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).