NEOATHEROSCLEROSIS -CAUSE OF LATE ISR AND VERY LATE STENT THROMBOSIS

1. IN-STENT
NEOATHEROSCLEROSIS
Coronary stents seal atherosclerotic
lesions but result in making a new problem of
atherosclerosis

2. • First revolution- balloon
angioplasty
• Invention of balloon
angioplasty as a
percutaneous treatment for
obstructive coronary
disease by Andreas Gruntzig
in 1977.

3. Plain Old Balloon Angioplasty (POBA)
 Dissections – Focal to threatened dissection
 Acute recoil
 Chronic constrictive remodeling

4. • Second revolution – BMS
• The advent of BMS and the landmark Belgian-Netherlands Stent Study
(BENESTENT) and Stent Restenosis Study (STRESS) trials have established
BMS as the second revolution in interventional cardiology.
• A solution to acute vessel occlusion by
– sealing the dissection flaps
– preventing recoil
– making emergency bypass surgery a rare occurrence.
– Serruys et al.A comparison of balloon-expandable-stent implantation with
balloon angioplasty in patients with coronary artery disease: Benestent Study
Group. N Engl J Med. 1994;331:489–495.

5. Plain Old Balloon
Angioplasty(POB
A)
Bare Metal
Stent(BMS)

6. Stent Restenosis -
(ISR) occurred in approximately 20%-30% of cases ,causing the long-term failure of PCI
that was bestowed the title of the “Achilles’ heel” of PCI.
• Pathophysiology of restenosis is
different
– Balloon angioplasty restenosis:
• occurs primarily because of
elastic recoil and negative
remodeling of the vessel
– Stent restenosis:
• occurs primarily because of
neointimal hyperplasia
Cutlip et al. JACC 2002; 40:2082-9

7. In-Stent Restenosis: Definitions
• “Angiographic” Restenosis
– Late lumen loss with > 50% diameter stenosis in
follow-up
• “Clinical” Restenosis
– Symptom or ischemia recurrence with >50%
diameter stenosis,
– Or >70% diameter stenosis without symptoms
Modified from Dangas et al. JACC 2010; 56:1897-1907

8. In-Stent Restenosis after Bare Metal Stenting
• STRESS and BENESTENT (1994) – original BMS trials
– improved initial result (larger MLD) with stenting
and reduction in 6 month restenosis compared to
balloon angioplasty
• Angiographic Restenosis Rate at 6 months:
– About 30%
• Clinical Restenosis (TLR) at 6 months:
– About 10%
Serruys PW et al. N Engl J Med 1994;331
Fischman DL et al. N Engl J Med 1994;331:496-501.

9. Benestent Trial: Stent vs Balloon Angioplasty
Serruys PW et al. N Engl J Med 1994;331:489-495.

10. In-Stent Restenosis after Drug Eluting
Stenting (DES)

11. Drug Eluting Stents: Restenosis
• Substantial reduction in angiographic restenosis and
in Target Lesion Revascularization compared to BMS
• Similar long term results for both Sirolimus- eluting
stents (SES) and Paclitaxel-eluting stents (PES)
• Some very late stent restenosis does occur
Garg, S. et al. J Am Coll Cardiol 2010;56:S1-S42
Raber L. SIRTAX-LATE; TCT: September 22, 2009; San Francisco, CA

12. Cypher Sirolimus DES vs Bare Metal Stent
(SIRIUS TRIAL)
Moses JW et al. N Engl J Med 2003;349:1315-1323.

13. n/a
Endeavor II
(n=581/598)
Sirius
(n=501/525)
Taxus IV
(n=618/650)
Late TLR “Creep” seen with All DES in long term followup
5.9
6.5
7.2 7.2
R2
= 0.9524
0
2
4
6
8
10
1 2 3 4 5
Years of Follow-up
4.9
6.8
7.9
9.4
6.3
R2
= 0.9762
0
2
4
6
8
10
1 2 3 4 5
Years of Follow-up
TLR(%)
4.4
5.6
6.9
7.8
9.1
R2
= 0.9973
0
2
4
6
8
10
Years of Follow-up
TLR(%)
1 2 3 4 5
4 Year Clinical Results of TAXUS IV, Stone, ACC 2006
4 year Outcomes in the Sirius Trial, Leon, TCT 2006
Endeavor II 4 year : Fajadet et al. PCR 2008Modified from Popma, J

