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Aha 2004-no-6-ather.vp,vp-15'

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Aha 2004-no-6-ather.vp,vp-15'

  1. 1. FROM THE VULNERABLE PLAQUE TO THE BURDEN OF DISEASE EVOLVING UNDERSTANDING OF THE VULNERABLE PATIENT Valentin Fuster MD,PhD AHA, New Orleans, November 6, 2004
  2. 2. CT AND MR IMAGING OF MAIN COMPONENTS OF ATHEROTHROMBOTIC PLAQUE Modality CT MR Unit HU SI* Sequence 200† T1W PDW T2W TOF Thrombus 20 +/- +/- +/- + Lipid 50 + + - +/- Fibrous 100 +/- + +/- +/- Calcium > 300 - - - - Z.A. Fayad, V.Fuster., Circ Res 2001;89:305 ZA Fayad, V Fuster, K Nikolaou, C Becker. Circ 2002;106:2026 RP Choudhury, V Fuster, JJ Badimon et al., ATVB 2002; 22:1065 † Vessel contrast enhancement - * Signal intensity (SI) relative to adjacent muscle + = hyperintense; +/- = isointense; - = hypointense
  3. 3. HIGH RISK PLAQUES (HRP) HIGH RISK BLOOD (HRB) BURDEN OF ATHEROTHROMBOSIS DISEASE (BAD) 1. HRP / HRB / BAD - SYSTEMIC 2. HRP - ABUNDANT 3. HRP AND HRB - REGIONALLY DIFFERENT 4. BAD - MRI / CT : DIAGNOSTIC VS PATHOGENETIC Maseri A, Fuster V, Circulation 2003; 107: 2068 Fuster V, Kim RJ, Circulation 2004 (In Press)
  4. 4. 0 10 20 30 40 50 60 70 80 76% 24% 61% 28% Percent Thrombus in culprit lesions Thrombus in non-isch vessels ACS Stable P<0.01 P<0.05 ACUTE CORONARY SYNDROME: A PAN-CORONARY PROCESS? ANGIOSCOPY of culprit ischemic lesions and non-ischemic related vessels in 33 ACS pts and 29 stable angina pts ANGIOSC.T Ohba et al JACC 2001;(Supl):349A–M Asakura et al JACC 2001;37:1284 Yellow ANGIOG. J A Goldstein et al NEJM 2000; 343: 915 AUTOPSY E Falk BHJ 1983;50:127- BIOK (WBC) A.Buffon et al NEJM 2002;347:5 - IVUS C Rioufol Circ 2002;106:804, MK Hong et al Circ 2004;110:928 M Madjid et al. “Finding Vulnerables Plaques, It is worth the effort?” ATVB 2004;24:1775
  5. 5. TF MMPs CAMs Macrophages Pro-Adhesion/Migration TXA2 PAI-1 Prothrombotic Platelet Aggregation Fibrinolysis Flow Reversal Mechanical & Biohumoral Risk Factors LDL ET Extracellular Matrix Fibroblasts Vasa Vasorum SMC contraction migration proliferation PDGF V Fuster et al 2004 (Subm)
  6. 6. Macrophages and Neovessels in Human Atherosclerotic Plaques – Predominant in Diabetes Moreno PR., Purushothaman KR., Fuster V., et al Circ. 2004;110:2032 Moreno PR., Fuster V., JACC Dec 2004 (In Press) CD-68 (Red) and CD-34 (Blue) Diabetes No Diabetes
  7. 7. PLAQUE WITH INFLAMMATION & RUPTURED IEL Moreno PR, Purushothaman K-R, O’Connor WN, Fuster V, Circ. 2002;105:2504 Moreno PR, Purushothaman KR, Fuster V, et al. Circ 2004;110:2032
