In-Stent NeoatherosclerosisSte t eoat e osc e os sas a Mechanism of Stent Failure

Soo-Jin Kang MD., PhD.

University of Ulsan College of Medicine, Heart InstituteAsan Medical Center, Seoul, Korea , ,

Di lDi lDisclosureDisclosure

I have nothing to disclose

Evolving Neointima gafter BMS Implantation

Histologic and Angioscopic Evidences

Bi-phasic Luminal Response3 Years after BMS Implantation

Tri-phasic Luminal ResponseExtended Follow-up Study 7-10 years3 Years after BMS ImplantationExtended Follow-up Study 7-10 years

4.0 Intermediate termD

(mm

)

3.0

0 001p<0.001

Intermediate-termRegression

MLD

1 0

2.0p<0.001

p

L t hE l Ph1.0

> 4Yr3YrPost PCI 6Mo

Late phaseRe-narrowing

Early PhaseRestenosis

> 4Yr3YrPost-PCI 6Mo

Traditionally, intimal hyperplasia has been believed to

Ki t l N E l J M d 1996 334 561 6

Traditionally, intimal hyperplasia has been believed to be stable with an early peak and a late quiescent period

Kimura et al. N Engl J Med 1996;334:561-6Kimura et al. Circulation 2002;105:2986-91

4.0)

LD (m

m)

2 0

3.0

p<0.001p<0.001

ML

1.0

2.0

> 4Yr3Yr6MoPost-PCI

LateRe-narrowing

IntermediateRegression

EarlyRestenotic

Pathologic Proteogl can rich

* Fibrotic maturation* SMC maturation

de no oPathologic mechanism

Proteoglycan-rich SMC proliferation * Proteoglycan↓

* Cellularity↓* Neointimal thinning

de-novo neoatherosclerosis

Neointimal thinning

Farb et al. Circulation 2004;110:940-7

Pathologic Definition of “Neoatherosclerosis”

Peri-strut foamy macrophage clusters with or without

NeoatherosclerosisPeri strut foamy macrophage clusters with or without

calcification, fibroatheroma, and ruptures with thrombosis in in-stent neointima

adherent thrombilipid-laden macrophage

neointimal disruption

p g

Hasegawa et al Cathe and Cardiovasc Interv 2006;68:554 8

5-year f/u of Palmaz–Schatz 3-year f/u of Palmaz–Schatz

Hasegawa et al. Cathe and Cardiovasc Interv 2006;68:554–8Inoue et al. Cardiovascular Pathology 2004;14:109–15

Atherosclerotic Transformationafter BMS Implantationafter BMS Implantation

Serial Angioscopic Observation at Extended Follow-Up121-month F/U

GFX Stent107-month F/U

Multilink

nosi

s (%

)

18.4%

met

er S

ten

3.6%∆Dia

m

White neointima often changes into yellow plaque over timeAth l ti d ti t d llg y p qLate luminal narrowing (∆%DS) between early (6-12 mo) and

late (≥4yr) follow-up is greater in segments with yellow plaque

Atherosclerotic degeneration represented as yellow plaque contributed to the late luminal narrowing

as ell as r pt re ith thrombotic e entsYokoyama et al. Circ Cardiovasc Interv 2009;2:205-12

as well as rupture with thrombotic events

Intimal Hyperplasia yp pafter DES Implantation

Histologic and Angioscopic Evidences

Dominant IHA G l M h i f DES ISRAs a General Mechanism of DES-ISR

(mm

2 ) 14

124% 75%

88%

MLA

site

10

8

88%

at th

e M 8

6

4

MLA 2 7mm2 nt a

rea

a 4

28% 13%MLA 2.7mm

Stent CSA 11.0mm2

%IH 75% %IH area at the MLA site (%)

Ste

100806040200

Kang et al. Circ Cardiovasc Interv 2011;4:9-14

“Late Catch-up” in DESSerial F/U %IH VolumeSerial F/U of MLD

mm

P<0.0001

5.0

4.020

All lesions

PES*p=0 049

* 6 mo vs. 2 yr

3.0

10

15

me

(%) SES

*p=0.010

p=0.049

2.0 2.592.41 2.26 5

10

H v

olum

*p=0.046

1.0

0

0

5%

IHPost-

Procedure6-Mo 2-Yr

0 -5

Post-Stenting

6 Mo 2 Yr

Park et al. Int J Cardiol. 2010 Sep in press Kang et al. Am J Cardiol 2010;105:1402-8

Early Histopathologic Findings within 1 year between BMS vs DES ISRbetween BMS- vs. DES-ISR