14. • The development of late adverse events with
permanent metallic stents may be related to:
persistent inflammation,
loss of normal vessel curvature,
impaired vasomotion,
strut fracture,
Neoatherosclerosis.

15. • Disadvantages
• Increased risk of late and very late ST.
• late ST rates of 0.53%/y, with a continued increase to 3% over 4 years.
– Late thrombosis in DES after discontinuation of antiplatelet therapy.
Lancet. 2004
• In the (ARTS II) trial, the rate of combined definite, probable, and possible
ST was as high as 9.4% at 5 years, accounting for 32% of MACE.
– J Am Coll Cardiol. 2009
–
• Postmortem specimens of DES revealed significant numbers of uncovered
struts with persistent inflammation around the stent struts.
• Vasomotion testing demonstrated vasoconstriction to Ach.
– Vascular responses to drug eluting stents: importance of delayed
healing. Arterioscler Thromb Vasc Biol. 2007

16. Stent Thrombosis

17. Stent Thrombosis
• Infrequent but serious complication:
– Occurs from 0.6% to 5% in studies
– Substantial mortality associated with stent
thrombosis
Garg, S. et al. J Am Coll Cardiol 2010;56:S1-S42

18. Lesion
 Long lesions
 Small diameter
 Multivessel
 AMI
 Diabetes
 Bifurcations
Technical
 Underexpansion
 Incomplete wall apposition
 Crush technique
 Overlapping
Patient
 Antiplatelet noncompliance
 Plavix bioavailability
Stent
 Material
 Polymer Matrix
 Antirestenosis agent
Stent Thrombosis: a Multifactorial Problem
Adapted and modified from: Kereiakes D., et. al., Rev Cardiovasc Med. 2004;5(1):9-15.
Stent
Thrombosis
Courtesy of Popma, J

19. Stent Thrombosis: ARC Definitions
ARC Categories of evidence:
• Definite - Angiographic-pathological conformation
• Probable - Unexplained death < 30 days or Target vessel MI
• Possible - Unexplained death > 30 days
ARC Timing
• Acute: 0 – 24 h post stent implantation
• Sub-acute: 2 – 30 days
• Late: > 30 days – 1 year
• Very late: > 1 year
Adapted from Cutlip DE, et al. Circulation. 2007;115;2344-2351

20. DES and Stent Thrombosis
• Early concerns raised of increased rates of late
stent thrombosis with DES
• Appropriate dual antiplatelet therapy is required
(DAT)
• Period of risk requiring DAT is longer with DES
due at least in part to delayed neointimal
coverage
Pfisterer M, et al, for the BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit
the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol.
2006; 48: 2584

21. DES and BMS Stent Thrombosis
• Stent thrombosis rates not significantly different
between BMS and DES in more recent analyses
• Stent thrombosis rates for DES
– SIRIUS Trial: 0.7% (one yr) to 1.2 % (five yr)
– Real world data: 3.3% (4 yr, Bern-Rotterdam)
Weisz G, et al. Five-year follow-up after sirolimus-eluting stent implantation
results of the SIRIUS Trial. J Am Coll Cardiol 2009; 53:1488 .
Wenaweser P, et al Incidence and correlates of drug-eluting stent thrombosis in
routine clinical practice. 4-year results from a large 2-institutional cohort study. J
Am Coll Cardiol. 2008;52: 1134.
Mauri, L et al. Stent Thrombosis in Randomized Clinical Trials of Drug-Eluting.N
Engl J Med 2007; 356:1020-1029.

