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(Circulation. 2000;101:e33.)
© 2000 American Heart Association, Inc.

Circulation Electronic Pages

Angiotensin-Converting Enzyme Tissue Activity in the Diffuse In-Stent Restenotic Plaque

Flavio Ribichini, MD; Francesco Pugno, MD; Valeria Ferrero, MD; Gianni Bussolati, MD, FRCPath; Germano Melissano, MD; Roberto Chiesa, MD; Carlo Di Mario, MD; Antonio Colombo, MD

From the Cardiac Catheterization Laboratory and Division of Cardiology (F.R., V.F.) and the Laboratory of Human Pathology (F.P.), Ospedale Santa Croce, Cuneo; the Department of Biomedical Science, Università di Torino (G.B.); and the Department of Vascular Surgery, Ospedale San Raffaele (G.M., R.C.) and Cardiac Catheterization Laboratory, Centro Cuore Columbus–Ospedale San Raffaele (C.D.M., A.C.), Milano, Italy.

Correspondence to Flavio Ribichini, MD, Laboratorio di Emodinamica, Ospedale Santa Croce, Via Michele Copino 26, 12100 Cuneo, Italy. E-mail emodinamica{at}scroce.sanitacn.it

	Introduction

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We present the 6-month anatomic, histological, and immunohistochemical (IHC) images of a diffuse and aggressive type of in-stent restenosis of a popliteal artery of a patient homozygous for the D (deletion) allele of the ACE gene (Figures 1, 2, and 3).

View larger version (123K): [in this window] [in a new window]   Figure 1. Macroscopic view of a section of artery showing diffuse tissue growth within stent wires.

View larger version (135K): [in this window] [in a new window]   Figure 2. Hematoxylin-eosin microscopy of the arterial wall after removal of the metallic struts of the stent. Right, Muscularis of media of arterial wall. Around wire is a "wire cuffing" composed of inflammatory and spindle-shaped cells. Left, Core of restenotic plaque shows spindle-shaped cells and neovessels.

View larger version (87K): [in this window] [in a new window]   Figure 3. Amplification of wire cuffing tissue. IHC for ACE (Biomedicals Ag) and for -actin (Dako) shows that (A) spindle-shaped cells in contact with metallic wires stain for ACE, and (B) spindle-shaped cells of plaque core, but not those close to stent wires, stain intensively for -actin.

A detailed description of the histological changes of the arterial wall with time after coronary stenting in humans was published recently.¹ These findings have confirmed that the ultrasound-detected "neointima" observed >1 month after implantation is composed primarily of smooth muscle cells (SMCs) and a proteoglycan-rich matrix. In the first weeks after stenting, the metallic struts associate with inflammatory cells, local thrombus formation, and "dedifferentiated" -actin–negative spindle-shaped cells. Later, multinucleated giant cells and -actin–positive spindle-shaped cells are observed in a more differentiated fibrocellular lesion.^{1 2} ACE increases up to 100-fold during the transformation of monocytes to macrophages, and most of the dedifferentiated SMCs (-actin–negative cells) stain for ACE.³ However, ACE activity is thought to be limited only to the first 2 months of the reparative process that follows postballoon injury.

Our samples reproduce the histological findings reported in 2 previous studies,^{1 2} but in contrast to the results of Ohishi et al³ obtained from postballoon restenotic samples, IHC staining for ACE was seen even 6 months after stent implantation. In fact, the spindle-shaped cells observed in the most external part of the restenotic plaque (close to the wire) stained for ACE in our sample (Figure 3A).

The data presented suggest that the transition of the stent-induced inflammatory process, rich in ACE-positive cells, into a fibrocellular lesion composed of differentiated SMCs is not a time-determined sequence. Rather, it might be an ongoing process, evolving from peripheral areas (close to the wire) to central areas and ultimately leading to progressive lumen occlusion in patients with enhanced ACE activity. This is consistent with clinical studies that advocate a role of ACE in restenosis of coronary stents.⁴

	Footnotes

 
The editor of Images in Cardiovascular Medicine is Hugh A. McAllister, Jr, MD, Chief, Department of Pathology, St Luke’s Episcopal Hospital and Texas Heart Institute, and Clinical Professor of Pathology, University of Texas Medical School and Baylor College of Medicine.

Circulation encourages readers to submit cardiovascular images to Dr Hugh A. McAllister, Jr, St Luke’s Episcopal Hospital and Texas Heart Institute, 6720 Bertner Ave, MC1-267, Houston, TX 77030.

	References

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1. Farb A, Sangiorgi G, Carter AJ, Walley VM, Edwards WD, Schwartz RS, Virmani R. Pathology of acute and chronic coronary stenting in humans. Circulation. 1999;99:44–52.[Abstract/Free Full Text]
   
2. Komatsu R, Ueda M, Naruko T, Kojima A, Becker AE. Neointimal tissue response at sites of coronary stenting in humans. Circulation. 1998;98:224–233.[Abstract/Free Full Text]
   
3. Ohishi M, Ueda M, Rakugi H, Okamura A, Naruko T, Becker AE, Hiwada K, Kamitani A, Kamide K, Higaki J, Ogihara Y. Upregulation of angiotensin-converting enzyme during the healing process after injury at the site of percutaneous transluminal coronary angioplasty in humans. Circulation. 1997;96:3328–3337.[Abstract/Free Full Text]
   
4. Ribichini F, Steffenino G, Dellavalle A, Matullo G, Colajanni E, Camilla T, Vado A, Benetton G, Uslenghi E, Piazza A. Plasma activity and insertion/deletion polymorphism of angiotensin I–converting enzyme: a major risk factor and a marker of risk for coronary stent restenosis. Circulation. 1998;97:147–154.[Abstract/Free Full Text]
   

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ribichini, F. Articles by Colombo, A. Search for Related Content PubMed PubMed Citation Articles by Ribichini, F. Articles by Colombo, A. Related Collections Restenosis ACE/Angiotension receptors Smooth muscle proliferation and differentiation Catheter-based coronary interventions: stents