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Badimon vp-05-jjb

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Badimon vp-05-jjb

  1. 1. The Cardiovascular Institute Mount Sinai School of Medicine, New York Concept ofConcept of Vulnerable BloodVulnerable Blood Juan Jose Badimon, Ph.DJuan Jose Badimon, Ph.D Director,Cardiovascular BiologyDirector,Cardiovascular Biology Research LaboratoryResearch Laboratory Professor of MedicineProfessor of Medicine IXth VP Symposium (AHA 2005)IXth VP Symposium (AHA 2005) November 12th, 2005November 12th, 2005 Dallas, TXDallas, TX
  2. 2. Atherosclerosis vs Atherothrombosis Atherosclerosis ProgressionAtherosclerosis Progression AtherothrombosisAtherothrombosis
  3. 3. ““Vulnerable“Vulnerable“ lesions play a criticallesions play a critical role in the onset of ACS.role in the onset of ACS. Atherothrombosis is aAtherothrombosis is a diffusediffuse disease while “disease while “Vulnerable“Vulnerable“ lesionslesions areare “focal“focal”” episodes.episodes. Do disruptedDo disrupted VulnerableVulnerable lesionslesions Always trigger an ACS?Always trigger an ACS?
  4. 4. CULPRIT LESION VS. DIFUSE DISEASECULPRIT LESION VS. DIFUSE DISEASE One single culprit lesion but multipleOne single culprit lesion but multiple plaque ruptures in the same patientplaque ruptures in the same patient 11 .. The difuse disease may be responsibleThe difuse disease may be responsible for the widespread coronaryfor the widespread coronary inflammation observed in UAinflammation observed in UA22 11 Rioufol G. Circ.2002;106:804-808Rioufol G. Circ.2002;106:804-808 22 Buffon A, NEJMBuffon A, NEJM 2002;347:5-122002;347:5-12 Multiple complex coronaryMultiple complex coronary plaques in AMI patients.plaques in AMI patients. Goldstein JA NEJM 2000;343:915Goldstein JA NEJM 2000;343:915
  5. 5. ++++++++++++PeripheralsPeripherals ++++++++++CarotidsCarotids ++++++++++++CoronariesCoronaries BloodBlood thrombogenicitythrombogenicity RheologyRheologyPlaquePlaque DisruptionDisruption Virchow’s Triad and Arterial BedsVirchow’s Triad and Arterial Beds
  6. 6. Vulnerable (High-risk) PlaqueVulnerable (High-risk) Plaque ++ == High-RiskHigh-Risk (Vulnerable)(Vulnerable) PatientPatient Plaque - Blood - High Risk PatientPlaque - Blood - High Risk Patient Vulnerable (High-Risk) BloodVulnerable (High-Risk) Blood
  7. 7. ““ Vulnerable /Hyper-reactive” BloodVulnerable /Hyper-reactive” Blood Several risk factors correlate with hyperreactive blood. These factorsSeveral risk factors correlate with hyperreactive blood. These factors may contribute to the clinical presentation after plaque disruptionmay contribute to the clinical presentation after plaque disruption ““Classic”Classic” Diabetes Smoking Hyperlipidemia Inflammation/ Apoptosis/ Infection? Cathecholamines Fibrinogen Lp(a) Homocysteinemia Factor 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 StressStress