22. Stent Thrombosis for DES vs BMS: No significant difference
Roiron C et al. Heart 2006;92:641-649

23. Stent Thrombosis for DES or BMS in STEMI
• No significant difference
between DES or BMS in
several studies out to 3-
5 years
• Suggestion that LST and
VLST may be more
common after DES
(single study)
Brodie, B. et al. J Am Coll Cardiol Intv 2011;4:30-38
Ziada, K, Charnigo, R, Moliterno, D. J Am Coll Cardiol Intv 2011;4:39-41

24. SIRTAX Late: concerns for ongoing incidence of
late thrombosis
Raber L. SIRTAX-LATE: : TCT; September 22, 2009; San Francisco, CA

25. • Next generation DES were developed with new
technology; specifically, the main feature of these DES
was the
inclusion of a biocompatible or biodegradable
polymer to reduce vessel inflammation
thin stent strut for normalization of rheological flow
around the strut to diminish thrombogenicity.
• The second-generation DES, namely, zotarolimus-eluting
stents, everolimus-eluting stents, and biodegradable
polymer-coated biolimus eluting stents, showed reduced
incidences of VLST.
• Nevertheless, the placement of second-generation DES
was found to cause acute coronary syndrome originating
from the stent segment

26. IN-STENT
NEOATHEROSCLEROSIS
CAUSE OF LATE ISR AND VERY LATE STENT
THROMBOSIS

28. • On initiation of an atherogenic diet, typically rich in
cholesterol and saturated fat, small lipoprotein
particles accumulate in the intima
Hyperlipidemia,
hypertension,homocysteine,
smoking,infection,toxins,
hemodynamic factors

29. VASCULAR RESPONSE AFTER PCI
Plaque
compression
Redistribution
fracture
Elastic recoil
Local vasospasm

30. VASCULAR RESPONSE AFTER PCI
• Mechanical injury of the vessel wall cannot be avoided by
PCI, such as balloon dilatation and stent implantation.
• PCI procedures cause denudation of the coronary artery
endothelium, resulting in exposure of the myointima,
fissures in the atheromatous plaque, and overstretching
of the circumferential vessel layers.
• The NORMAL endothelium regulates
• vascular tone,
• controls inflammation,
• maintains lipid and tissue-fluid homeostasis,
• possesses antithrombotic properties.

31. • The vascular endothelium protects against thrombus
formation and blood coagulation through its production of
– nitric oxide,
– prostacyclin,
– tissue plasminogen activator,
– heparin like molecules,
– tissue-factor pathway inhibitor,
– thrombomodulin, and other molecules.
• Perturbation of the normal endothelium function by PCI is
related to the pathogenesis of atherosclerosis and results in
accelerated formation of atheromatous lesions.

32. • Incomplete re-endothelialization in the coronary
vascular wall induces thrombotic events after stent
implantation in the early, late (> 1 mo, ≤ 1 year post-
stenting), or very late phase.
• Denudation of the endothelium after PCI causes VSMCs
to be exposed to blood flow directly, which modulates
the proliferation and viability of the VSMCs.
• Although BMS implantation is superior to POBA with
respect to procedural success and long-term target
lesion patency, dysfunction of the regenerated
endothelium is more pronounced after stent
implantation than after ballooning.

