J A C C : B A S I C T O T R A N S L A T I O N A L S C I E N C E VO L . 5 , N O . 1 , 2 0 2 0

ª 2 0 2 0 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E AM E R I C A N

C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

EDITORIAL COMMENT

In-Stent RestenosisChasing Our Tails in Search of a Solution*

Anna Lena Lahmann, MD,a Michael Joner, MDa,b

SEE PAGE 1

T he introduction of percutaneous coronaryintervention with stent implantation hasrevolutionized the treatment of patients

with obstructive coronary artery disease since thefirst balloon angioplasty performed by AndreasGrüntzig in 1977.

With the widespread use of bare metal stent im-plantation, the angioplasty-induced complicationssuch as arterial dissection and elastic recoil could beresolved, but this came at the cost of augmentedneointimal hyperplasia within the stented vascularsegment. This issue prompted the development ofdrug-eluting stents (DES), which successfully tar-geted the problem of neointimal overgrowth by sus-tained release of antiproliferative substances.

However, persistence of these drugs resulted insubstantial delay of vascular healing, the majorpathologic mechanism underlying late and very latestent thrombosis. More recently, in-stent neo-atherosclerosis (i.e., progression of atherosclerosiswithin the stented vascular segment) was identifiedas additional consequence of delayed vascular heal-ing after DES implantation and associated with latestent failure (1).

ISSN 2452-302X

*Editorials published in JACC: Basic to Translational Science reflect the

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

Basic to Translational Science or the American College of Cardiology.

From the aDeutsches Herzzentrum München, Technische Universität

München, Munich, Germany; and the bDZHK (German Centre for

Cardiovascular Research), partner site Munich Heart Alliance, Munich,

Germany. Dr. Joner has received research grants from Biotronik; and has

received lecture fees from Orbus Neich, Biotronik, Coramaze, and Bayer.

Dr. Lahmann has reported that she has no relationships relevant to the

contents of this paper to disclose.

The authors attest they are in compliance with human studies

committees and animal welfare regulations of the authors’ institutions

and Food and Drug Administration guidelines, including patient consent

where appropriate. For more information, visit the JACC: Basic to

Translational Science author instructions page.

Ever since the inception of research related tofinding solutions to overcome the problem of reste-nosis, systemic pharmacological therapy becamehighly attractive (2). Yet, most of these approacheswere later abandoned because of unacceptable sideeffects at drug dosages needed to prevent restenosis(3).

In this issue of JACC: Basic to Translational Science,Kee et al. (4) report the results of a preclinical studyinvestigating a novel site-directed pharmacologicapproach to reduce in-stent restenosis following stentimplantation in a hypercholesterolemic porcinemodel.

They used a combined endovascular ultrasound(EUS) and delivery system to ensure local applicationof therapeutics from echogenic liposomes (ELIPs) intostented peripheral arteries. The ELIP infusion con-sisted of an initial nitric oxide (NO) dose to triggerimmediate antioxidative and antiplatelet effects andto increase vessel wall permeability for improveddelivery of the peroxisome proliferator-activatorreceptor (PPAR)-g agonist pioglitazone (PGN) coupledto anti–intercellular adhesion molecule (ICAM)–directed ELIP. Animals assigned to ELIP payload de-livery were randomly allocated to EUS activation orcontrol (absence of EUS activation). Neointimalgrowth was assessed by intravascular ultrasoundimaging and histology 8 weeks after bare-metal stentimplantation. To show payload delivery, a separategroup of animals underwent balloon dilatation tosimulate stent implantation, followed by applicationof fluorescently labelled ELIP. Intravascular ultra-sound imaging showed reduction of neointimal vol-ume in the stented arteries treated by NO-activatedand anti–ICAM-1-PGN-ELIP activated by ultrasoundcompared to the vessels that lacked ultrasound acti-vation. Histologic analysis confirmed reduced neo-intima formation in the vessels treated with NO- and

https://doi.org/10.1016/j.jacbts.2019.12.002

FIGURE 1 Early Atherosclerotic Lesion in an Animal Model Versus Late-Stage Human Fibroatheroma

(A) Early-stage atherosclerotic lesion (schematic and Movat’s pentachrome stain) in the Yucatan miniswine (modified from Kim et al. [7]).

(B) Late-stage human fibroatheroma (schematic and Movat‘s pentachrome stain).

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anti–ICAM-PGN-ELIP with ultrasound activationcompared to those without.

First and foremost, the authors must be congratu-lated for pursuing tremendous effort to establishnovel, site-directed pharmacologic approaches toinhibit in-stent restenosis in a highly translationalsetting. Preclinical studies using diseased and non-diseased animal models remain an important stepduring translation of novel therapeutic strategies incardiovascular medicine (5). Although nondiseasedanimal models prevail in device-based safety studiesbecause of lower variability in vascular response,diseased animal models represent an importantcornerstone during evaluation of pharmacologictherapies against cardiovascular disease conditions,especially atherosclerosis. Despite the predominanceof genetically engineered mouse models in

atherosclerosis research, use of large animal modelssuch as hypercholesterolemic swine or rabbit modelsremains an important opportunity for studying localand systemic effects of therapeutic agents in thepresence of lesions resembling human atheroscle-rosis, especially in the setting of human-sizedvascular stents. Despite the successful delivery of 2sequential liposome formulations aimed at moleculartargeting of inflammatory reactions as shown in thecurrent study, a general concern remains whethersuch artificial environment (i.e., atherosclerotic le-sions secondary to vascular injury in combinationwith supraphysiological cholesterol diet) enables tostudy novel site-directed pharmacologic therapy un-der conditions close enough to human atherosclerosisto allow prediction of vascular safety and efficacy. Inparticular, expression of inflammatory adhesion

