(Circulation. 1997;95:1998-2002.)
© 1997 American Heart Association, Inc.
Articles |
From the Departments of Medicine (Cardiology), Pathology, and Biomedical Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass.
Correspondence to Jeffrey M. Isner, MD, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135.
| Abstract |
|---|
|
|
|---|
Methods and Results Tissue specimens were retrieved by directional atherectomy from 10 patients in whom in-stent restenosis complicated percutaneous revascularization of peripheral artery disease. Analysis of cellular composition was performed quantitatively after cell-specific immunostaining. For specimens preserved in methanol (7 of 10), cellular proliferation was evaluated by use of antibodies to proliferating cell nuclear antigen (PCNA), cyclin E, and cdk2. TUNEL staining for apoptosis was performed on 8 paraformaldehyde-preserved specimens. Each of the 10 specimens contained extensive foci of hypercellularity composed predominantly of SMCs (mean±SEM, 59.3±3.0%). Evidence of ongoing proliferative activity was documented in all 7 methanol-preserved specimens: 24.6±2.3% of SMCs were PCNA-positive, 24.8±3.1% were cyclin Epositive, and 22.5±2.2% were cdk2-positive. Apoptotic cells were detected in all 8 specimens that had been appropriately preserved to permit DNA nick-end labeling. Macrophages and leukocytes were identified in each of the 10 specimens but accounted for a proportionately smaller number of cells (14.5±1.9% and 9.5±1.4%, respectively). Organized thrombus was observed in 6 of the 10 specimens.
Conclusions These findings support the notion that in-stent restenosis results from SMC hyperplasia and suggest that adjunctive therapies designed to inhibit SMC proliferation may further enhance the utility of endovascular stents.
Key Words: stents restenosis muscle, smooth cyclins
| Introduction |
|---|
|
|
|---|
| Methods |
|---|
|
|
|---|
|
Specimen Retrieval and Preparation
All specimens were retrieved percutaneously by
directional atherectomy.10 Tissues were fixed in either
10% buffered formalin (n=3) or 100% methanol (n=7). In addition, a
portion of tissue from 8 patients was also preserved in 4%
paraformaldehyde fixative to permit DNA nick-end
labeling (see below). All tissues were embedded in paraffin, cut at
5-µm intervals, and stained with hematoxylin-eosin, elastic
trichrome, and immunohistochemical stains for SMCs,
macrophages, and leukocytes (see below).
Immunostaining for PCNA, cyclin E, and cdk2 were used
to establish evidence of proliferative activity among cellular elements
in the atherectomy specimens.11 Because formalin fixation
has previously been shown to attenuate the antigenicity of
PCNA,11 12 13 we limited immunostaining for
PCNA, cyclin E, and cdk2 to sections from those specimens that had been
preserved in 100% methanol; sections of human tonsil12
were used as a positive control.
Antibodies
Immunohistochemical staining for proliferating cells was carried
out with a mouse MAb against human PCNA (Signet) as well as two rabbit
polyclonal antibodies against cyclin E and cdk2 (Santa Cruz). SMCs and
macrophages were identified with an
-actin alkaline
phosphataseconjugated MAb (Sigma) and HAM-56 MAb (Enzo),
respectively. Leukocytes were identified with an MAb to CD-45
(Dako).
