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Moreno mort meeting
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
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
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. 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. The Hypothesis Than Metallic and DES can
Stabilize Vulnerable Plaques MUST Be
Tested in Animal Models First.
11. Histological Pattern of Swine Coronary Plaques After
Percutaneous Needle Injection
Granada JF, Moreno PR, et al. Corn Art Disease 2005
4 weeks after
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. 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. 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. 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. 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. 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. Rabbit Lesions: Thin Cap Fibroatheroma
Moreno PR., et al. Mount Sinai Hospital, New York, NY
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)
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. 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. 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. 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. 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. 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. Fig 3 . INFLAMMATION SCORE
Score I Score II
Score III Score IV
EcheverriD,PurushothamanKR,MorenoPR.2003
37. Fig 4. FIBRIN SCORE
EcheverriD,PurushothamanKR,MorenoPR.2003
Score I Score II
Score III Score IV
38. Fig 5. HEMORRHAGE SCORE
EcheverriD,PurushothamanKR,MorenoPR.2003
Score I
Score II Score III
Score 0
39. Fig 7. ENDOTHELIZATION SCORE
EcheverriD,PurushothamanKR,MorenoPR.2003
Score IIScore I
Score III Score IV
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. Figure 3. ATHEROESCLEROTIC PLAQUE INJURY SCORE
Fibrous Cap without rupture
APIS = 1APIS = 0
Fibrous Cap with rupture
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
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. 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. New stent design reducing fibrous cap rupture
may provide optimal stabilization of
thin-cap fibroatheroma
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. 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. 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. 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
Notes de l'éditeur
In order to satisfy the FC rupture prevention requirement, we will likely expand our device with very low forces. In the realm of balloon-expandable bVPSS this will require low deployment pressures. We could have terrific apposition at high pressures, but then we’d probably rupture the cap. We’d like to have apposition to prevent thrombus and stent migration (having the stent float away). To achieve this, we know that we will have challenges minimizing creep and recoil. Compounding this challenge is maintaining apposition during the degradation process. As I already mentioned, there’s a sensitive tradeoff bt cap rupture prevention and apposition. This is particularly true if we want to appose a multi-diameter vessel such as this one.
In order to satisfy the FC rupture prevention requirement, we will likely expand our device with very low forces. In the realm of balloon-expandable bVPSS this will require low deployment pressures. We could have terrific apposition at high pressures, but then we’d probably rupture the cap. We’d like to have apposition to prevent thrombus and stent migration (having the stent float away). To achieve this, we know that we will have challenges minimizing creep and recoil. Compounding this challenge is maintaining apposition during the degradation process. As I already mentioned, there’s a sensitive tradeoff bt cap rupture prevention and apposition. This is particularly true if we want to appose a multi-diameter vessel such as this one.