  8. 8. BLOOD BORNE - TISSUE FACTORBLOOD BORNE - TISSUE FACTOR Giesen P et al.Giesen P et al. PNAS 1999; 96:2311PNAS 1999; 96:2311 Thrombus formation isThrombus formation is inhibited by theinhibited by the systemic administrationsystemic administration of an anti-TF antibodyof an anti-TF antibody
  9. 9. Tissue Factor:Tissue Factor: a key player for thrombosis and inflammationa key player for thrombosis and inflammation Juno, the two-faced GodJuno, the two-faced God Vessel Wall TFVessel Wall TF Circulating TFCirculating TF
  10. 10. Diabetes and Blood ThrombogenicityDiabetes and Blood Thrombogenicity Rauch U et al. Am J Cardiol 2000; 86:246Rauch U et al. Am J Cardiol 2000; 86:246
  11. 11. Probability of CV Event in theProbability of CV Event in the nextnext 5 Years5 Years No DiabetesNo Diabetes Men Women 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 Age 70 Age 60 Age 50 Nonsmoker Smoker Nonsmoker Smoker Total Chol.: HDL Chol. Total Chol.: HDL Chol. > 20%> 20% 15% - 20%15% - 20% 10% - 15%10% - 15% 5% - 10%5% - 10% 2.5% - 5%2.5% - 5% < 2.5%< 2.5% P. Deedwania at the 2002P. Deedwania at the 2002
  12. 12. 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 DiabetesDiabetes Men Women 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 Age 70 Age 60 Age 50 Nonsmoker Smoker Nonsmoker Smoker Total Chol.: HDL Chol. Total Chol.: HDL Chol. > 20%> 20% 15% - 20%15% - 20% 10% - 15%10% - 15% 5% - 10%5% - 10% 2.5% - 5%2.5% - 5% < 2.5%< 2.5% Probability of CV Event in the next 5 YearsProbability of CV Event in the next 5 Years P. Deedwania at the 2002P. Deedwania at the 2002
  13. 13. Risk factors and circulating TF activityRisk factors and circulating TF activity Control Smokers Hyperlipidemic Diabetics 0 100 200 300 400 500 TissueFactoractivity (pmolFXa/L) Sambola A. Circulation 2003; 107: 973-979
  14. 14. BloodThrombogenicityBloodThrombogenicity CirculatingTFactivityCirculatingTFactivity Glycemic ImprovementGlycemic Improvement No Glycemic ImprovementNo Glycemic Improvement Glycemic Control & Blood ThrombogenicityGlycemic Control & Blood Thrombogenicity Sambola Circ. 2003Sambola Circ. 2003
  15. 15. monocyte TF PMN BLOOD VESSEL WALL AT plaque SMC lipid core macrophage fibroblast myocyte HEART myocardial ischemia TF Circulates in Blood: Possible Cellular Sources EndothelialEndothelial cellcell
  16. 16. Circulating TF activity and Cardiovascular DiseasesCirculating TF activity and Cardiovascular Diseases Several studies have associated high levels of plasma TF activitySeveral studies have associated high levels of plasma TF activity with severity of atherosclerosis, certain cardiovascular risk factorswith severity of atherosclerosis, certain cardiovascular risk factors and events.and events. Tan K Thromb Haemost. 2005Tan K Thromb Haemost. 2005 Tissue Factor ActivityTissue Factor Activity CellularCellular SystemicSystemic asTFasTF MicroparticlesMicroparticles platelets apoptotic cellsplatelets apoptotic cellsWBC’s origin???WBC’s origin???