  8. 8. Independent Predictors of Plaque Rupture Multivariate Analysis P value OddsRatio Lower Upper Cap Thickness< 60 microns <0.001 23.5 9.3 58.9 Rupture of Internal Elastic Lamina <0.001 13.7 4.02 46.9 Cap Inflammation Score 0.002 3.12 1.51 6.45 Plaque Base Neovessel Density 0.003 1.47 1.14 1.9 Lipid Area 0.037 1.15 1.01 1.32 95%Confidence Intervals Moreno PR, Purushothaman KR, Fuster V et al Circ 2004;110:2032
  9. 9. 1)-CT Evaluation Fuster V, Kim RJ, Circ 2004 (In Press)
  10. 10. BAA 62 HU DC Despite the increasedDespite the increased spatial resolutionspatial resolution of the new generation ofof the new generation of MDCTMDCT scanners,scanners, MRIMRI is better foris better for plaqueplaque characterization (Rabbitcharacterization (Rabbit model)model) s JF, Poon M, Sanz J, Rius T, Fuster V, Badimon JJ.s JF, Poon M, Sanz J, Rius T, Fuster V, Badimon JJ. Circ.Circ. 20042004 (In Pre(In Pre
  11. 11. 2) - In vivo MR evaluation of aortic Atherosclerosis, risk factors and CAD at angiography MRI slices of aorta and plaque scores Taniguchi, H et. al. Am Heart J 2004;148:137 (Japan). BAD-MAPI – (Fayad ZA et al) 2004-2005
  12. 12. 1 2 3 4 0 5 10 15 1 2 3 4 0 5 10 15 LDL-cholesterol quartiles Thoracic Aorta Abdominal Aorta Plaque Extent Score P=NS P<0.02 (by Kruskal/Wallis test) 1 2 3 4 0 10 20 30 P<0.001 (by Kruskal/Wallis test) Total Plaque Extent Score 1 2 3 4 0 10 20 30 P<0.002 Thoracic Aorta Score Predicts CAD H Taniguchi et al., AHJ 2004; 148:137 2A) MRI AORTA ATHEROSCLEROSIS SCORE Fibrinogen quartiles CRP quartiles Plaque Extent also related to Age & Systolic BP (T & A Aorta) and degree of Smoking (A Aorta)
  13. 13. Mid heart Aorta- 12 slices Longitudinal View Ca++ 68 year old patient with CAD showing aortic plaque MRI Plaque Imaging BAD-MAPI (Fayad ZA et al.) 2004-2005
  14. 14. CHD RISK IN WOMEN - FRAMINGHAM SCORING (FRS) - 10 y Age, y HDL cholesterol < 35 -9 ≥ 60 -3 35-39 -4 50-59 0 40-44 0 45-49 1 45-49 3 35-44 2 50-54 6 < 35 5 55-59 7 Syst BP 60-64 8 < 120 -3 65-69 8 120-129 0 70-74 8 130-139 1 Cholesterol 140-149 2 < 160 -2 > 160 3 169-199 0 Diabetes 200-239 1 No 0 240-279 2 Yes 4 ≥ 280 3 Smoking No 0 Yes 2 Points 0 1 2 3 4 5 6 7 8 9 10 11 12 13 >14 Total CHD (%) 2 3 4 5 7 8 10 13 16 20 25 31 37 45 > 53 Hard CHD (%) 2 2 3 4 5 6 7 9 13 16 20 25 30 35 > 45 Grundy SM, Pasternak R, Greenland P, Smith S, Fuster V, Circ 1999; 100:1481 ATP III - Aggressive Rx: Framingham, Diabetes, Metab. Synd: obese, BP, HDL, TC, Gluc - Physical inactivity JAMA 2001; 285:2475
  15. 15. Descriptive StatisticsParameter No Mean St dev Min Max Range Age 99 54.3 20.55 9 87 78 Framingham Score 44 7.27 3.99 1 20 19 10-Year Risk 42 0.118 0.069 0.03 0.31 0.28 Total Chol 84 199.9 57.3 105 366 261 LDL 83 120.7 54.5 46 303 257 HDL 84 53.2 16.8 20 100 80 TGC 83 139.3 122.9 32 891 859 HbA1C 20 6.75 1.57 4.7 10.9 6.2 BMI 82 25.98 5.2 15.1 42.5 27.3 BSA (m2 ) 80 1.89 0.30 1.13 2.85 1.72 BAD-MAPI (Fayad ZA et al.) 2004-2005
