelets PDGFThrombin

IL-6

TFMMP

ICAM-1

IL-1

CRP

CV

Ris

k Fa

ctor

sA

CS

The Inflammation-ThrombosisThe Inflammation-Thrombosis LinkLink

Clinical evidence: Septic shockClinical evidence: Septic shockInflammation subsequent to bacterial endotoxin induces endothelialInflammation subsequent to bacterial endotoxin induces endothelialTF and PAI-1 expression leading to thrombotic complications (DIC) TF and PAI-1 expression leading to thrombotic complications (DIC)

CONTROLCONTROL TFPI-TreatedTFPI-Treated

TF INHIBITION and THROMBOSIS TF INHIBITION and THROMBOSIS

Badimon Perfusion chamber Badimon Perfusion chamber Human lipid rich atherosclerotic lesionsHuman lipid rich atherosclerotic lesions

Badimon JJ et al. Circulation 1999; 99:1780-1787Badimon JJ et al. Circulation 1999; 99:1780-1787

TF Plasma Levels and CADTF Plasma Levels and CAD

Soejima H et al. Circulation 1999;99:2908

The existence of circulating particles with procoagulant The existence of circulating particles with procoagulant activity have been reported by several groups activity have been reported by several groups (Mallat,Tedgui)(Mallat,Tedgui)

BLOOD BORNE - TISSUE FACTORBLOOD BORNE - TISSUE FACTOR

Giesen P et al.Giesen P et al.PNAS 1999; 96:2311PNAS 1999; 96:2311

Risk factors and circulating TF activityRisk factors and circulating TF activity

Control Smokers Hyperlipidemic Diabetics0

100

200

300

400

500

Tiss

ue F

acto

r ac

tivi

ty

(pm

ol F

Xa/L

)

Sambola A. Circulation 2003; 107: 973-979

Blo

od T

hrom

boge

nici

tyB

lood

Thr

ombo

geni

city

Circ

ulat

ing

TF a

ctiv

ityC

ircul

atin

g TF

act

ivity

Glycemic ImprovementGlycemic Improvement

No Glycemic ImprovementNo Glycemic ImprovementSambola Circulation 2003Sambola Circulation 2003

Glycemic Control, Circulating TF activity Glycemic Control, Circulating TF activity and Blood Thrombogenicityand Blood Thrombogenicity

Apoptosis and Tissue Factor Protein ExpressionApoptosis and Tissue Factor Protein Expression in Macrophages of Human Coronary Atheromain Macrophages of Human Coronary Atheroma

R. Hutter R. Hutter et al., 2002et al., 2002

Blood MonocytesBlood Monocytesin vitro oxLDLin vitro oxLDL

Human CarotidHuman CarotidLipid-rich lesionLipid-rich lesion

aCAS-3aCAS-3 TF TF aCas-3/TF aCas-3/TF

Hutter R et al, 2003Hutter R et al, 2003

monocyte

TF PMN

BLOOD

VESSEL WALL

AT plaqueSMC

lipid core

macrophage

fibroblast

myocyte

HEARTmyocardial ischemia

TF Circulates in Blood: Possible Cellular Sources

Endothelial Endothelial cellcell

Inhibitors of the intrinsic pathwayInhibitors of the intrinsic pathwayHEPARINHEPARINWARFARINWARFARINLOW MOLECULAR WEIGHT HEPARINSLOW MOLECULAR WEIGHT HEPARINSDIRECT THROMBIN INHIBITORSDIRECT THROMBIN INHIBITORS

Antiplatelet agentsAntiplatelet agentsASPIRINASPIRINTICLOPIDIN, CLOPIDOGREL TICLOPIDIN, CLOPIDOGREL (±ASA)(±ASA)GP IIb/IIIa RECEPTOR ANTAGONISTSGP IIb/IIIa RECEPTOR ANTAGONISTSDIRECT THROMBIN INHIBITORSDIRECT THROMBIN INHIBITORS

Other ApproachesOther Approaches::THROMBOLYTICS, THROMBOLYTICS, ANTI IX, ANTI IX, P2T ANTAGONISTS, P2T ANTAGONISTS, TX-ANTAGONISTSTX-ANTAGONISTS

Antithrombotic Antithrombotic TherapyTherapy

Inhibitors of the intrinsic pathwayInhibitors of the intrinsic pathwayHEPARINHEPARINWARFARINWARFARINLOW MOLECULAR WEIGHT HEPARINSLOW MOLECULAR WEIGHT HEPARINSDIRECT THROMBIN INHIBITORSDIRECT THROMBIN INHIBITORS

Antiplatelet agentsAntiplatelet agentsASPIRINASPIRINTICLOPIDIN, CLOPIDOGREL (±ASA)TICLOPIDIN, CLOPIDOGREL (±ASA)GP IIb/IIIa RECEPTOR ANTAGONISTSGP IIb/IIIa RECEPTOR ANTAGONISTSDIRECT THROMBIN INHIBITORSDIRECT THROMBIN INHIBITORS

Inhibitors of Tissue Factor PathwayInhibitors of Tissue Factor PathwayTFPITFPI TAPTAPINHIBITORS OF FACTORS VIIa and/or XaINHIBITORS OF FACTORS VIIa and/or Xa

Other ApproachesOther Approaches::THROMBOLYTICS, ANTI IX, P2T ANTAGONISTS, TX-ANTAGONISTSTHROMBOLYTICS, ANTI IX, P2T ANTAGONISTS, TX-ANTAGONISTS

Antithrombotic Antithrombotic TherapyTherapy

XX XaXa IX IX IXa IXa ++ ++ VaVa VIIIa VIIIa

Xa:VaXa:Va VIIIa:IXa VIIIa:IXa + Va+ Va

ProthrombinProthrombin ThrombinThrombin

TFTF + + VIIaVIIa TF:VIIaTF:VIIa

TF Pathway and its potential TF Pathway and its potential inhibitioninhibition

TFPITFPI

Clinical Implications - BloodClinical Implications - Blood

Inhibitors of TF pathwayInhibitors of TF pathway are the most promising are the most promisingantithrombotic agents being investigated.antithrombotic agents being investigated.

TargetTarget AgentAgentTF:TF: Several humanized antibodiesSeveral humanized antibodiesTF: FVIIaTF: FVIIa TFPITFPI , , FFR-FVIIa,FFR-FVIIa, Corsevin MCorsevin MFXaFXa Dx-6905a, C-1031, DPC-906, Dx-6905a, C-1031, DPC-906,

FondaparinuxFondaparinuxThrombin:Thrombin: Hirudin, Hirulog, Bivalirudin Hirudin, Hirulog, Bivalirudin ( parent.)( parent.)

Ximelagatran and MCC-977 Ximelagatran and MCC-977 (oral)(oral)

Antithrombotic agents have reduced approx. 20%Antithrombotic agents have reduced approx. 20%of ACS in CAD patients of ACS in CAD patients (BMJ 2002;324:71-86).BMJ 2002;324:71-86).