JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 7, NO. 12, 2014

ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 1936-8798/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jcin.2014.06.024

EDITORIAL COMMENT

Shedding Light on Scaffold Vascular Response* Bill (Vasileios) D. Gogas, MD, PHD, Habib Samady, MD

The excessive increase of anything causes

indicated using optical coherence tomographic (OCT)

a reaction in the opposite direction.

A

—Plato (428

BC –348 BC )

imaging matched with histology that at 2 years the (1)

rterial healing or vascular response after percutaneous coronary interventions (PCIs) describes a reparative mechanism to acute

procedural injury attributed to balloon barotrauma and/or stent deployment itself (2,3). Early vascular

responses after bare metal stent or drug-eluting stent (DES) placement are driven by fibrin- and plateletrich thrombi depositions and migration of smooth muscle cells. In contrast, late vascular responses to DES are primarily attributed to delayed strut healing subsequent to drug toxicity, polymer-induced inflammation followed by hypersensitivity reactions, and in-stent neoatherosclerosis leading to late target lesion revascularization (TLR) or late stent thrombosis. Further technological innovations in the quest for optimal coronary stenting (4) led to the develop-

polymeric struts are being replaced by proteoglycanrich matrix (glycoconjugates), which at 3 years is substituted with connective tissue, and at 4 years by a layer of homogeneous fibrous neointimal tissue (7,8). Prospective clinical intravascular imaging studies investigating the Absorb BVS have shown the following: 1) in-scaffold late lumen loss comparable to that observed with metal everolimus-eluting stents at 1, 2, and 3 years; 2) restoration of coronary vasomotor function at 1 year assessed with intracoronary methylergonovine or acetyl choline; 3) nonobstructive neointimal proliferation proximal to the scaffold (proximal edge vascular response) at 2 years and edge restenosis of 3% resulting in TLR (edge effect) comparable to that observed with metal DES; and 4) scaffold area expansion attributed to loss of scaffold integrity at 3 years (9,10).

ment of bioresorbable scaffolds (BRSs) made of biodegradable polymers or biocorrodible metals. The property of transient vessel scaffolding (w6 months) and complete resorption over a period of 3 years with subsequent restoration of vessel anatomy (form), physiology (function), and local hemodynamic milieu promises to eliminate or reduce the risk of late vascular responses (5,6). Bench work in experimental porcine models after Absorb Bioresorbable Vascular Scaffold (BVS) (Abbott Vascular, Santa Clara, California) deployment has

SEE PAGE 1361

In this issue of JACC: Cardiovascular Interventions, Zhang et al. (11) report a substudy of the ABSORB Cohort B trial describing the in-scaffold and edge vascular responses after implantation of the Absorb BVS. The ABSORB Cohort B trial (B 1 and B2 subgroups) in which intravascular imaging and clinical assessment at multiple time points was performed (Figure 1) was the first international registry to provide an in depth evaluation of the second-generation BVS (Revision 1.1) approved for clinical use in Europe since 2011. The current longitudinal investigation, which excludes patients with clinically relevant edge

*Editorials published in JACC: Cardiovascular Interventions reflect the

restenosis (angiographic diameter stenosis >50% at

views of the authors and do not necessarily represent the views of JACC:

follow-up), reports truly serial OCT imaging findings

Cardiovascular Interventions or the American College of Cardiology.

and demonstrates at 3 years the following: 1) signifi-

From the Andreas Gruentzig Cardiovascular Center, Department of

cantly

Medicine, Division of Cardiology, Emory University School of Medicine,

compared with edge vascular responses; 2) numeri-

Atlanta, Georgia. Dr. Samady has received a research grant from Abbott

greater

in-scaffold

neointimal

responses

Vascular. Dr. Gogas has reported that he has no relationships relevant to

cally greater neointimal proliferation at the proximal

the contents of this paper to disclose.

compared with the distal edge, which appears to be

Gogas and Samady

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 12, 2014 DECEMBER 2014:1370–3

Shedding Light on Scaffold Vascular Response

F I G U R E 1 The ABSORB Cohort B Trial Design and the IVUS- Versus OCT-Based Edge Demarcation After BRS Implantation

(A) The last frame of the scaffolded segment with IVUS and OCT (longitudinal views are also shown). (B to F) The IVUS-derived edge includes cross sections with struts (presence of scrambling effect) as opposed to the OCT-derived edge, which sharply demarcates the edge as a segment with no struts. Reprinted, with permission, from Gogas et al. (10,12). (Green asterisk) Coronary computed tomography was also performed at 18 months. BRS ¼ bioresorbable scaffold; IVUS ¼ intravascular ultrasound; OCT ¼ optical coherence tomography; PB ¼ pullback.