Immunohistochemistry
Immunoperoxidase staining was performed on serial
sections.14 This involved blocking endogenous
peroxidase with 3% hydrogen peroxide, preincubation in blocking serum,
and applying the primary antibody at the appropriate dilution (PCNA,
1:40; cyclin E, 1:100; cdk2, 1:400;
-actin, 1:300; HAM-56,
undiluted; and CD-45, 1:50) overnight at 4°C. A biotinylated
anti-mouse or anti-rabbit secondary antibody (Signet) was then applied
for 30 minutes at room temperature, followed by a
streptavidinhorseradish peroxidase complex. Sections were rinsed with
PBS and visualized by incubation with either 0.05% (wt/vol)
3,3'-diaminobenzidine tetrahydrochloride dihydrate,
3-amino-9-ethylcarbazole, or fast red substrate. A counterstain of 10%
Gill's hematoxylin was applied before coverslipping. To detect
apoptosis in situ, fragmented DNA was nick-end labeled with
biotinylated dUTP introduced by terminal deoxytransferase and then
stained with avidin-conjugated peroxidase.15 For each
tissue, one section was processed as a positive control by pretreatment
with DNase I, 1 µg/mL (Sigma), and one negative control was incubated
in the absence of the terminal deoxytransferase enzyme.
Light Microscopic Analysis
Hematoxylin-eosinstained sections were used to assess the
presence of inflammatory cell infiltrates, calcific deposits, organized
thrombus, foam cells, and cholesterol clefts. Elastic
tissuestained sections were used to assess the presence of media and
adventitia. Quantitative analysis for each
immunostain was performed by manually counting all cells in
five randomly chosen high-power fields (x600); results of these
quantitative analyses are reported as the percentage
(mean±SEM) of positively stained cells among the five high-power
fields.
| Results |
|---|
|
|
|---|
|
Cellularity
All 10 specimens contained extensive foci of hypercellularity (Fig 1
). These foci were composed of
-actinpositive
cells with phenotypic characteristics of "activated"
SMCs,12 including stellate morphology, surrounded by a
loose, light-staining extracellular matrix. In all 10 specimens,
-actinpositive cells represented the predominant cell
type (mean±SEM, 59.3±3.0%).
|
Evidence of ongoing proliferative activity was documented in all 7
specimens that were preserved in methanol fixative for
immunostaining with antibodies to PCNA, cyclin E, and
cdk2. Double immunostaining (Fig 2
)
indicated that most PCNA-, cyclin E, and cdk2-positive cells were
SMCs. Analysis of five randomly selected high-power (x600)
fields from each of these 7 specimens indicated that 24.6±2.3%
(16.7% to 36.0%) of the SMCs were PCNA-positive, 24.8±3.1% (14.0%
to 40.5%) were cyclin Epositive, and 22.5±2.2% (12.8% to 30.0%)
were cdk2-positive.
|
Apoptosis
Apoptotic cells were detected in all 8 specimens that had
been appropriately preserved to permit DNA nick-end labeling (Fig 2
).
The extent of apoptotic cells (12.2±2.9%) was much greater
than that described previously in atherectomy specimens retrieved from
restenosis lesions.14
Macrophages and leukocytes were identified in all 10 specimens
but accounted for a proportionately smaller number of cells
(14.5±1.9% and 9.5±1.4%, respectively) (Fig 2
). Foam cells were not
observed in any specimen.
Thrombus
Thrombus was observed in 6 (60.0%) of 10 specimens; in all cases,
thrombus was organized and integral to the excised tissue, as opposed
to periprocedural collections of red blood cells. In all 10 cases,
thrombus was limited to <5% of the area of the specimen.
Other Findings
Media was observed in one specimen retrieved from the superficial
femoral artery; this portion of the specimen was excluded from further
analysis. Adventitia was not observed in any specimen. Focal
calcific deposits were limited to a single specimen.
| Discussion |
|---|
|
|
|---|
Histological findings reported for a limited number of patients have suggested that in-stent restenosis is characterized by SMC hyperplasia. Pathological analysis of graft segments surgically retrieved from two patients described by Anderson et al5 revealed SMCs "with abundant eosinophilic cytoplasm and minimal interstitial tissue" in the tissue overlying the stent wires. Among four patients with in-stent restenosis described by van Beusekom et al,4 "... tissue that narrowed the vessels always consisted of SMCs (often with a `dendritic' appearance) within an extensive extracellular matrix." The extent of residual proliferative activity among these hypercellular foci was not specifically investigated in either series of patients.