  16. 16. Correlation of Age & Wall Area of Carotid (mm2) using MRI 0 20 40 60 80 0 10 20 30 40 50 60 70 80 90 100 Age vs WACAR Age WACAR r = 0.522 BAD-MAPI (Fayad ZA et al.) 2004-200
  17. 17. MRI - MAXIMAL THORACIC WALL THICKNESS INTEROBSERVER VARIATION MESA (AE Li et al.) AJR 2004; 182:593 2 3 4 5 6 7 8 9 10 2 3 4 5 6 7 8 9 Observer 2 Observer1
  18. 18. Comparing Framingham Risk Factor Score and Coronary Artery Disease (CAD) 0 2 4 6 8 10 12 14 NO YES CAD FraminghamScore p = 0.447 BAD-MAPI (Fayad ZA et al.) 2004-2000
  19. 19. Comparing Wall Area (mm2 ) and Coronary Artery Disease (CAD) Wall Area Aorta - CAD 100 150 200 250 300 NO YES CAD WADA p < 0.001 * BAD-MAPI (Fayad ZA et al.) 2004-2000
  20. 20. Wyttenbach R……..Corti R. Circ 2004;110:1156 EFFECTs OF PTA & EVBT ON VASCULAR REMODELING HUMAN FEMOROPOPLITEAL ARTERY - MRI
  21. 21. T1W PDW T2W RGB Fibrous cap Lipid Core Clustered 2B) Lipid Rich Plaque Itskovich VV, Samber D, Mani V, et al Magn Reson Med 2004; 52: 515
  22. 22. 2C) Targeted Contrast Agent - Approaches Choudhury RP; Fuster V; Fayad ZA Nature Drug Disc. 2004;3:1
  23. 23. Cell & Molecular MRI Targets In Atherothrombotic Plaques Lipinski MJ, Fuster V, Fisher EA, Fayad ZA, Nature Cardiov. Med. 2004;1:1
  24. 24. Lipid-Rich Atherosclerotic Plaques Detected by Gadofluorine-Enhanced In Vivo Magnetic Resonance Imaging Sirol, M et. al. Circulation 2004; 109: 2890. In vivo T1W MR image of the rabbit abdominal aorta 24-hours post-gadofluorine injection
  25. 25. Lipid Rich Atherosclerotic Rabbit 24h Post Gadofluorine n=10 NZW Atherosclerotic rabbits No Enhancement in Controls (n=6) Pre Contrast 24 H Post Gadofluorine Sirol, M et. al. Circulation 2004; 109: 2890 – AHA 2004 -
  26. 26. In Vivo Aortic Atherosclerotic Plaque in ApoE-KO Mice Gd Immunomicelles Macrophages scavenger receptor I&II Murine (CD204) 9.4T TR=500 ms; TE= 8.6 ms 101 µm in plane spatial resolution 500 µm slice thickness Injected - 13.7µmol/kg Lipinski M; Fayad ZA, Fuster V et al. ISMRM 2004 A. DAPI cell nuclei (blue) B. Gd Immunomicelle-CD204-NDB (green) C. Ab CD 68 (Mφ) D. Merge (orange) - localization in Mφ Merge PRE-CONTRAST 24 hours POST-CONTRAST
  27. 27. Pre-contrast 48 hours post-contrast1 hr post-contrast 24 hr post-contrast 20x lumen wall 40x Frias JC, Fayad ZA, Fuster V et al. ISMRM 2004 rHDL-Gd-DTPA-DMPE-NBD conjugate (green) rHDL-Gd-DTPA-DMPE apoE-KO mice, 4.36 mmol/kg, 9.4T MRM
  28. 28. 4x Acute Thrombus 4x 1-week-old Thrombus 10x 8-week-old Thrombus 4x 6-week-old Thrombus Fibrin Gradually Replaced by Collagen in Older Thrombi
  29. 29. Detection of Occlusive thrombus in the Rabbit Using Fibrin-Targeted MR Contrast Agent Pre Contrast Post Contrast T1-Weighted sequence 2D BB FSE Sirol M. et al. Circ 2004 (In Press) - AHA 2004