33. • Any interventional procedure, even POBA, causes
denudation of the endothelium and is associated
with the same risk of very late thrombosis as BMS,
and the regenerated endothelial cells are not
structurally and functionally normal.
• Stent implantation into the vessel leads to
perturbations in blood flow, and flow reversal and
disturbed shear stress around the stent strut
promote vascular inflammation and injury

34. • The thickness of the stent struts determines the size of
blood flow recirculation, which is associated with
thrombogenicity within the stent segment.
• Compared with the BMS, the first-generation DES,
namely, SES and PES, which incorporated anti-
proliferative drugs and durable polymers, were
associated with dramatic reductions in the proliferation
of the neointimal hyperplasia and ISR.
• However, an increased risk of VLST was observed for
these first-generation DES compared with BMS

35. • Autopsy studies showed that a lack of re-
endothelialization with > 30% of the stent strut
uncovered per cross-section was a strong predictor of
late stent thrombosis (LST) and VLST.
• Moreover, the polymer-induced type IV hypersensitivity
reaction is one of the mechanisms of LST or VLST
associated with SES.
• In contrast, excessive fibrin deposition and consequent
stent mal-apposition (detachment of the stent struts
from the coronary arterial wall) are associated with
thromboses in the case of PES

36. • The new stent technology of second-generation DES
involved minimization of vessel injury and
normalization of micro-rheology around the stent strut,
thinner struts, and the use of a biocompatible or
biodegradable polymer.
• The pathophysiology of LST and VLST is multifactorial,
And several other mechanisms are possibly linked to
stent thrombosis.
• LST or VLST after placement of BMS and DES is an
unresolved problem, and the new pathological concept
of neoatherosclerosis is another mechanism of stent
failure.

37. Comparison with native vessel atherosclerosis

39. COMPARISON
• In contrast to the decades that it takes for atherosclerosis
to develop in native coronary disease,in-stent
neoatherosclerosis develop over a period of months to a
few years.
• This temporal difference might reflect the morphological
diversity relative to the natural history of progression
among these entities.
• SMC proliferation without macrophage foam cell
infiltration is frequently observed in BMS implants,
especially in those aged <5 years.
• The most recognized feature of atherosclerosis common
to stents is macrophage infiltration, which best resembles
‘fatty streaks’.

40. Simplified scheme for
classifying
atherosclerotic lesions
in human coronary
arteries. Solid arrows
indicate the main
pathway of plaque
progression, and
dashed arrows indicate
infrequent pathways.
Abbreviations: MMP,
matrix
metalloproteinase;
SMC, smooth muscle
cell.

41. Rather than individual foam cells interspersed throughout the intima,
macrophages in stents have a tendency to accumulate as surface clusters or in
peristrut regions, which is different from native disease.
Another important distinction is that intimal xanthomas or ‘fatty streaks’ in
native arteries might regress and are considered nonprogressive lesions, whereas
foamy macrophage clusters in stents seem to progress to form necrotic cores
through cell death.
In native coronary disease, pathological intimal thickening with lipid pools are
common and considered a passageway to lesion progression; however,
pathological intimal thickening is rarely present in DES, but can be seen in BMS .
In native disease, lipid pools and necrotic cores are localized to the deep intimal
layers. The necrotic cores in neoatherosclerosis are more frequently superficial
and, consequently, rarely present as early fibroatheromas; they instead occur as
late fibroatheromas or, in some cases, TCFAs

42. NEOATHEROSCLEROSIS IN BMS
• Neointimal hyperplasia associated with BMS was
considered to be stable, with peaks at 6 mo and 1 year
after stenting during a 3-year follow-up.
Kimura T, et al. Three-year follow- up after implantation of metallic coronary-artery stents. N Engl J Med 1996; 334: 561-566
• However, extended follow-up of BMS showed that late
luminal re-narrowing beyond 4 years was also
common.
Kimura T, et al. Long-term clinical and angiographic follow-up after coronary stent placement in native coronary
arteries. Circulation 2002; 105: 2986-2991

43. • Moreover, one-third of patients implanted with BMS
who had restenosis presented with acute myocardial
infarction or unstable angina 5 years after the index
procedure that was not clinically benign.
Doyle B, Rihal CS, O’Sullivan CJ, Lennon RJ, Wiste HJ, Bell M, Bresnahan J, Holmes DR. Outcomes of stent thrombosis and
restenosis during extended follow-up of patients treated with baremetal coronary stents. Circulation 2007; 116: 2391-2398
• Some reports have documented the occurrence of
ACS due to the disruption of neoatherosclerosis after
BMS implantation
Takano M, Yamamoto M, Mizuno K. Two cases of coronary stent thrombosis very late after bare-metal stenting.
JACC Cardiovasc Interv 2009; 2: 1286-1287