The findings in the present series of atherectomy specimens are
consistent with the aforementioned histopathology studies. Each
specimen contained extensive foci of hypercellularity, predominantly
SMCs. Moreover, when these tissues were preserved in fixative
specifically intended to preserve the antigenicity of PCNA,
immunostaining performed with the corresponding
monoclonal antibody disclosed that proliferative activity was abundant
in all such specimens. Because one21 of three previous
studies of native-vessel restenosis lesions21 22 23
was interpreted to show a paucity of SMC proliferation after
immunostaining for PCNA, we used polyclonal antibodies
to two additional cell cycleregulatory proteins (cyclin 2 and cdk2)
to confirm the extent of SMC proliferation observed for in-stent
restenosis. Double immunostaining for all three
cell cycle proteins and
-actin confirmed that SMCs accounted for
most of the proliferative activity.
The findings in this study constitute the first direct evidence that SMC proliferation contributes to in-stent restenosis in human subjects and implies a potential role for adjunctive therapies intended to reduce in-stent restenosis by inhibiting SMC proliferation.
The extent of cellular proliferation and apoptosis in the present series of in-stent restenosis specimens exceeds that observed in restenosis specimens retrieved from native vessels.11 14 Cardiovascular and noncardiovascular studies have typically disclosed a relationship between cellular proliferation and apoptosis,24 a concept that is consistent with the extensive proliferative activity demonstrated in the present series of specimens. The basis for this relationship between proliferative activity and programmed cell death remains to be established, but as suggested previously,14 25 26 apoptosis may act to limit the extent of cellular accumulation.
Inflammatory cells, including foreign body granulomata formation, have been described in at least one previous animal study.27 Although neither giant cells nor granulomata were observed in the present series of specimens, occasional inflammatory cells were identified by CD-45 immunostaining. A relatively small HAM-56 macrophage population was identified as well, but the contribution of both cell types to restenosis in these 10 cases appears to be limited.
The role of thrombus in restenosis, including in-stent restenosis, is enigmatic. Schwartz et al28 suggested that mural thrombus may constitute the primordial infrastructure that is subsequently colonized by activated SMCs. Thrombus was in fact observed in 6 of 10 specimens (60.0%) in the present cohort and thus cannot be excluded as a factor contributing to the genesis of peripheral vascular in-stent restenosis.
The limited number of specimens (10) in the present series may be viewed as a limitation of this study. It should be noted, however, that the opportunity to study a larger number of specimens, particularly coronary specimens, has to date been limited by technical concerns regarding the use of directional atherectomy within stents.6 7 8 9 At least two cases7 8 of target-stent disruption secondary to (coronary) atherectomy have been reported previously, one of which required urgent bypass surgery. Although animal models have failed to disclose evidence of site-specific variation in the histopathology of in-stent neointimal thickening,4 29 it must be acknowledged that the extent to which the pathological features of in-stent restenosis described here in the lower-extremity vasculature can be extrapolated to other vascular beds, as well as other types of stents, awaits further confirmation.
| Selected Abbreviations and Acronyms |
|---|
|
| Acknowledgments |
|---|
Received January 22, 1997; revision received February 25, 1997; accepted February 28, 1997.
| References |
|---|
|
|
|---|
2.
Serruys PW, DeJaegere P, Kiemeneij F, Macaya C, Rutsch
W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi
J, Sigwart U, Colombo A, Goy JJ, Van Den Heuvel P, Delcan J, Morel
M-A. A comparison of balloon-expandable-stent implantation with
balloon angioplasty with coronary artery disease.
N Engl J Med. 1994;331:489-495.