  30. 30. Chronic Thrombus Detection Age Characterization Using Fibrin-Targeted MR Contrast Agent N=14 NZW Rabbits Acute 1 Week 2 Weeks 4 Weeks 6 Weeks 8 WeeksNormal Artery Pre Post contrast Sirol M. et al. Circ 2004 (In Press) - AHA 2004
  31. 31. HIGH RISK PLAQUES (HRP) HIGH RISK BLOOD (HRB) BURDEN OF ATHEROTHROMBOSIS DISEASE (BAD) VULNERABLE PATIENT’S MYOCARDIUM (VPM) 1 1. HRP / HRB / BAD - SYSTEMIC 2. HRP - ABUNDANT 3. HRP AND HRB - REGIONALLY DIFFERENT 4. BAD - CT / MRI: PATHOGENETIC VS DIAGNOSTIC 5. VMP Maseri A, Fuster V, Circulation 2003; 107: 2068 Fuster V, Kim RJ, Circulation 2004 (In Press)
  32. 32. ROLE OF IMAGING TECHNOLOGY (MRI) Ischemia at Stress (epicard. vs microv.) - Decreased Perfusion (Dipyrid., Adenosine) - Decreased Contractility (Dobutamine) Non Viability (i.e., scarring), Myoc.Dysfunction - Contrast Hyperenhancement - No Increased Contractility (Dobutamine) Viability (hibernation, stunning), Myoc.Dysfunct - No Contrast Hyperenhancement - Increase Contractility Dobutamine)
  33. 33. Molecular Genetic Advances in Cardiovascular Medicine Focus on the Myocyte Anversa, P et. al. Circulation 2004;109:2832. Process of differentiation of adult stem cells in cell lineages of the organ of origin 24
  34. 34. AUTOLOGOUS CARDIAC STEM CELL THERAPY FOR ISCHEMIC MYOCARDIAL DISEASE Principal Investigator: Valentin Fuster, MD, PhD Co-Principal Investigator: Bernardo Nadal-Ginard, MD, PhD T=0 min Pig preparation T=12 min Short-axis cine sequences : Ventricular Function and Site of Injection. T=19 min T2-weighted dark-blood imaging to detect Myocardial Edema. T=29 min Start Adenosine Infusion. T=33 min Gadolinium injection and Stress Perfusion imaging T=36 min Long asix views of the Left Venricle (4-chamber, two-chamber) T=48 min Rest Perfusion. T=58 min Delayed Enhancement imaging to assess extent of infarction T=65 min Repeated Delayed Enhancement (contrast washout kinetics) T=± 90 min End of study. S Rajagopalan: MRI-Project Leader),
  35. 35. T=0 min Patient preparation T=12 min Short-axis cine sequences for Ventricular Function and Site of Injection. T=20 min Start Adenosine Infusion. T=-24 min Gadolinium injection and Stress Perfusion. T=36 min Long-axis cine views of the Left Ventricle (4-chamber, 3-chamber, 2 chamber). T=40 min Rest Perfusion. T=50 min Delayed Enhancement imaging to assess extent of infarction. T=60 min End of study. S Rajagopalan: MRI-Project Leader AUTOLOGOUS CARDIAC STEM CELL THERAPY FOR ISCHEMIC MYOCARDIAL DISEASE Principal Investigator: Valentin Fuster, MD, PhD Co-Principal Investigator: Bernardo Nadal-Ginard, MD, PhD
  36. 36. FROM THE VULNERABLE PLAQUE TO THE BURDEN OF DISEASE EVOLVING UNDERSTANDING OF THE VULNERABLE PATIENT Valentin Fuster MD,PhD AHA, New Orleans, November 6, 2004

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