Experts "Live" CTO Workshop 2015 Septemper, 18th – 19th , 2014 in Istanbul, Turkey

1. Pathology of CTO
Michael Joner, MD
CVPath Institute
Gaithersburg, USA

2. Agenda
• Historical background of CTO lesions
• Differences in CTO lesions of long vs. short duration and
those with prior CABG
• Micro-channels and type of occlusion (abrupt vs.
tapered) in CTO lesions
• Arterial remodeling in CTO lesions
• Insights into Stent Performance in CTO lesions

3. Agenda
• Historical background on CTO lesions
• Differences in CTO lesions of long vs. short duration and
those with prior CABG
• Micro-channels and type of occlusion (abrupt vs.
tapered) in CTO lesions
• Arterial remodeling in CTO lesions
• Plaque progression in patients with CTO lesions

4. Why a tapering proximal lumen pattern is
associated with greater success of CTO PCI?
Tapering types Abrupt types
* * *Side
branch
Side
branch
Katsuragawa M, et al.
JACC 1993;21:604-11
Number of cases 4 (80%) 1 (20%) 2 (40%) 3 (60%)
Small recanalization (+) (-) (-) (-)
Loose fibrous tissue Continuous Disperse Disperse Continuous
CTO length Short Long Long Short

5. 25%
24%29%
22%
Histological stenosis
90-95% stenosis
96-98% stenosis
99% stenosis
100% occlusion
Angiographically
Chronic Total
Occlusion (100%
occlusion)
Srivatsa S, et al.
JACC 1997;29:955-63
78% of angiographically CTO is not totally occluded in Histology
A quarter of angio CTO is
≤ 95% stenosis !

6. What is the determinant for procedure
failure in current CTO PCI?
Variable OR 95%CI P
Age (per 10 yr increase) 0.87 0.73-1.03 0.114
Years since CTO PCI initiation at
each center (per 1 yr increase)
1.52 1.36-1.70 <0.001
Men 0.51 0.28-0.87 0.012
Diabetes 0.81 0.58-1.14 0.241
History of myocardial infarction 0.95 0.68-1.34 0.784
History of CABG 0.49 0.35-0.70 <0.001
1,361 consecutive patients underwent native coronary PCI at 3 US institutions from 2006 to 2011
Michael TT, et al. Am J Cardiol 2013; 112: 488-
History of CABG is a significant negative predictor for procedure success.

7. Agenda
• Historical background on CTO lesions
• Differences in CTO lesions of long vs. short duration and
those with prior CABG
• Micro-channels and type of occlusion (abrupt vs.
tapered) in CTO lesions
• Arterial remodeling in CTO lesions
• Insights into Stent Performance in CTO lesions

8. A total of 95 CTO lesions were
enrolled from CVPath autopsy registry
CTO with prior CABG
(n=34 lesions)
CTO without CABG
of long-duration
(n=49 lesions)
CTO without CABG
of short-duration
(n=12 lesions)
CVPath Human Autopsy Study

9. CTO definition
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422

10. Long-duration CTO Short-duration CTO
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422
Type I collagen Proteoglycan and fibrin

11. PRC
Vein
Graft
MRC
DRC
PD
P-1 CTO-2CTO-1
CTO-9CTO-8
CTO-7CTO-6CTO-5CTO-4
D-1CTO-12
RMB
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422
Representative images of CTO with CABG

12. P-2
IEL 10.7mm2
P-1
IEL 10.6mm2
CTO-1
IEL 8.7mm2
CTO-2
IEL 5.9mm2
CTO-3
IEL 5.0mm2
CTO-4
IEL 3.9mm2
CTO-6
IEL 6.4mm2
CTO-5
IEL 4.5mm2
D-1
IEL 5.1mm2
D-2
IEL 6.6mm2
Proximal
Distal
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422
Representative images of long-duration CTO without CABG

13. Organizing
Thrombus
Organized
Thrombus
Organized
ThrombusProximal Distal
CTO Proximal CTO Distal
CTO-1 CTO-6CTO-5CTO-4CTO-3CTO-2
CTO-5 (x100)CTO-4 (x100)CTO-3 (x100)
Thr ThrThr NCNC NC
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422
Representative images of short-duration CTO without CABG