3. Dussaillant GR, Mintz GS, Pichard AD, Kent KM, Satler LF, Popma JJ, Wong SC, Leon MB. Small stent size and intimal hyperplasia contribute to restenosis: a volumetric intravascular ultrasound analysis. J Am Coll Cardiol. 1995;26:720-724.[Abstract]
4. van Beusekom HMM, van der Giessen WJ, van Suylen RJ, Bos E, Bosman FT, Serruys PW. Histology after stenting of human vein bypass grafts: observations from surgically excised grafts 3 to 320 days after stent implantation. J Am Coll Cardiol. 1993;21:45-54.[Abstract]
5. Anderson PG, Bajaj RK, Baxley WA, Roubin GS. Vascular pathology of balloon-expandable flexible coil stents in humans. J Am Coll Cardiol. 1992;19:372-381.[Abstract]
6. Topaz O, Vetrovec GW. The stenotic stent: mechanisms and revascularization options. Cathet Cardiovasc Diagn. 1996;37:293-299.[Medline] [Order article via Infotrieve]
7. Mecander PJ, Roubin GS, Agrawal SK, Cannon AD, Dean LS, Baxley WA. Balloon angioplasty for treatment of in-stent restenosis: feasibility, safety and efficacy. Cathet Cardiovasc Diagn. 1994;32:125-131.[Medline] [Order article via Infotrieve]
8. Bowerman RE, Pinkerton CA, Kirk B, Waller BF. Disruption of a coronary stent during atherectomy for restenosis. Cathet Cardiovasc Diagn. 1993;71:364-366.
9. Satler LF. Remedies for in-stent restenosis. Cathet Cardiovasc Diagn. 1996;37:320-321.[Medline] [Order article via Infotrieve]
10. Simpson JB, Salmon MR, Robetson GC, Cipriano PR, Hayden WG, Johnson DE, Fogarty TJ. Transluminal atherectomy for occlusive peripheral vascular disease. Am J Cardiol. 1988;61:96G-101G.[Medline] [Order article via Infotrieve]
11. Pickering JG, Weir L, Jekanowski J, Kearney MA, Isner JM. Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization. J Clin Invest. 1993;91:1469-1480.
12. Isner JM, Kearney M, Bauters C, Leclerc G, Nikol S, Pickering JG, Riessen R, Weir L. Use of human tissue specimens obtained in vivo by directional atherectomy to study restenosis and related human vascular disorders. Trends Cardiovasc Med. 1994;4:213-221.
13. Gelb AB, Kamel OW, LeBrun DP, Warnke RA. Estimation of tumor growth fractions in archival formalin-fixed, paraffin-embedded tissues using two anti-PCNA/cyclin monoclonal antibodies. Am J Pathol. 1992;141:1453-1458.[Abstract]
14.
Isner JM, Kearney M, Bortman S, Passeri J.
Apoptosis in human atherosclerosis and
restenosis. Circulation. 1995;91:2703-2711.
15.
Gavrieli Y, Sherman Y, Ben-Sasson SA.
Identification of programmed cell death in situ via specific labeling
of nuclear DNA fragmentation. J Cell Biol. 1992;119:493-501.
16.
Isner JM. Vascular remodeling: Honey, I think I
shrunk the artery. Circulation. 1994;89:2937-2941.
17.
Hehrlein C, Gollan C, Donges BS, Metz J, Riessen R,
Fehsenfeld P, von Hodenberg E, Kubler W. Low-dose radioactive
endovascular stents prevent smooth muscle cell proliferation and
neointimal hyperplasia in rabbits.
Circulation. 1995;92:1570-1575.
18.
Waksman R, Robinson KA, Crocker IR, Gravanis MB, Palmer
SJ, Wang C, Cipolla GD, King SB III. Intracoronary
radiation before stent implantation inhibits neointima
formation in stented porcine coronary arteries.
Circulation. 1995;92:1383-1386.
19.
Laird JR, Carter AJ, Kufs WA, Hoopes TG, Farb A, Nott
SH, Fischell RE, Fischell DR, Virmani R, Fischell TA. Inhibition
of neointimal proliferation with low-dose irradiation from
a ß-particle-emitting stent. Circulation. 1996;93:529-536.