Lahmann and Joner J A C C : B A S I C T O T R A N S L A T I O N A L S C I E N C E V O L . 5 , N O . 1 , 2 0 2 0

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molecules such as ICAM-1 in this model is rapidlyinduced by artificial vascular injury combined withhypercholesterolemic diet unlike human atheroscle-rosis, where local expression of inflammatory adhe-sion molecules is upregulated in early stages ofatherosclerosis and is subject to substantial interin-dividual dynamics during progression of atheroscle-rosis. Consequently, it remains unclear to whatextend artificially induced atherosclerosis in theporcine model, which only displays early stages ofatherosclerosis, may be representative for humandisease conditions (Figures 1A and 1B).

Most importantly, relative efficacy of a new tech-nology can only be recognized when appropriatecontrol is incorporated into study design, which is animportant prerequisite for successful clinical trans-lation. Despite the elegant demonstration of payloaddelivery into target vascular segments in combinationwith reduced neointimal hyperplasia when ultra-sound was applied, the authors unfortunately did notcompare their novelty against established treatmentsuch as coronary DES, which would have enabled usto understand its relative merits before translationinto clinic (5). Moreover, no specific study group wasapplied to control for the active pharmacologiccomponent (i.e., PGN), which has known anti-inflammatory and antiproliferative properties uponactivation of the PPAR-g receptor. PGN is available asan oral pill and can be customized and provided aspowder for preclinical applications. Inclusion of anadditional study group to receive oral PGN at con-centrations known to prevent in-stent restenosismight have enlightened our comparative under-standing of pharmacologic efficacy (6). Yet, it must be

recognized that implementation of preclinical studiesbased on ideal study design is often difficult to ach-ieve and frequently yields to pragmatic and feasiblestudy flow determined by prior knowledge andfinancial constraints. Consequently, the authors ofthe current study are encouraged to continue theirworthwhile investigation of site-directed pharmaco-logic approaches to reduce the burden of in-stentrestenosis since only recently late accrual of adversecardiovascular events including late catch-up phe-nomena of restenosis and progression of atheroscle-rosis within the stented vascular segments (i.e.,neoatherosclerosis) were recognized as importantand deleterious consequences of delayed arterialhealing after implantation of conventional DES (1).Furthermore, site-directed pharmacologic targetingof in-stent restenosis using EUS activation mayenable payload delivery using a diversity of differentpharmacologic substances that may exhibit synergis-tic effects.

We have come a long way to study the patho-physiology of in-stent restenosis and yet got lostduring search for causative treatment, while tran-sitioning into an era of tremendous commercial in-terest with the introduction of DES. Endeavors suchas the current one create important momentum to getback on track with finding enduring solution for thisclinically impactful dilemma.

ADDRESS FOR CORRESPONDENCE: Dr. MichaelJoner, Deutsches Herzzentrum München, TechnischeUniversität München, Lazarettstrasse 36, Munich80636, Germany. E-mail: joner@dhm.mhn.de.

RE F E RENCE S

1. Otsuka F, Byrne RA, Yahagi K, et al. Neo-atherosclerosis: overview of histopathologicfindings and implications for intravascular im-aging assessment. Eur Heart J 2015;36:2147–59.

2. Marx N, Wohrle J, Nusser T, et al. Pioglitazonereduces neointima volume after coronary stentimplantation: a randomized, placebo-controlled,double-blind trial in nondiabetic patients. Circu-lation 2005;112:2792–8.

3. Hausleiter J, Kastrati A, Mehilli J, et al.Randomized, double-blind, placebo-controlled

trial of oral sirolimus for restenosis preven-tion in patients with in-stent restenosis: theOral Sirolimus to Inhibit Recurrent In-stentStenosis (OSIRIS) trial. Circulation 2004;110:790–5.

4. Kee PH, Moody MR, Huang S-L, et al. Stabilizingperi-stent restenosis using a novel therapeuticcarrier. J Am Coll Cardiol Basic Trans Science2020;5:1–11.

5. Joner M, Byrne RA. The importance of preclin-ical research in contemporary interventional car-diology. EuroIntervention 2010;6:19–23.

6. Joner M, Farb A, Cheng Q, et al. Pioglitazoneinhibits in-stent restenosis in atherosclerotic rab-bits by targeting transforming growth factor-betaand MCP-1. Arterioscler Thromb Vasc Biol 2007;27:182–9.

7. Kim H, Kee PH, Rim Y, et al. Nitric oxide im-proves molecular imaging of inflammatoryatheroma using targeted echogenic immunolipo-somes. Athereosclerosis 2013;231:252–60.

KEY WORDS liposomes, percutaneouscoronary intervention, restenosis, ultrasound