IN-STENT NEOATHEROSCLEROS

ISCoronary stents seal atherosclerotic

lesions but result in making a new problem ofatherosclerosis

• First revolution- balloon angioplasty

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

Plain Old Balloon Angioplasty (POBA)

Dissections – Focal to threatened dissectionAcute recoilChronic constrictive remodeling

• 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.

Plain Old Balloon

Angioplasty(POBA)

Bare Metal Stent(BMS)

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

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

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;331Fischman DL et al. N Engl J Med 1994;331:496-501.

Benestent Trial: Stent vs Balloon Angioplasty

Serruys PW et al. N Engl J Med 1994;331:489-495.

In-Stent Restenosis after Drug Eluting Stenting (DES)

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-S42Raber L. SIRTAX-LATE; TCT: September 22, 2009; San Francisco, CA

Cypher Sirolimus DES vs Bare Metal Stent (SIRIUS TRIAL)

Moses JW et al. N Engl J Med 2003;349:1315-1323.

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

5.96.5

7.2 7.2

R 2 = 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

6.97.8

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 20064 year Outcomes in the Sirius Trial, Leon, TCT 2006

Endeavor II 4 year : Fajadet et al. PCR 2008Modified from Popma, J

• 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.

• 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

Stent Thrombosis

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

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.

StentThrombosis

Courtesy of Popma, J

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

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

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.

Stent Thrombosis for DES vs BMS: No significant difference

Roiron C et al. Heart 2006;92:641-649

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

SIRTAX Late: concerns for ongoing incidence of late thrombosis

Raber L. SIRTAX-LATE: : TCT; September 22, 2009; San Francisco, CA

• 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

IN-STENT NEOATHEROSCLEROS

ISCAUSE OF LATE ISR AND VERY LATE STENT

THROMBOSIS

• 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

VASCULAR RESPONSE AFTER PCI

Plaque compressionRedistributionfracture

Elastic recoilLocal vasospasm

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.

• 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.

• 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.

• 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

• 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

• 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

• 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.

Comparison with native vessel atherosclerosis

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’.

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.

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

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

• 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

• 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

• 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

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

Representative sequential images of conventional- and IB-IVUS.

Hirohiko Ando et al. Eur Heart J Cardiovasc Imaging 2013;14:996-1001

FOCALDISTRIBUTION

UNIFORMDISTRIBUTION

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.

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.

NEOATHEROSCLEROSIS WAS ASSOCIATED WITH HIGHER RATES OF ACS

STENT TYPE DID NOT CONTRIBUTE TO NEOATHEROSCLEROSIS

Stent type BMS Ist Gen DES 2nd Gen DES BRS

Strutthickness

Thick Thick Thin Thick

Incorporateddrug

None Rapamycinderivatives/paclitaxel

Rapamycinderivatives

None/rapamaycinderivatives

Polymer None Durable Durable/biodegradable

Durable/biodegradable

Inflammation Not availableForeign-bodyinflammatoryreaction

Strong Slightly Slightly

Onset ofneoathero-sclerosis

After 4 yr SES 70 dPES 120 d

CoCr EES270 d

Not available

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.

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

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

• 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.

Bioabsorbable stents??

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.