20. Asahara T, Chen D, Kearney M, Rossow S, Passeri J, Symes JF, Isner JM. Accelerated re-endothelialization and reduced neointimal thickening following catheter transfer of phVEGF165. J Am Coll Cardiol. 1996;27:1A. Abstract.
21. O'Brien ER, Alpers CE, Stewart DK, Ferguson M, Tran N, Gordon D, Benditt EP, Hinohara T, Simpson JB, Schwartz SM. Proliferation in primary and restenotic coronary atherectomy tissue: implications for antiproliferative therapy. Circ Res. 1993;3:223-231.
22. Pickering JG, Bacha P, Weir L, Jekanowski J, Nichols JC, Isner JM. Prevention of smooth muscle cell outgrowth from human atherosclerotic plaque by a recombinant fusion protein specific for epidermal growth factor receptor. J Clin Invest. 1993;91:724-729.
23.
Rekhter M, Ferguson SN, Gordon D. Cell
proliferation in human arteriovenous fistulas used for
hemodialysis. Arterioscler Thromb. 1993;13:609-617.
24. Kerr JFR, Winterford CM, Harmon BV. Apoptosis: its significance in cancer and cancer therapy. Cancer. 1994;73:2013-2026.[Medline] [Order article via Infotrieve]
25. Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerosis plaques. J Clin Invest. 1995;95:2226-2274.
26. Geng Y-J, Libby P. Evidence for apoptosis in advanced human atheroma. Am J Pathol. 1995;147:251-266.[Abstract]
27. Karas SP, Gravanis MB, Santoian EC, Robinson KA, Anderberg KA, King SB III. Coronary intimal proliferation after balloon injury and stenting in swine: an animal model of restenosis. J Am Coll Cardiol. 1992;20:467-474.[Abstract]
28. Schwartz RS, Holmes DR Jr, Topol EJ. The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. J Am Coll Cardiol. 1992;20:1284-1293.[Abstract]
29. Carter AJ, Laird JR, Farb A, Kufs W, Wortham DC, Virmani R. Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restonis model. J Am Coll Cardiol. 1994;24:1398-1405.[Abstract]
This article has been cited by other articles:
![]() |
J. J. Fuster, P. Fernandez, H. Gonzalez-Navarro, C. Silvestre, Y. N. Abu Nabah, and V. Andres Control of cell proliferation in atherosclerosis: insights from animal models and human studies Cardiovasc Res, December 3, 2009; (2009) cvp363v2. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. D. Vesely, C. W. Heilig, and F. C. Brosius III GLUT1-induced cFLIP expression promotes proliferation and prevents apoptosis in vascular smooth muscle cells Am J Physiol Cell Physiol, January 1, 2009; 297(3): C759 - C765. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. Iwata and M. Sata Origin of Cells That Contribute to Neointima Growth Circulation, June 17, 2008; 117(24): 3060 - 3061. [Full Text] [PDF] |
||||
![]() |
K. Tanaka, M. Sata, T. Natori, J.-r. Kim-Kaneyama, K. Nose, M. Shibanuma, Y. Hirata, and R. Nagai Circulating progenitor cells contribute to neointimal formation in nonirradiated chimeric mice FASEB J, February 1, 2008; 22(2): 428 - 436. [Abstract] [Full Text] [PDF] |
||||
![]() |
Z. W. Q. Moore and D. Y. Hui Apolipoprotein E inhibition of vascular hyperplasia and neointima formation requires inducible nitric oxide synthase J. Lipid Res., October 1, 2005; 46(10): 2083 - 2090. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. A. Costa and D. I. Simon Molecular Basis of Restenosis and Drug-Eluting Stents Circulation, May 3, 2005; 111(17): 2257 - 2273. [Full Text] [PDF] |
||||
![]() |