47. • Regenerated endothelium after PCI forms poor
endothelial cell junctions and expresses reduced
numbers of antithrombotic molecules and nitric oxide,
which contributes to neoatherosclerosis.
• Neoatherosclerosis is now recognized as chronic
inflammation in the vessel wall caused by the stent
itself and subsequent neo-vessel formation, which causes
continuous recruitment of macrophages and forms
unstable lesions called thin-cap fibroatheroma (TCFA)
that contribute to disruption of neointima and thrombus
formation, leading to VLST
Otsuka F, Finn AV, Yazdani SK, Nakano M, Kolodgie FD, Virmani R. The importance of the endothelium in
atherothrombosis and coronary stenting. Nat Rev Cardiol 2012; 9: 439-453

49. • OCT observation of BMS segments was performed in
the early phase (< 6 mo) and late phase (≥ 5 years)
after BMS implantation.
• The normal neointima proliferated homogeneously,
and the lipid-laden intima was not observed in the
early phase.
• In the late phase, the lipid-laden intima was found in
67% of cases

50. NEOATHEROSCLEROSIS IN DES
• Chronic inflammation and insufficient functional
endothelialization induce neoatherosclerosis inside both
BMS and DES, causing ISR and thrombosis in the late phase.
Nakazawa G eta l. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol
2011; 57: 1314-1322
• In intravascular ultrasound (IVUS) analyses of VLST,
neointimal rupture was observed within the stent segment
in 43.5% of the DES and all of the BMS.
• Lee CW et al. Intravascular ultrasound findings in patients with very late stent thrombosis after either drug-eluting or baremetal stent
implantation. J Am Coll Cardiol 2010; 55: 1936-1942
• OCT also indicated that ruptured atherosclerosis and
thrombosis in BMS and DES was the most common
mechanism of definite VLST presenting as myocardial
infarction with ST-segment elevation
• Kang SJ et al.OCT analysis in patients with very late stent thrombosis. JACC Cardiovasc Imaging 2013; 6: 695-703

54. Representative sequential images of conventional- and IB-IVUS.
Hirohiko Ando et al. Eur Heart J Cardiovasc Imaging 2013;14:996-1001
FOCAL
DISTRIBUTION
UNIFORM
DISTRIBUTION

55. Why more in DES ????
• Neoatherosclerosis occurs more rapidly in DES than
BMS, possibly because
– the eluted drug prevents endothelial cell
proliferation, viability, and migration,
– which allows infiltration of lipid-laden foamy
macrophage into the vessel,
– thereby accelerating atherosclerotic changes.

56. 1ST GENERATION VS 2ND GENERATION DES???
The principal findings of the present autopsy study are as follows:
(1) CoCr-EES showed a lower frequency of LST/VLST with fewer uncovered
struts, less inflammation (with no hypersensitivity), and less fibrin
deposition compared with SES and PES in humans;
(2) Greater strut coverage in CoCr-EES versus SES and PES was consistently
identified irrespective of lesion characteristics and indications for
stenting;
(3) Neointimal thickness in CoCr-EES was similar to that in SES and PES and
progressively increased with time;
(4) CoCr-EES showed the presence of neoatherosclerosis, the frequency of
which was comparable to that in SES and PES; and
(5) Overall stent fracture was less frequent in CoCr-EES versus SES, whereas
the prevalence of fracture-related adverse events (restenosis and
thrombosis) in CoCr-EES did not differ from that in SES and PES.