contiguous with the adjacent in-scaffold vascular

edge vascular response at this time point? The

response; and 3) numerically lesser neointimal pro-

underlying mechanisms leading to early edge and

liferation

scaffold

in-scaffold vascular responses are similar to those

compared with the scaffold edges. This is the first

driving early DES responses and likely relate to

in vivo light-based imaging study to investigate

the geographic miss (axial or longitudinal) during

edge

scaffold deployment, scaffold design and effect on

at

vascular

the

mid-segment

responses

after

of

the

implantation

of

BRS technologies. Previous intravascular ultrasound

vascular curvatures affecting local fluid mechanics

(IVUS)–based observations have indicated modest

and wall shear stress conditions, underlying plaque

proximal edge constrictive remodeling and slight but

burden and phenotype, as well as biological factors

significant proximal lumen loss of w7% at 1 and

related to the antiproliferative agent eluted from the

2 years, respectively (10,12,13). The current OCT-

platform (10,14).

based study confirms the aforementioned IVUS-

Due to scaffold resorption, the factors driving late

based observations of an edge vascular response

vascular responses to the BRS are more likely driven by

with further considerations at a 3-year time point and

the changing solid biomechanical environment (strut-

raises 3 provocative mechanistic questions.

wall interaction) and fluid mechanics within the scaf-

First, why should a biodegradable scaffold that is

fold and over the transition zones. Indeed, changes in

replaced by proteoglycan-rich matrix at 2 years and

solid mechanical properties at stent edges can induce

by connective tissue at 3 years result in a persistent

zones of increased stress concentration and high stress

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Gogas and Samady

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 12, 2014 DECEMBER 2014:1370–3

Shedding Light on Scaffold Vascular Response

gradients inducing neointimal proliferation. BRSs are

OCT’s higher spatial resolution and faster pullback

designed with an mean strut thickness of 150 m m

speeds (20 to 40 mm/s for OCT vs. 0.5 mm/s for IVUS)

(similar to the Cypher stent) to compensate for the

minimize the effect of longitudinal displacement of

inferior tensile strength and modulus of elasticity

the imaging transducer, allowing for sharper demar-

compared with conventional metal DES. This rectan-

cation of the proximal and distal scaffold edges

gular and thick strut design generates zones of flow

compared with IVUS (Figure 1).

stagnation or recirculation with low wall shear stress

Some limitations of the current study should be

at the sides of the struts generating an initial rapid

noted. First, this study was of limited size with a

vascular response that slows down as soon as resorp-

dropout rate of almost 50%. In the setting of this

tion occurs. The edge that is considered a transitional

small final sample size, the results of this study

segment from the supported (scaffold) to an unsup-

should be considered as hypothesis generating. Sec-

ported

area

(no

scaffold)

undergoes

additional

ond, it should be clarified that this assessment

straightening and is prone to changes in the local solid

included non-TLR cases excluding 2 proximal and 1

and fluid mechanical environment. The rate and

distal edge effects, which raised the rate of edge-

magnitude of strut resorption and restoration of

derived TLR in the complete ABSORB Cohort B trial

vascular anatomy are anticipated to define the extent

to 3%. Third, discrepancies in the rates of proximal

of vascular responses as described by Plato: “The

edge neointimal proliferation between the 2 cohorts

excessive increase of anything causes a reaction in the

(B1 and B2) are not explicable by the data provided.

opposite direction” (1).

Data on degree of vascular curvature and angulation

The aforementioned pathogenetic mechanisms

of the treated coronary segments might explain the

remain to be elucidated in the randomized imaging

varied stimulus for differential neointimal growth.

substudy of ABSORB III, RESTORATION (Evaluation

Finally, the majority of lesions treated were type B

and Compa R ison of Three-Dimensional Wall Sh E ar

(95%), with a maximal length of 14 mm (scaffold

Stress Pattern S and Neoin T imal Healing F O llowing

length, 18 mm), and what the vascular response

Pe R Cutaneous Coron A ry Interven TION with Absorb

would be in the setting of real-world PCI cannot be

Everolimus-Eluting Bioresorbable Vascular Scaffold

predicted from this study. We hope to gain greater

Compared to Xience V or Xience Prime Everolimus-

insights into the effect of Absorb BVS in more com-

Eluting Metallic Stent) trial, which intends to eval-

plex lesion subsets and subsequent in-segment

uate and compare the rheological implications of BRSs

vascular responses from the ongoing randomized

versus metal stents over 3 years (15). This OCT- and

RESTORATION study.

IVUS-based study will provide additional evidence of

In vivo multimodality imaging after BRS im-

the interaction of fluid mechanics with subsequent late

plantation has provided important insights into the

vascular response over the scaffolded segments and

biological and mechanical properties of this novel

the proximal and distal edges in straight or curved

revolutionary

geometries.

vascular response evaluated by light-based imaging

The second mechanistic question is why was the

technology.