14. CTO with CABG
n=34 (IQR)
Long-duration CTO
n=49 (IQR)
Short-duration
n=12 (IQR)
P value
Proximal segments % organized thrombus area 9.3 (1.2-14.5) 5.0 (0-15.6) 7.0 (0-26.6) 0.67
CTO segments % organized thrombus area 27.7 (19.8-35.4) 23.2 (15.1-33.2) § 36.9 (25.9-48.0) 0.02
Distal segments % organized thrombus area 11.2 (6.3-16.3) 9.0 (2.7-25.9) 12.7 (5.8-33.3) 0.81
Proximal segments % necrotic core area 1.1 (0-4.1) 2.4 (0-10.6) 8.7 (0-20.9) 0.08
CTO segments % necrotic core area 4.5 (0-23.2) ‡ 7.8 (0-15.0) § 18.6 (6.4-48.0) 0.02
Distal segments % necrotic core area 0 (0-5.6) 0 (0-1.7) 0 (0-4.1) 0.29
Proximal segments % calcification area 31.5 (7.8-52.2) ‡ 12.1 (0-40.6) 0 (0-18.1) 0.001
CTO segments % calcification area 29.2 (19.5-49.5) † 16.8 (1.9-39.9) 12.1 (0.4-37.0) 0.009
Distal segments % calcification area 28.8 (9.7-44.4) †‡ 1.2 (0-13.9) 0 (0-6.7) <0.001
Comparison of plaque components
between CTO with CABG, Long-duration CTO, and short-duration CTO
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422

15. Agenda
• Historical background on CTO lesions
• Differences in CTO lesions of long vs. short duration and
those with prior CABG
• Micro-channels and type of occlusion (abrupt vs.
tapered) in CTO lesions
• Arterial remodeling in CTO lesions
• Insights into Stent Performance in CTO lesions

16. A CB
Movat CD 31Movat
MC
MC
MC
MC
MC
MC
MC
MC
N=209
N=183
N= 42
N = 14
N = 6 N = 5 N = 3
0
5
10
15
20
25
30
35
40
45
50
<20μm 20μm-<40μm 40μm-<60μm 60μm-<80μm 80μm-<100μm 100μm-<200μm ≥200μm
(%)
Size of micro channel
CVPath unpublished data

17. CTO with
CABG
n=34 (IQR)
Long-duration
CTO n=49
(IQR)
Short-
duration
n=12 (IQR)
P value
Mean Number of
microchannel
(>200μm) in CTO
0.5
(0.3-0.8)
0.5
(0.3-0.8)
0.7
(0.5-0.8)
0.30
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422
Microchannel >200um is not frequent

18. Proximal and distal lumen pattern
Abrupt or Tapering?

19. Abrupt Pattern Morphology
P-3 CTO-1(proximal end)P-1P-2
CTO-1 (proximal end)P-1P-2
Bifurcation
Proximal Distal
Proximal Distal
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422

20. Tapered Pattern Morphology
P-3 CTO-1 (proximal end)P-1P-2
D-1 D-3D-2CTO-8 (distal End)
Proximal Distal
Proximal Distal
NC
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422

21. All
n=95
CTO with
CABG
lesions
n=34
Long-
duration
CTO
n=49
Short-
duration
CTO
n=12
P value
Proximal Lumen pattern
Abrupt 49 (51.6) 20 (58.8) 23 (46.9) 6 (50.0) 0.56
Tapered 46 (48.4) 14 (41.2) 26 (53.1) 6 (50.0)
Distal lumen pattern
Abrupt 20 (21.1) 4 (11.8) 12 (24.5) 4 (33.3) 0.20
Tapered 75 (78.9) 30 (88.2) 37 (75.5) 8 (66.7)
P value for Proximal lumen pattern
vs. Distal lumen pattern <0.0001 <0.0001 0.02 0.41
Comparison of proximal and distal lumen pattern
between CTO with CABG, Long-duration CTO, and short-duration CTO
Half of proximal lumen pattern is Abrupt.
Most of distal lumen pattern is Tapered.
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422

22. Agenda
• Historical background on CTO lesions
• Differences in CTO lesions of long vs. short duration and
those with prior CABG
• Micro-channels and type of occlusion (abrupt vs.
tapered) in CTO lesions
• Arterial remodeling in CTO lesions
• Insights into Stent Performance in CTO lesions

23. Section analysis CTO with CABG
sections
n=194
Long-duration CTO
n=241
Short-duration
CTO
n=111
P value
Remodeling index (RI) 0.72 (0.53-0.97) † 0.68 (0.51-0.96) § 0.86 (0.63-1.16) <0.001
Severe negative remodeling section (RI<0.5) n, (%) 41 (21.1) 58 (24.1) 15 (13.5) 0.02
Mild to moderate negative remodeling section
(0.5≤RI<0.75) n, (%)
61 (31.4) 80 (33.2) 27 (24.3)
No negative remodeling section (RI≥0.75) n, (%) 92 (47.4) 103 (42.7) 69 (62.2)
Comparison of negative remodeling
between CTO with CABG, Long-duration CTO, and short-duration CTO
Proximal
Distal
Remodeling
Index 0.75
Remodeling
Index 0.50
25% IEL area
Decrease vs.
Reference 50% IEL area
Decrease vs.
Reference
Normal tapering Mild /Moderate
Negative remodeling
Severe
Negative remodeling
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422

