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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