In-scaffold

and

edge

at 3 years demonstrate a favorable pattern of

lumen loss at the proximal edge numerically greater

tissue proliferation that does not significantly differ

compared with that at the distal edge at 3 years?

from that of conventional DES. However, after almost

Although similar proximal edge vascular responses

a decade of intense clinical and translational re-

have been reported after deployment of metal DES,

search within this space, the ongoing phase III and IV

one might expect greater distal edge neointimal pro-

clinical trials with intermediate-term outcomes are

liferation with BRS due to the scaffold deployment in

designed to demonstrate noninferiority and not su-

a vessel that tapers distally causing potentially

periority of BRSs compared with third-generation

step down regions responsible for hemodynamic

DES. The promised advantage of the BRS remains

disturbances and subsequent greater edge responses

the potential for long-term superior outcomes re-

and a higher rate of distal versus proximal edge

sulting from gradual scaffold resorption and a more

healed dissections (42% vs. 24%, respectively). These

favorable short- and long-term biomechanical and

observations might inform the future manufacturing

vascular response.

of tapered tubes or hybrid scaffolds with more elastic materials at the inflow areas or proximal segments

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

compared with the middle or outflow segments.

Habib Samady, Interventional Cardiology, Emory

The third important angle of this observational

University School of Medicine, 1364 Clifton Road,

study has to do with the OCT evaluation of the edge

Suite F606, Atlanta, Georgia 30322. E-mail: hsamady@

vascular response. Despite its limited penetration,

emory.edu.

Gogas and Samady

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 12, 2014 DECEMBER 2014:1370–3

Shedding Light on Scaffold Vascular Response

REFERENCES 1. Plato. Republic. Oxford World’s Classics. New York, NY: Oxford University Press, 2008. 2. Schwartz RS, Huber KC, Murphy JG, et al. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol 1992;19:267–74. 3. Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans. Circulation 1999;99:44–52. 4. Gogas BD, McDaniel M, Samady H, King SB 3rd. Novel drug-eluting stents for coronary revascularization. Trends Cardiovasc Med 2014;24: 305–13. 5. Serruys PW, Garcia-Garcia HM, Onuma Y. From metallic cages to transient bioresorbable scaffolds: change in paradigm of coronary revascularization in the upcoming decade? Eur Heart J 2012;33:16b–25b. 6. Stone GW. Bioresorbable vascular scaffolds: is imaging everything? EuroIntervention 2014;9: 1255–7. 7. Onuma Y, Serruys PW, Perkins LE, et al. Intracoronary optical coherence tomography and histology at 1 month and 2, 3, and 4 years after implantation of everolimus-eluting bioresorbable vascular scaffolds in a porcine coronary artery model: an attempt to decipher the human optical coherence tomography images in the ABSORB trial. Circulation 2010;122:2288–300.

8. Gogas BD, Radu M, Onuma Y, et al. Evaluation with in vivo optical coherence tomography and histology of the vascular effects of the everolimus-eluting bioresorbable vascular scaffold at two years following implantation in a healthy porcine coronary artery model: implica-

12. Gogas BD, Serruys PW, Diletti R, et al. Vascular response of the segments adjacent to the proximal and distal edges of the ABSORB everolimuseluting bioresorbable vascular scaffold: 6-month and 1-year follow-up assessment: a virtual histology intravascular ultrasound study from

tions of pilot results for future pre-clinical studies. Int J Cardiovasc Imaging 2012;28: 499–511.

the first-in-man ABSORB cohort B trial. J Am Coll Cardiol Intv 2012;5:656–65.

9. Serruys PW, Onuma Y, Garcia-Garcia HM, et al. Dynamics of vessel wall changes following the implantation of the absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months. EuroIntervention 2014;9: 1271–84. 10. Gogas BD, Garcia-Garcia HM, Onuma Y, et al. Edge vascular response after percutaneous coronary intervention: an intracoronary ultrasound and optical coherence tomography appraisal: from radioactive platforms to first- and second-generation drug-eluting stents and bioresorbable scaffolds. J Am Coll Cardiol Intv 2013;6:211–21.

13. Gogas BD, Bourantas CV, Garcia-Garcia HM, et al. The edge vascular response following implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold and the XIENCE V metallic everolimus-eluting stent. First serial follow-up assessment at six months and two years: insights from the first-in-man ABSORB Cohort B and SPIRIT II trials. EuroIntervention 2013;9:709–20. 14. Farooq V, Gogas BD, Serruys PW. Restenosis: delineating the numerous causes of drug-eluting stent restenosis. Circ Cardiovasc Interv 2011;4: 195–205. 15. Gogas BD, King SB 3rd, Timmins LH, et al. Biomechanical assessment of fully bioresorbable devices. J Am Coll Cardiol Intv 2013;6:

11. Zhang Y-J, Iqbal J, Nakatani S, et al. Scaffold and edge vascular response following implantation of everolimus-eluting bioresorbable vascular scaffold: a 3-year serial optical coherence tomography study. J Am Coll Cardiol Intv 2014;7:

760–1.

1361–9.

response, optical coherence tomography

KEY WORDS bioresorbable scaffold, edge vascular response, in-scaffold vascular

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