Pedro R. Moreno, MD, FACCAssociate Professor of Medicine

DirectorInterventional Cardiology Research

Mount Sinai Medical CenterNew York, New York

Stents In Vulnerable Plaque:

Pre-Clinical Results

Disclosure: Grant from Guidant Co.Advisor Prescent Tec

Saka

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Coronary Thrombosis Before and After Stenting

30 day post Stenting 6 months post Stenting

Before PTCA After PTCA After Stenting

Vulnerable Plaque (TCFA)

Falk E, et al Circulation 1995;92:657-71

Atheromatous Core

Fibrous CapMacrophages

Dilemma: Hypothesis Versus a Real Clinical Problem

Can stents stabilize vulnerable plaques?What about Drug-Eluting Stents?

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 M

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:24:

541

<50%(n=124)

50-99%(n=1266)

>99%(n=94)

PTC A(n=1484)

<50%(n=96)

50-99%(n=2128)

>99%(n=104)

Stent(n=2328)

38 12p atien ts

Outcome of PTCA & Stenting In Coronary Lesions <50% Diameter Stenosis

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

The Hypothesis Than Metallic and DES can Stabilize Vulnerable Plaques MUST Be

Tested in Animal Models First.

RabbitsWatanabe

Transgenic ModelsCholesterol-fed White New Zealand

Animal Models For Invasive Vulnerable Plaque Research

SwineCoronary Injection Models

Streptosotozyn-induced Diabetes

Coronary Percutaneous Needle Injection Catheters

Moreno PR, et al. 2003

Coronary Swine Model: Needle Injection Catheter

Procedure

Histological Pattern of Swine Coronary Plaques After Percutaneous Needle Injection

Granada JF, Moreno PR, et al. Corn Art Disease 2005

4 weeks after

RabbitsWatanabe

Transgenic ModelsCholesterol-fed White New Zealand

Animal Models For Invasive Vulnerable Plaque Research

SwineCoronary Injection Models

Streptosotozyn-induced Diabetes

Swine Diabetic Atherosclerotic Model

Diabetic + Cholesterol

Non-Diabetic+ Cholesterol

Aortic Lesions Coronary Lesions

Diabetic Diabetic

Diabetic Non-DiabeticGerrity RG, et al. Diabetes 2001;50:1654-1665

RabbitsWatanabe

Transgenic ModelsCholesterol-fed White New Zealand

Animal Models For Invasive Vulnerable Plaque Research

SwineCoronary Injection Models

Streptosotozyn-induced Diabetes

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

Aik

awa

M. C

irc 1

998;

97:2

433

Smooth Muscle Cells Macrophages

Short-Term Exposure to Atherogenic Diet

Rabbits AGE EQIVALENCE Humans4-6 months 1-10 years old 18 months 20-30 years old 4 year 60 + years old

Ref # 3

Przyklenk JACC 2001;38:1741 Altman P. 1972: 229-35 Abete P. JACC 2002;39:1701

Exposure to Cholesterol

Fetal Human Aortic PlaqueHypercholesterolemic 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 PlaqueCholesterol 2% x 16 weeks

Short-Term Exposure to Atherogenic Diet

Early Lesions, Foamy-Like Fatty Streaks (Xantomata)

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

Prolonged Exposure to Atherogenic DietWhite 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

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

Rabbit Lesions: Thin Cap Fibroatheroma

Moreno PR., et al. Mount Sinai Hospital, New York, NY

Stabilizing Vulnerable Plaques with Stenting

Moreno PR., et al. Mount Sinai Hospital, New York, NY

Rabbit Lesions: Lipid Necrotic Core

Elastic Trichrome

Moreno PR., et al. University of Kentucky

Rabbit Atheroma: Macrophage Infiltration (RAM 11)Ec

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0.2

0.3

0.4

Thin Cap Thick Cap Fibrotic

0

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18

27

36

45

Thin Cap Thick Cap Fibrotic

Macrophage area (mm2)

Fibrous cap mac count

Can stents stabilize vulnerable plaques?

What about Drug-Eluting Stents?

What about the Polymer?

Stabilizing Vulnerable Plaques with Stenting

n=6

Beta Estradiol Everolimus

n=5 n=5

Polymer

Metallic

De-novo

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)

Vessel wall Injury score

Score0

Score1

Score2

Score3

Schwartz RS, et al. J Am Coll Cardiol. 1992;19:267–274

NeointimaNew Fibrous

Cap Area

Old Fibrous Cap Area

Lipid Core Strut

Strut Quantitative Measurements

• 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

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

0

20

40

60

80

100

120

Lipid Area Old Fibrous CapArea

New Cap Area

0.0001 0.0001 0.0001

De-novo Vs. Metallic

0

20

40

60

80

100

120

Lipid Area Old Fibrous CapArea

New Cap Area

0.0001 0.004 0.0001

De-novo Vs. -Estradiol

0

20

40

60

80

100

120

Lipid Area Old Fibrous CapArea

New Cap Area

0.0001 0.001 0.0001

m2

De-novo Vs. Everolimus

De-Novo

-Estradiol

Metallic

Everolimus

Eche

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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.

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

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*

Fig 3 . INFLAMMATION SCORE

Score I Score II

Score III Score IV Eche

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Fig 4. FIBRIN SCORE

Eche

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Score I Score II

Score III Score IV

Fig 5. HEMORRHAGE SCORE

Eche

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Score I

Score II Score III

Score 0

Fig 7. ENDOTHELIZATION SCORE

Eche

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03 Score IIScore I

Score III Score IV

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=46Everolimus Stent*. n=41

NS

Score Comparison with Metallic Stents

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

Figure 3. ATHEROESCLEROTIC PLAQUE INJURY SCORE

Fibrous Cap without rupture

APIS = 1APIS = 0

Fibrous Cap with rupture

Results

Intact Fibrous Cap.n=88Rupture fibrousCap. 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

0102030405060708090

100

Metallic n=39/88

Intact Fibrous Cap Ruptured Fibrous Cap

P=0.03

Metallic StentsMetallic Stents

Fibrous Cap Rupture: Metallic Stents

Neointimal area (µm2)

0102030405060708090

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)

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)

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,

New stent design reducing fibrous cap rupture may provide optimal stabilization of

thin-cap fibroatheroma

• 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

Circumferential Stress, Cap Thickness and Stents

Cap=55 m

Cap=250 m

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

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)

Acknowledgements

Mount Sinai Medical Center• K-Raman Purushothaman, MD• Juan J. Badimon, PhD• Valentin Fuster, MD, PhD

Fundacion CardioInfantil• Dario Echeverri, MD

University of KentuckyWilliam O’Connor, MD

Guidant Vulnerable Plaque Team