57. NEOATHEROSCLEROSIS WAS ASSOCIATED WITH HIGHER RATES OF ACS
STENT TYPE DID NOT CONTRIBUTE TO NEOATHEROSCLEROSIS

58. Stent type BMS Ist Gen DES 2nd Gen DES BRS
Strut
thickness
Thick Thick Thin Thick
Incorporated
drug
None Rapamycin
derivatives/
paclitaxel
Rapamycin
derivatives
None/
rapamaycin
derivatives
Polymer None Durable Durable/
biodegradable
Durable/
biodegradable
Inflammation Not available
Foreign-body
inflammatory
reaction
Strong Slightly Slightly
Onset of
neoathero-
sclerosis
After 4 yr SES 70 d
PES 120 d
CoCr EES
270 d
Not available

59. CONFRONTING NEOATHEROSCLEROSIS
• OCT follow up have demonstrated certain predictors
of IN-STENT NEOATHEROSCLEROSIS :
– CKD
– SMOKING
– LDL>70 mg/dl
• Whether interventions addressing these risk factors
and aggressive lipid-lowering therapy can improve
neoatherosclerosis should be assessed in prospective
trials.

60. DRUG ELUTING BALOON FOR TREATMENT OF
NEOATHERISCLEROSIS -ISR
Regarding PCI, OCT observation at 9 mo following treatment for DES-ISR using a paclitaxel-
coated balloon to avoid repeated stenting showed a heterogeneous pattern in the
neointima with speckled structures consistent with macrophage infiltration and a lipid pool
consistent with neoatherosclerosis, indicating insufficient treatment of DES-ISR

61. New stent technologies
• New stent technologies that accelerate endothelial healing:
• luminal surface coating with CD34 antibody (COMBO™;
Orbusneich Medical Technologies) to capture endothelial
precursor cells, rendering the stents free from
neoatherosclerosis.
• Although a randomized trial indicates that these stents are safe
and noninferior to paclitaxel-eluting stents, there are no long-
term intravascular studies to determine whether or not they
prevent neoatherosclerosis.
• This seems unlikely as current preclinical evidence confirms that
regenerated endothelial cells originate from adjacent cells and
not from endothelial progenitor cells suggesting that the main
benefit of the combination stent may extend beyond restoring
the endothelial monolayer

63. • Efforts are on to repopulate the stent luminal surface with
competent endothelial cells and prevent neoatherosclerosis.
• This could be accomplished by delivery of fully functional cells
by coating a stent with an endothelial cell-specific antibody (ie,
von Willebrand factor or vascular endothelial-cadherin) coupled
with stop-flow infusion of genetically engineered endothelial
cells (based on gene-profiling studies) that are expanded ex vivo
and infused immediately after stent placement.
• Another plausible method is to generate a stent, such as a
bioabsorbable self-expanding platform (to avoid crush injury to
the cells) that is prepopulated with a layer of endothelial cells.
• Similarly, a modified balloon delivery system could also be used
to adhere functional endothelial cells to the luminal surface.

64. Bioabsorbable stents??
Potentially: no late stent thrombosis and no need for prolonged antiplatelet
therapy
Leaves no stent behind long-term
no chronic inflammation,
no long-term impact on local vasomotion
Provides stent scaffolding and radial strength properties as long as needed to
ensure an open lumen – same as permanent stent

65. TAKE HOME MESSAGES
• We have been combatting coronary atherosclerosis through stent
implantation and preventive medicine.
• DES introduction- aimed at solving problem of ISR
• But Late and Very Late Stent Thrombosis and ISR increased.
• Neoatherosclerosis is now emerging as a new problem seen in both
DES and BMS (earlier in DES).
• Although coronary stenting resolves the problem of atherosclerotic
lesion-induced myocardial ischemia, it results in a new problem of
neoatherosclerosis.
• Neoatherosclerosis Contributes to luminal narrowing during extended
follow-up periods after stent implantation
• New stent technology or drugs may solve this problem in the future.