R t ti i ti d f t lRestenotic neointima was composed of proteoglycan-rich SMC with different phenotypes and fibrolipid

Chieffo et al. Am J Cardiol 2009;104:1660–7

E l ti ith N th l tiEarly necrotic core with cholesterol clefts

No atherosclerotic change

BMS 15 monthsDES 13 monthsNeoatherosclerosis was more frequent in DES-lesions BMS 15 monthsDES 13 monthsNakazawa et al. JACC Cariovasc Imaging 2009;2:625-8

q(DES 35% vs. BMS 10%) and occurs earlier

Different Timing of NeoatherosclerosisBMS DES

Different Timing of NeoatherosclerosisBMS DESBMS vs. DESBMS vs. DES

100

(%)

80

60 DES c

hang

e

40

20 BMSoscl

erot

ic

03 6 9 12 18 24 48 >60

BMS

Ath

ero

Duration (months)

Earliest atherosclerotic change with foamy macrophage In addition, the earliest necrotic core formation in DES infiltration began from 4 months after DES implantation,

while the change in BMS occurred beyond 2 years

,was observed at 9 months, which was earlier than BMS

lesions developed at 5 yearsNakazawa et al. JACC Cariovasc Imaging 2009;2:625-8

p y

NeoatherosclerosisNeoatherosclerosisDES BMS

Incidence 31% 16%Median F/UMedian F/U time point 14 Mo 72 Mo

Nakazawa et al. JACC 2011;57:1314–22

Various Stages of Neoatherosclerosis

FA, Late NC (17mo-SES)FA, Early NC (13mo-SES)

DES

TCFA (61mo-BMS)

Th

BMS

Rupture, thrombi(61mo BMS)(61mo-BMS)

Nakazawa et al. JACC 2011;57:1314-22

Independent Risk Factorsfor Neoatherosclerosis

Independent Risk Factorsfor Neoatherosclerosisfor Neoatherosclerosisfor Neoatherosclerosis

OR 95% CIOR 95% CI p

Age, /year 0.963 0.942-0.983 <0.001

Stent duration (/month) 1.028 1.017-1.041 <0.001

SES usage 6 534 3 387 12 591 <0 001SES usage 6.534 3.387-12.591 <0.001

PES usage 3.200 1.584-6.469 0.001

Underlying unstable lesion(rupture, TCFA) 2.387 1.326-4.302 0.004

Nakazawa et al. JACC 2011;57:1314–22

More Advanced Neoatherosclerosis TCFA C t i i N i tiTCFA-Containing Neointima

Intimal rupture Th b iThrombosis

“Unstable Neointima”>5 years in BMS5 years in BMS≤2 years in DES

23-month SES 96-month BMS

Although uncovered struts remains the primary cause

23 month SES 96 month BMS

g p yof DES-VLST, neointimal rupture may be added as

another risk factor

Nakazawa et al. JACC 2011;57:1314-22

Angioscopic DES Follow-Up at 10 MonthsYellow Grade Changes Prevalence of ThrombiYellow Grade Changes Prevalence of Thrombi

1.9

p<0.01 vs. white

25

30

1.4

1.9

14/55

10

15

20

3/570

5

10

0

Yellow White

The development of atherosclerotic yellow plaquesmay be a possible substrate for late stent thrombosis

Higo et al. JACC Cardiovasc Imaging 2009;2:616-24

may be a possible substrate for late stent thrombosis

Neoatherosclerosis Neoatherosclerosis Contributing Mechanism of Stent Failure

Broad Spectrum of Clinical Presentationsf I S R ifrom In-Stent Restenosis

to Very Late Stent Thrombosisy

30 AMI ith VLST (M F/U 33 M i DES 108 M i BMS)DES

(n=23)BMS(n=7)

30 AMI with VLST (Mean F/U 33 Mo in DES, 108 Mo in BMS)

(n=23) (n=7)Mean EEM CSA, mm2

Mean Lumen CSA, mm2

19.5±6.04.2±1.4

18.3±4.14.7±4.6,

Mean Neointima, mm2

Minimal stent CSA, mm2

4.2±1.43.0±1.16.1±1.5

4.7±4.65.0±1.7*7.4±3.7

Neointima ruptureMalapposition

10 (44%)22 (74%)