T Ishikawa, K Hatakeyama, T Imamura, K Ito, S Hara, H Date, Y Shibata, Y Hikichi, Y Asada, and T Eto Increased adrenomedullin immunoreactivity and mRNA expression in coronary plaques obtained from patients with unstable angina Heart, October 1, 2004; 90(10): 1206 - 1210. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. H. Walter, M. Cejna, L. Diaz-Sandoval, S. Willis, L. Kirkwood, P. W. Stratford, A. B. Tietz, R. Kirchmair, M. Silver, C. Curry, et al. Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents: An Alternative Strategy for Inhibition of Restenosis Circulation, July 6, 2004; 110(1): 36 - 45. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. Andres Control of vascular cell proliferation and migration by cyclin-dependent kinase signalling: new perspectives and therapeutic potential Cardiovasc Res, July 1, 2004; 63(1): 11 - 21. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Skowasch, A. Jabs, R. Andrie, S. Dinkelbach, B. Luderitz, and G. Bauriedel Presence of bone-marrow- and neural-crest-derived cells in intimal hyperplasia at the time of clinical in-stent restenosis Cardiovasc Res, December 1, 2003; 60(3): 684 - 691. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Sata, K. Tanaka, N. Ishizaka, Y. Hirata, and R. Nagai Absence of p53 Leads to Accelerated Neointimal Hyperplasia After Vascular Injury Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1548 - 1552. [Abstract] [Full Text] [PDF] |
||||
![]() |
Z. H. Mnjoyan, R. Dutta, D. Zhang, B.-B. Teng, and K. Fujise Paradoxical Upregulation of Tumor Suppressor Protein p53 in Serum-Stimulated Vascular Smooth Muscle Cells: A Novel Negative-Feedback Regulatory Mechanism Circulation, July 29, 2003; 108(4): 464 - 471. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. W. Losordo, J. M. Isner, and L. J. Diaz-Sandoval Endothelial Recovery: The Next Target in Restenosis Prevention Circulation, June 3, 2003; 107(21): 2635 - 2637. [Full Text] [PDF] |
||||
![]() |
D. T. Ashby, G. Dangas, E. A. Aymong, I. Iakovou, F. Kuepper, R. Mehran, G. W. Stone, M. B. Leon, and J. W. Moses Effect of percutaneous coronary interventions for in-stent restenosis in degenerated saphenous vein grafts without distal embolic protection J. Am. Coll. Cardiol., March 5, 2003; 41(5): 749 - 752. [Abstract] [Full Text] [PDF] |
||||
![]() |
H C Lowe, M Mino, E J Mark, B D Mac Neill, I F Palacios, and S L Houser Histopathology of coronary in-stent restenosis following {gamma} brachytherapy Heart, January 1, 2003; 89(1): 11 - 13. [Abstract] [Full Text] [PDF] |
||||
![]() |
I.-M. o Chung, H. K. Gold, S. M. Schwartz, Y. Ikari, M. A. Reidy, and T. N. Wight Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2072 - 2081. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Sata, A. Takahashi, K. Tanaka, M. Washida, N. Ishizaka, J. Ako, M. Yoshizumi, Y. Ouchi, T. Taniguchi, Y. Hirata, et al. Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia via a p21WAF1-Dependent Pathway Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1305 - 1309. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. R. Ward, A. Agrotis, P. Kanellakis, J. Hall, G. Jennings, and A. Bobik Tranilast Prevents Activation of Transforming Growth Factor-{beta} System, Leukocyte Accumulation, and Neointimal Growth in Porcine Coronary Arteries After Stenting Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 940 - 948. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Cejna, J. M. Breuss, H. Bergmeister, R. de Martin, Z. Xu, M. Grgurin, U. Losert, H. Plenk Jr, B. R. Binder, and J. Lammer Inhibition of Neointimal Formation after Stent Placement with Adenovirus-mediated Gene Transfer of I{kappa}B{alpha} in the Hypercholesterolemic Rabbit Model: Initial Results Radiology, June 1, 2002; 223(3): 702 - 708. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. B. Buchwald, A. H. Wagner, C. Webel, and M. Hecker Decoy oligodeoxynucleotide againstactivator protein-1 reducesneointimal proliferation after coronaryangioplasty in hypercholesterolemic minipigs J. Am. Coll. Cardiol., February 20, 2002; 39(4): 732 - 738. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. C. Lowe, S. N. Oesterle, and L. M. Khachigian Coronary in-stent restenosis: Current status and future strategies J. Am. Coll. Cardiol., January 16, 2002; 39(2): 183 - 193. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. J. Fitzgerald, A. Takagi, M. P. Moore, M. Hayase, F. D. Kolodgie, D. Corl, M. Nassi, R. Virmani, and P. G. Yock Intravascular Sonotherapy Decreases Neointimal Hyperplasia After Stent Implantation in Swine Circulation, April 10, 2001; 103(14): 1828 - 1831. [Abstract] [Full Text] [PDF] |
||||
![]() |
M.Y Salame, S Verheye, I.R Crocker, N.A.F Chronos, K.A Robinson, and S.B King III Intracoronary radiation therapy Eur. Heart J., April 2, 2001; 22(8): 629 - 647. [PDF] |
||||
![]() |
I. L. Gordon, R. M. Conroy, M. Arefi, J. M. Tobis, E. A. Stemmer, and S. E. Wilson Three-Year Outcome of Endovascular Treatment of Superficial Femoral Artery Occlusion Arch Surg, February 1, 2001; 136(2): 221 - 228. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Zhu, D. G. Kuhel, D. P. Witte, and D. Y. Hui Apolipoprotein E Inhibits Neointimal Hyperplasia after Arterial Injury in Mice Am. J. Pathol., December 1, 2000; 157(6): 1839 - 1848. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Walsh, R. C. Smith, and H.-S. Kim Vascular Cell Apoptosis in Remodeling, Restenosis, and Plaque Rupture Circ. Res., August 4, 2000; 87(3): 184 - 188. [Full Text] [PDF] |
||||
![]() |
I. Bossi, C. Klersy, A. J. Black, R. Cortina, R. Choussat, B. Cassagneau, C. Jordan, J.-C. Laborde, J.-P. Laurent, M. Bernies, et al. In-stent restenosis: long-term outcome and predictors of subsequent target lesion revascularization after repeat balloon angioplasty J. Am. Coll. Cardiol., May 1, 2000; 35(6): 1569 - 1576. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Rivard, N. Principe, and V. Andres Age-dependent increase in c-fos activity and cyclin A expression in vascular smooth muscle cells: A potential link between aging, smooth muscle cell proliferation and atherosclerosis Cardiovasc Res, March 1, 2000; 45(4): 1026 - 1034. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. J. Feldman, L. Aguirre, M. Ziol, J.-P. Bridou, N. Nevo, J.-B. Michel, and P. G. Steg Interleukin-10 Inhibits Intimal Hyperplasia After Angioplasty or Stent Implantation in Hypercholesterolemic Rabbits Circulation, February 29, 2000; 101(8): 908 - 916. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Walsh and J. M. Isner Apoptosis in inflammatory-fibroproliferative disorders of the vessel wall Cardiovasc Res, February 1, 2000; 45(3): 756 - 765. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. H. Grewe, T. Deneke, A. Machraoui, J.u. Barmeyer, and K.-M. Muller Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen J. Am. Coll. Cardiol., January 1, 2000; 35(1): 157 - 163. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. Ishibashi-Ueda, C. Yutani, M. Imakita, S. Kuribayashi, M. Takamiya, H. Uchida, K. Kichikawa, T. Suzuki, and H. Ishibashi-Ueda Histologic Comparison of Coronary and Iliac Atherectomy Tissue from Cases of In-Stent Restenosis Angiology, December 1, 1999; 50(12): 977 - 987. [Abstract] [PDF] |