24. Lesion analysis Organizing
thrombus
n=46
Proteoglycan
rich thrombus
n=82
Calcified CTO
(≥10% calcification
area) n=186
Non-calcified
CTO rich in
collagen (<10%
calcification
area) n=232
P value
Remodeling
index
0.99 (0.75-1.35) † 0.77 (0.61-1.03)
‡
0.79 (0.56-1.15) § 0.63 (0.47-0.86) <0.001
Organizing thrombus Proteoglycan rich thrombus Non-calcified CTO rich
in type I collagen
Calcified CTO
Comparison of negative remodeling between 4 types of CTO sections
Sakakura K, et al. Eur Heart J 2013 doi:10.1093/eurheartj/eht422
Organizing
thrombus
(Very early phase)
Type I collagen
rich CTO
(Late phase)
Proteoglycan
rich thrombus
(Early phase)
Shrinkage Shrinkage
Calcification prevent
shrinkage as solid frameDevelopment of Negative remodeling

25. Agenda
• Historical background on CTO lesions
• Differences in CTO lesions of long vs. short duration and
those with prior CABG
• Micro-channels and type of occlusion (abrupt vs.
tapered) in CTO lesions
• Arterial remodeling in CTO lesions
• Insights into Stent Performance in CTO lesions

26. Four distinct Plaque Types of In-stent CTO
Organizing thrombus
(short duration)
Organized thrombus
(Long duration)
Restenosis Healed rupture
Organizing
thrombus
With fibrin
Neointima
Necrotic
core
Organized
thrombus
Rupture
Recanalization likely++ Recanalization likely+ Recanalization likely- Recanalization likely++
Secondary to Stent Thrombosis Secondary to Restenosis Secondary to Rupture

27. Case 1
LAD
LAD
LOM
LCx
RCA
51 year-old male found unresponsive wearing a nitroglycerin patch, two non-
overlapping BMS placed in CTO

28. Case 1Proximal
Distal
In-stent
restenosis

29. False
lumen
Media tear
Case 1
True lumen
(CTO)
Ca++
False
Lumen
True
lumen
True
lumen

30. Proximal
Distal
Case 2
RCA
52-year-old black female with hypertension, DM and CAD underwent
Stenting (BMS) of a totally occluded RCA (4 months prior to death).

31. Case 2
Stent in
false lumen,
larger than
the native
vessel size
TL
FL
True
lumenTrue
lumen
True
lumen
False
Lumen
Proximal edge
Fresh
thrombus

32. *stent struts
Patent
(<50%, n=22)
Intermediate
(50-75%, n=20)
Severe stenosis
(>75%, n=14)
Total occlusion
(n=9)
P value
Media disruption, % 27% 50% 42% 88% 0.023
Strut penetration into
necrotic core, % 18% 15% 5% 11% 0.33
Vessel Injury is associated with Occlusion in DES
Total
occlusion
* *
*

33. Summary
• Severe calcification was observed in CTO with CABG, which may
decrease the success rate of PCI
• Long-duration CTO without CABG demonstrated severe negative
remodeling, whereas short-duration CTO without CABG demonstrated
abundant organized thrombus and larger necrotic core with least
negative remodeling.
• The prevalence of the tapering pattern in the distal lumen was
significantly higher than that in the proximal lumen, suggesting the
advantage of retrograde approach.
• The majority of micro-channels in less than 40μm in diameter
• Four types of in-Stent CTO have been characterized: organizing
thrombus of short duration and long duration, occlusive in-stent
restenosis, and in-stent plaque rupture (neoatherosclerosis)
• Severe media injury secondary to stenting of the false lumen frequently
results in restenosis and occlusion at the longer-term

34. Acknowledgments
Washington DC
CVPath Institute, Inc.
CVPath Institute
Kenichi Sakakura, MD
Fumiyuki Otsuka, MD, PhD
Kazuyuki Yahagi, MD
Frank D Kolodgie, PhD
Elena Ladich, MD
Robert Kutz, MS
Ed Acampado, DVM
Abebe Atiso, HT
Hedwig Avallone, HT
Xin Xu,
Lila Adams, HT
Renu Virmani, MD.
Funding
CVPath Institute Inc.