  17. 17. Inflammation Thrombosis Atherosclerosis ApoptosisApoptosis Tissue factorTissue factor micro-particlesmicro-particles Aggregated Platelets PDGF Thrombin IL-6 TF MMP ICAM-1 IL-1 CVRisk Factors ACS The Inflammation-ThrombosisThe Inflammation-Thrombosis LinkLink Clinical evidence: Septic shockClinical evidence: Septic shock Inflammation subsequent to bacterial endotoxin induces endothelialInflammation subsequent to bacterial endotoxin induces endothelial TF and PAI-1 expression leading to thrombotic complications (DIC)TF and PAI-1 expression leading to thrombotic complications (DIC) CD40L/CRPCD40L/CRP
  18. 18. Caspase-3 and TFCaspase-3 and TF Co-localization inCo-localization in Lipid-Rich Area ofLipid-Rich Area of Human AtheromaHuman Atheroma Hutter R, Badimon J et al, Circulation, 2004;109:2001Hutter R, Badimon J et al, Circulation, 2004;109:2001
  19. 19. Inflammatory Cytokines Release Soluble TF from HUVECInflammatory Cytokines Release Soluble TF from HUVEC CONTROLCONTROL TNFTNF αα IL-6IL-6 asTFasTF NucleusNucleus ComboCombo Incubation time : 6 hoursIncubation time : 6 hours Szotowski B et al. Circ Res 2005; 96: 1233Szotowski B et al. Circ Res 2005; 96: 1233
  20. 20. QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. asTFasTF participatesparticipates in the growth andin the growth and maintainance ofmaintainance of acute thrombosisacute thrombosis Bogdanov et al. Nature Med 2003Bogdanov et al. Nature Med 2003
  21. 21. Independently of its source, the more important issueIndependently of its source, the more important issue is to define the pathophysiologic role of high levelsis to define the pathophysiologic role of high levels of circulating TF:of circulating TF: Do they have aDo they have a “predictive”“predictive” value for CVD events?value for CVD events? Do they play aDo they play a “causative”“causative” role on the severity ofrole on the severity of CVD events by modulating the magnitude of theCVD events by modulating the magnitude of the thrombotic response to plaque disruption??thrombotic response to plaque disruption?? Several methodological factors such as difficulty,Several methodological factors such as difficulty, time consuming and use of different antibodiestime consuming and use of different antibodies complicates the responses to the above questions.complicates the responses to the above questions.
  22. 22. F XF X F IxaF Ixa F VIIIaF VIIIa ProthrombinProthrombin F XaF Xa Tenase complexTenase complex ThrombinThrombin Prothrombinase complexProthrombinase complex F XaF Xa F VaF Va F VIIaF VIIa Tissue factorTissue factor Potential therapeutic targetsPotential therapeutic targets TF: FVIIaTF: FVIIa FXaFXa ThrombinThrombin
  23. 23. Platelet-derived growth factorPlatelet-derived growth factor RANTES (CCL5)RANTES (CCL5) CD 40LCD 40L ENA-78 (CXCL5)ENA-78 (CXCL5) ThrombospondinThrombospondin MIP (CCL3)MIP (CCL3) Platelet activating factor (PAF)Platelet activating factor (PAF) Platelet factor IV (CXCL4)Platelet factor IV (CXCL4) Platelet Activation - Plaque Stability - InflammationPlatelet Activation - Plaque Stability - Inflammation Exposure of monocytes to PAF and P-selectin activates NFKBExposure of monocytes to PAF and P-selectin activates NFKB
  24. 24. Life-styleLife-style StatinsStatins AntiplateletsAntiplatelets AnticoagulantsAnticoagulants etcetc Life-styleLife-style StatinsStatins ACE’sACE’s ARB’sARB’s Hypoglicemics,Hypoglicemics, HDL-raisers,HDL-raisers, etcetc High-Risk PatientHigh-Risk Patient Vulnerable PlaqueVulnerable Plaque Vulnerable BloodVulnerable Blood ++ == High-Risk PatientHigh-Risk PatientHigh-Risk PatientHigh-Risk Patient
  25. 25. QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture.
  26. 26. Alternatively spliced Tissue FactorAlternatively spliced Tissue Factor  Spliced TFSpliced TF contains most of the extracellular domain of TFcontains most of the extracellular domain of TF  Lacks a transmembrane domainLacks a transmembrane domain  Terminates with an unique peptide sequenceTerminates with an unique peptide sequence  Soluble and circulates in bloodSoluble and circulates in blood  Exhibits pro-coagulant activity (exposed to PL)Exhibits pro-coagulant activity (exposed to PL)  Is incorporated into thrombiIs incorporated into thrombi Bogdanov et al. Nature Med 2003Bogdanov et al. Nature Med 2003 PlateletsPlatelets asTFasTF

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