||||
![]() |
O F Bertrand, S Lehnert, R Mongrain, and M G Bourassa Early and late effects of radiation treatment for prevention of coronary restenosis: a critical appraisal Heart, December 1, 1999; 82(6): 658 - 662. [Full Text] |
||||
![]() |
D. G. Macejak, H. Lin, S. Webb, J. Chase, K. Jensen, T. C. Jarvis, J. M. Leiden, and L. Couture Adenovirus-Mediated Expression of a Ribozyme to c-myb mRNA Inhibits Smooth Muscle Cell Proliferation and Neointima Formation In Vivo J. Virol., September 1, 1999; 73(9): 7745 - 7751. [Abstract] [Full Text] |
||||
![]() |
J. Ruef, A. S. Meshel, Z. Hu, C. Horaist, C. A. Ballinger, L. J. Thompson, V. D. Subbarao, J. A. Dumont, and C. Patterson Flavopiridol Inhibits Smooth Muscle Cell Proliferation In Vitro and Neointimal Formation In Vivo After Carotid Injury in the Rat Circulation, August 10, 1999; 100(6): 659 - 665. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Koster, C. W. Hamm, R. Seabra-Gomes, G. Herrmann, H. Sievert, C. Macaya, E. Fleck, K. Fischer, J. J. R. M. Bonnier, J. Fajadet, et al. Laser angioplasty of restenosed coronary stents: results of a multicenter surveillance trial J. Am. Coll. Cardiol., July 1, 1999; 34(1): 25 - 32. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. A. Giese, M. M. H. Marijianowski, O. McCook, A. Hancock, V. Ramakrishnan, L. J. Fretto, C. Chen, A. B. Kelly, J. A. Koziol, J. N. Wilcox, et al. The Role of Alpha and Beta Platelet-Derived Growth Factor Receptor in the Vascular Response to Injury in Nonhuman Primates Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 900 - 909. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Gershlick Endovascular manipulation to restrict restenosis Vascular Medicine, August 1, 1998; 3(3): 177 - 188. [Abstract] [PDF] |
||||
![]() |
C. J. McKenna, S. E. Burke, T. J. Opgenorth, R. J. Padley, L. J. Camrud, A. R. Camrud, J. Johnson, P. J. Carlson, A. Lerman, D. R. Holmes Jr, et al. Selective ETA Receptor Antagonism Reduces Neointimal Hyperplasia in a Porcine Coronary Stent Model Circulation, June 30, 1998; 97(25): 2551 - 2556. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. Van Belle, C. Bauters, T. Asahara, and J. M. Isner Endothelial regrowth after arterial injury: from vascular repair to therapeutics Cardiovasc Res, April 1, 1998; 38(1): 54 - 68. [Full Text] [PDF] |
||||
![]() |
S. Baek and K. L. March Gene Therapy for Restenosis : Getting Nearer the Heart of the Matter Circ. Res., February 23, 1998; 82(3): 295 - 305. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. R. Edelman Vessel Size, Antioxidants, and Restenosis : Never Too Small, Not Too Little, but Often Too Late Circulation, February 10, 1998; 97(5): 416 - 420. [Full Text] [PDF] |
||||
![]() |
M. Sata, H. Perlman, D. A. Muruve, M. Silver, M. Ikebe, T. A. Libermann, P. Oettgen, and K. Walsh Fas ligand gene transfer to the vessel wall inhibits neointima formation and overrides the adenovirus-mediated T cell response PNAS, February 3, 1998; 95(3): 1213 - 1217. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. C. Lowe, R. G. Fahmy, M. M. Kavurma, A. Baker, C. N. Chesterman, and L. M. Khachigian Catalytic Oligodeoxynucleotides Define a Key Regulatory Role for Early Growth Response Factor-1 in the Porcine Model of Coronary In-Stent Restenosis Circ. Res., October 12, 2001; 89(8): 670 - 677. [Abstract] [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 1997 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |