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Moreno mort meeting

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Moreno mort meeting

  1. 1. Pedro R. Moreno, MD, FACC Associate Professor of Medicine Director Interventional Cardiology Research Mount Sinai Medical Center New York, New York Stents In Vulnerable Plaque: Pre-Clinical Results Disclosure: Grant from Guidant Co. Advisor Prescent Tec
  2. 2. SakaiS,etal.JACC(Nov5)2003;42:1558-1565 Coronary Thrombosis Before and After Stenting 30 day post Stenting 6 months post Stenting Before PTCA After PTCA After Stenting
  3. 3. Vulnerable Plaque (TCFA) Falk E, et al Circulation 1995;92:657-71 Atheromatous Core Fibrous Cap Macrophages Dilemma: Hypothesis Versus a Real Clinical Problem
  4. 4. Can stents stabilize vulnerable plaques? What about Drug-Eluting Stents?
  5. 5. Benestent-1, Benestent-2, West-1, West-2, Flare, Wellstent Native, Flare, Rose, Duet-2000, Sophos-2000, Excite-2000, Easi-2001, Magic-5L, Trapist-2001 MercadoN,MaierW,Boersma,E,SerruysP,etal.EHJ2003:24:541 < 5 0 % ( n = 1 2 4 ) 5 0 - 9 9 % ( n = 1 2 6 6 ) > 9 9 % ( n = 9 4 ) P T C A ( n = 1 4 8 4 ) < 5 0 % ( n = 9 6 ) 5 0 - 9 9 % ( n = 2 1 2 8 ) > 9 9 % ( n = 1 0 4 ) S t e n t ( n = 2 3 2 8 ) 3 8 1 2 p a t ie n ts Outcome of PTCA & Stenting In Coronary Lesions <50% Diameter Stenosis
  6. 6. PTCA Population Stent Population > 99% pre 50- 99% < 50% pre > 99% pre 50- 99% < 50% pre Outcome of PTCA & Stenting In Coronary Lesions <50% Diameter Stenosis Mercado N, Maier W, Boersma, E, Serruys P, et al. EHJ 2003:24:541
  7. 7. The Hypothesis Than Metallic and DES can Stabilize Vulnerable Plaques MUST Be Tested in Animal Models First.
  8. 8. Rabbits Watanabe Transgenic Models Cholesterol-fed White New Zealand Animal Models For Invasive Vulnerable Plaque Research Swine Coronary Injection Models Streptosotozyn-induced Diabetes
  9. 9. Coronary Percutaneous Needle Injection Catheters
  10. 10. Moreno PR, et al. 2003 Coronary Swine Model: Needle Injection Catheter Procedure
  11. 11. Histological Pattern of Swine Coronary Plaques After Percutaneous Needle Injection Granada JF, Moreno PR, et al. Corn Art Disease 2005 4 weeks after
  12. 12. Rabbits Watanabe Transgenic Models Cholesterol-fed White New Zealand Animal Models For Invasive Vulnerable Plaque Research Swine Coronary Injection Models Streptosotozyn-induced Diabetes
  13. 13. Swine Diabetic Atherosclerotic Model Diabetic + Cholesterol Non-Diabetic + Cholesterol Aortic Lesions Coronary Lesions Diabetic Diabetic Diabetic Non-Diabetic Gerrity RG, et al. Diabetes 2001;50:1654-1665
  14. 14. Rabbits Watanabe Transgenic Models Cholesterol-fed White New Zealand Animal Models For Invasive Vulnerable Plaque Research Swine Coronary Injection Models Streptosotozyn-induced Diabetes
  15. 15. HumansNew Zealand Rabbit 81 y/o man Cholesterol x 16 weeks 6 months old Falk E. Circulation 1995; 92:657-71 Cholesterol (16 weeks) Echeverri D., et al. JACC 2003;41 (Supl) 1:238
  16. 16. AikawaM.Circ1998;97:2433 Smooth Muscle Cells Macrophages Short-Term Exposure to Atherogenic Diet Rabbits AGE EQIVALENCE Humans 4-6 months 1-10 years old 18 months 20-30 years old 4 year 60 + years old Ref # 3 zyklenk JACC 2001;38:1741 Altman P. 1972: 229-35 Abete P. JACC 2002;39:1701 Exposure to Cholesterol
  17. 17. Fetal Human Aortic Plaque Hypercholesterolemic Mother Echeverri D., et al. JACC 2003;41 (Supl) 1:238 Macrophages Smooth Muscle Cells Napoli C, et al. JCI 1997;100:2680-2690 Oil Red O White Rabbit Aortic Plaque Cholesterol 2% x 16 weeks Short-Term Exposure to Atherogenic Diet Early Lesions, Foamy-Like Fatty Streaks (Xantomata)
  18. 18. Aikawa M., et al. Circ 1998;97:2433-2444 Human Aortic Plaque in 1-2 Decade of Life Hypercholesterolemic Mother White Rabbit Aortic Plaque Sirius Red Stain Chol 0.3% 4 m + Normal Diet 16 m Napoli C, et al. Lancet 1999;354:1234-41 Advanced, Raised Atherosclerotic Lesions Intermediate Exposure to Atherogenic Diet 20 months 1-2 decade
  19. 19. Prolonged Exposure to Atherogenic Diet White Rabbit Aortic Plaque Hematoxylin & Eosin Stain Alternate Chol 1 % 8 months total 4 years Human Thin-Cap Fibroatheroma Trichrome Stain Autopsy Specimen Moreno PR., et al. Circ 2002; 105:923-927 4½ year 7th Decade Moreno PR., et al. Mount Sinai Hospital
  20. 20. New Zealand Atherosclerotic Rabbit Model Chronic Atherosclerotic Rabbit Model Chol 1% Chol 1% Chow Chow End 8 months 2 months 3 months Stabilization Phase Blood Cholesterol Up to 4 years Up to 4 years Abela GS, Muller JE., et al. Circulation 1995;91:776-784
  21. 21. Rabbit Lesions: Thin Cap Fibroatheroma Moreno PR., et al. Mount Sinai Hospital, New York, NY
  22. 22. Stabilizing Vulnerable Plaques with Stenting Moreno PR., et al. Mount Sinai Hospital, New York, NY
  23. 23. Rabbit Lesions: Lipid Necrotic Core Elastic Trichrome Moreno PR., et al. University of Kentucky
  24. 24. Rabbit Atheroma: Macrophage Infiltration (RAM 11) EcheverriD,PurushothamanKR,O’ConnorWN,MorenoPR..2003 0 0.1 0.2 0.3 0.4 Thin Cap Thick Cap Fibrotic 0 9 18 27 36 45 Thin Cap Thick Cap Fibrotic Macrophage area (mm2) Fibrous cap mac count
  25. 25. Can stents stabilize vulnerable plaques? What about Drug-Eluting Stents? What about the Polymer?
  26. 26. Stabilizing Vulnerable Plaques with Stenting n=6 Beta Estradiol Everolimus n=5 n=5 Polymer Metallic De-novo
  27. 27. De Novo Aorta Lesions Stents Segments in Aorta Cross Sectional Vessel Segment Analysis Plaque Area (mm2) Percent Lipid Area (%) Lipid Area (mm2) Fibrous Cap Thickness (µm)
  28. 28. Vessel wall Injury score Score 0 Score 1 Score 2 Score 3 Schwartz RS, et al. J Am Coll Cardiol. 1992;19:267–274
  29. 29. Neointima New Fibrous Cap Area Old Fibrous Cap Area Lipid Core Strut Strut Quantitative Measurements
  30. 30. • De-novo: Seventy-six segments were analyzed to identify 33 de-novo TCFA lesions. • Stents: 64 stents and 192 stented segments with a total of 1584 struts analyzed. Metallic (n= 127) Beta-Estradiol (n=46) Everolimus (n=41) Polymer (n=23) 237 struts deployed on TCFA plaques
  31. 31. Metallic and DES as a Potential Treatment to Stabilize Vulnerable Plaques  Lipid Core Area & Fibrous Cap Thickness  Vascular Healing Patterns  Stent-Induced Fibrous Cap Rupture
  32. 32. 0 20 40 60 80 100 120 Lipid Area Old Fibrous Cap Area New Cap Area 0.0001 0.0001 0.0001 De-novo Vs. Metallic 0 20 40 60 80 100 120 Lipid Area Old Fibrous Cap Area New Cap Area 0.0001 0.004 0.0001 De-novo Vs. β-Estradiol 0 20 40 60 80 100 120 Lipid Area Old Fibrous Cap Area New Cap Area 0.0001 0.001 0.0001 µm2 De-novo Vs. Everolimus De-Novo β-Estradiol Metallic Everolimus EcheverriD,PurushothamanKR,MorenoPR.
  33. 33. De-novo Vs. Metallic and DES In comparison with de-novo TCFA, stented TCFA shows reduced lipid core area, reduced old fibrous cap thickness and increased new fibrous cap thickness areas.
  34. 34. Metallic and DES as a Potential Treatment to Stabilize Vulnerable Plaques  Lipid Core Area & Fibrous Cap Thickness  Vascular Healing Patterns  Stent-Induced Fibrous Cap Rupture
  35. 35. Score 0: No inflammation around strut. Score I: Scattered; cells <25% around strut. Score II: cells covering 25-50% around strut. Score III: Deposition 50-75% around strut. Score IV: Deposition 100% around strut. Inflammation Score 0: No fibrin present around strut. Score I: Deposition in <25% around the strut. Score II: Deposition 25-50% around strut. Score III: Deposition 50-75% around strut. Score IV: Deposition 100% around strut. Fibrin Deposition Score 0: No red cells present around strut. Score I: Deposition in <25% around the strut. Score II: Deposition in 25-50% around strut. Score III: Deposition in 50-75% around strut. Score IV: Deposition in 100% around strut. Hemorrhage Score 0: No EC present on the strut. Score I: Covered <25% on the strut by EC Score II: Covered 25-75% on the strut by EC Score III: Covered 100% around strut by EC Score IV: Strut covered by neointimal tissue. Endothelization Healing Scores*
  36. 36. Fig 3 . INFLAMMATION SCORE Score I Score II Score III Score IV EcheverriD,PurushothamanKR,MorenoPR.2003
  37. 37. Fig 4. FIBRIN SCORE EcheverriD,PurushothamanKR,MorenoPR.2003 Score I Score II Score III Score IV
  38. 38. Fig 5. HEMORRHAGE SCORE EcheverriD,PurushothamanKR,MorenoPR.2003 Score I Score II Score III Score 0
  39. 39. Fig 7. ENDOTHELIZATION SCORE EcheverriD,PurushothamanKR,MorenoPR.2003 Score IIScore I Score III Score IV
  40. 40. 0 0.5 1 1.5 2 2.5 3 3.5 4 Inflam. Hemorr. Fibrin Endothel. Metallic Stents. n=127 Polymer Stent*. n=23 P=0.19 P=0.74P=0.004P=0.03 0 0.5 1 1.5 2 2.5 3 3.5 4 Inflam. Hemorr. Fibrin Endothel. Metallic Stents. n=127 Beta Estradiol Stents *. n=46 P=0.05 P=0.04P=0.0001P=0.93 P=0.04 P=0.01P=0.03 0 0.5 1 1.5 2 2.5 3 3.5 4 Inflam. Hemorr. Fibrin Endothel. Metallic Stents. n=127 Everolimus Stents *. n=41 P=0.18 0 0.5 1 1.5 2 2.5 3 3.5 4 Inflam. Hemorr. Fibrin Endothel. Polymer Stent*. n=23 Beta-Estradiol Stent*. n=46 Everolimus Stent*. n=41 NS Score Comparison with Metallic Stents
  41. 41. Metallic and DES as a Potential Treatment to Stabilize Vulnerable Plaques  Lipid Core Area & Fibrous Cap Thickness  Vascular Healing Patterns  Stent-Induced Fibrous Cap Rupture
  42. 42. Figure 3. ATHEROESCLEROTIC PLAQUE INJURY SCORE Fibrous Cap without rupture APIS = 1APIS = 0 Fibrous Cap with rupture
  43. 43. Results Intact Fibrous Cap. n=88 Rupture fibrous Cap. n=188APIS=1 63% APIS=0 27% • TCFA with stent-induced fibrous cap rupture were more frequently found than TCFA without stent- induced fibrous cap rupture APIS= Atherosclerotic Plaque Injury Score
  44. 44. 0 10 20 30 40 50 60 70 80 90 100 Metallic n=39/88 Intact Fibrous Cap Ruptured Fibrous Cap P=0.03 Metallic Stents Metallic Stents Fibrous Cap Rupture: Metallic Stents Neointimal area (µm2)
  45. 45. 0 10 20 30 40 50 60 70 80 90 100 Beta-Estradiol* n=20/26 Intact Fibrous Cap Ruptured Fibrous Cap P=0.19 Fibrous Cap Rupture: Beta-Estradiol Eluting Stents Neointimal area (µm2)
  46. 46. Fibrous Cap Rupture: Everolimus Eluting Stents 0 20 40 60 Everolimus* n=20/21 Intact Fibrous Cap Ruptured Fibrous Cap p=0.35 Neointimal area (µm2)
  47. 47. In comparison with de-novo TCFA, metallic and DES reduced lipid core and increased fibrous cap thickness. Conclusions stent-induced fibrous cap rupture was high and associated with increased neointimal proliferation. However, As a result,
  48. 48. New stent design reducing fibrous cap rupture may provide optimal stabilization of thin-cap fibroatheroma
  49. 49. • Tradeoff between vessel injury & vessel wall apposition –Axial variability in lesion diameter • VPSS* Designs –Stent A –Stent B 3 mm 1.5 mm VP with 50% Stenosis Necrotic Core Hypothesis: Low Force Stents May Reduce Injury & Improve Clinical Outcomes *VPSS: Vulnerable plaque specific stent The Guidant VP Team 2004-2005
  50. 50. Circumferential Stress, Cap Thickness and Stents Cap=55 µm Cap=250 µm Loree HM, Lee RT. Circ Res 1992;71:850-858 Control Stent BStent A Ultimate Cap Stress Threshold = 0.6 MPa1 Lendon, et al. J Biomed Eng. 1993 Jan;15(1):27-33
  51. 51. Vulnerable Plaque Specific Stent (VPSS) Study Randomized Stent Deployment n=15The Guidant VP Team & Moreno PR. 2005 • 15 old hypercholesterolemic NZW rabbits • ASA 10 mg/kg PO (3 days before) • Anesthesia: Isofluorane 2% • Femoral arteriotomy + introducer • IV fractionated heparin: 100 u/Kg • Distal aortogram by hand injection • 3 stents/animal, random placement • Control (1:1, stent:artery) •Stent A • Stent B • 28 d-euthanasia (pentobarb 150 mg/kg)
  52. 52. Acknowledgements Mount Sinai Medical Center • K-Raman Purushothaman, MD • Juan J. Badimon, PhD • Valentin Fuster, MD, PhD Fundacion CardioInfantil • Dario Echeverri, MD University of Kentucky William O’Connor, MD Guidant Vulnerable Plaque Team

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