7 (100%)*0 (0%)*Neoatheroclerosis may contribute to the development of

Lee CW et al. J Am Coll Cardiol 2010;55:1936-42

y pVLST as a common mechanism in BMS and DES

6-mo Taxus %NC 8%

9-mo Taxus%NC 28%

22-mo Taxus%NC 39%

48-mo BMS %NC 40%

57-mo BMS%NC 57%

%DC 2% %DC 8% %DC 20% %DC 25% %DC 15%

Kang SJ et al. AJC 2010 ;106:1561-5At the Maximal %IH Site

Neointimal Composition at Various FU Time117 ISR Lesions (BMS and DES) with %IH>50%

52.2* 5.6* 27.2* 15.0*>36Mo (n=26)

117 ISR Lesions (BMS and DES) with %IH>50%

54.9*

52.2

7.1#

5.6

25.8*

27.2

12.2*

15.0

24-36Mo (n=15)

36Mo (n 26)

62.5

54.9

8.1

7.1

22.3

25.8

7.3#

12.2

12-24Mo (n=12)

( )

64.5 12.5 18.5 4.56-12Mo (n=42)

67.2 15.4 14.6 2.8<6Mo (n=22)

0 20 40 60 80 100 (%)

* <0 01 d # <0 05 l i t f ll ti <6 th

Neoatherosclerosis degeneration increases intimal vulnerability with extended follow-up period *p<0.01 and #p<0.05, vs. lesions at follow-up time <6 months

Kang SJ et al. AJC 2010 ;106:1561-5

u e ab ty t e te ded o o up pe od

Neointima transforms into lipid-laden atherosclerotic tissue in late phase after BMS

Lipid-laden intima frequently has intimal disruption, thrombi

d l i iand neovascularization

Takano et al. J Am Coll Cardiol 2009;55:26-32

71 Year-Old Female8YA Stable angina s/p BMS at pRCA and mLAD8YA Stable angina s/p BMS at pRCA and mLAD7YA mLAD diffuse ISR triple anti-plateletResting chest pain “Unstable Angina”Resting chest pain Unstable Angina

Virtual Histologygy

In-Stent NeoatherosclerosisOCT Analysis in 50 DES-ISR Lesions with %IH>50%

Total Stable UnstableP

OCT Analysis in 50 DES-ISR Lesions with %IH>50%

PN=50 N=30 N=20

Follow-up (months) 32 (9-52) 14 (8-51) 41 (16-56) 0.178p ( ) ( ) ( ) ( )

Lipid neointima 45 (90%) 25 (83%) 20 (100%) 0.067

Fibrous cap thickness µm 60 (50 162) 100 (60 205) 55 (42 105) 0 006Fibrous cap thickness, µm 60 (50-162) 100 (60-205) 55 (42-105) 0.006

Incidence of thrombi 29 (58%) 13 (43%) 16 (80%) 0.010

I id f d th bi 7 (14%) 1 (3%) 6 (30%) 0 012Incidence of red thrombi 7 (14%) 1 (3%) 6 (30%) 0.012

Incidence of rupture 29 (58%) 14 (47%) 15 (75%) 0.044

Incidence of TCFA 26 (52%) 11 (37%) 15 (75%) 0.008

Neovascularization 30 (60%) 15 (50%) 15 (75%) 0.069

Kang et al. Accepted in Circulation 2011

DES Follow-up >20 MonthsBest Cut Off to Predict TCFA-Containing Neointima

100%

Best Cut-Off to Predict TCFA-Containing Neointima

100

60%

80% 80

vity

40%

60% 60

40Sen

sitiv

F/U time =20 Mo20%

20

0

F/U time 20 Mo

N TCFA(Months)

0%

<12 12-36 >360 20 40 60 80 100

100-Specificity

AUC=0 73No TCFASingle TCFAMultiple (≥2)

AUC 0.73Sensitivity 75% Specificity 68%

Kang et al. Accepted in Circulation 2011

p y

TCFA-Containing Intima Neointimal Rupture100% 100%

60%

80%

60%

80%

NoneSingleMultiple20%

40%

20%

40%

Type of Thrombi Longitudinal Extent

p

0%SA UA AMI

0%SA UA AMI

Type of Thrombi Longitudinal Extent

80%

100%

80%

100%

No thrombi No thrombi60% 60%

WhiteRedMixed

<25%25-75%>75%20%

40%

20%

40%

Various size and extent of thrombi, the degree of flow-limiting0%

SA UA AMI0%

SA UA AMIAMC data

Various size and extent of thrombi, the degree of flow limiting obstruction and acuteness may determine the diversity

SUMMARYSUMMARYIn-stent neoatherosclerosis may increase neointimal

vulnerability and contribute to the development ofvulnerability and contribute to the development of stent failure as one of causative mechanisms,

i ll l t ft t t i l t tiespecially late after stent implantation