This Article Abstract 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 Farb, A. Articles by Virmani, R. Search for Related Content PubMed PubMed Citation Articles by Farb, A. Articles by Virmani, R. Related Collections Restenosis Catheter-based coronary interventions: stents

(Circulation. 2001;103:1912.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Late Arterial Responses (6 and 12 Months) After ³²P ß-Emitting Stent Placement

Sustained Intimal Suppression With Incomplete Healing

Andrew Farb, MD; Sweta Shroff, MS; Michael John, BA; William Sweet, MD; Renu Virmani, MD

From the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology (A.F., S.S., M.J., R.V.), Washington, DC, and the Isostent Corporation (W.S.), Belmont, Calif.

Correspondence to Renu Virmani, MD, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
pick;5248p1-foo;0;;clb/clb>Background—Three-month studies of stent-delivered brachytherapy in the rabbit model show reduced neointimal growth. However, intimal healing is delayed, raising the possibility that intimal inhibition is merely delayed rather than prevented. The purpose of this study was to explore the long-term histological changes after placement of ß-emitting radioactive stents in normal rabbit iliac arteries.

Methods and Results—Three-millimeter ß-emitting ³²P stents (6, 24, and 48 µCi) were placed in normal rabbit iliac arteries with nonradioactive stents as controls. Animals were euthanatized at 6 and 12 months, and histological assessment, morphometry, and analysis of endothelialization were performed. Morphometric measurements demonstrated a >50% reduction in intimal growth and percent lumen stenosis within 24- and 48-µCi stents versus control nonradioactive stents at both 6 and 12 months. However, the 24- and 48-µCi stents also showed delayed healing of the intimal surface, characterized by persistent fibrin thrombus with nonconfluent areas of matrix, incomplete endothelialization, and increased intimal cellular proliferation. Stent edge stenosis was present at 12 months in the 24- and 48-µCi stent groups, characterized by both intimal thickening and negative arterial remodeling.

Conclusions—Inhibition of intimal growth is maintained 6 and 12 months after ³²P ß-emitting stent placement. However, delayed arterial healing, incomplete endothelialization, and edge effects are present.

Key Words: angioplasty • atherosclerosis • pathology • stents

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Catheter and stent-based brachytherapy have shown promise for preventing coronary restenosis.^{1 2 3} However, with radioactive stents, arterial healing is incomplete at 1 month in porcine coronary arteries treated with 3.0-µCi radioactive stents⁴ and at 3 months in rabbit iliac arteries treated with 6-µCi stents.⁵ The issue of incomplete healing by stent-delivered brachytherapy raises the question of whether early suppression of neointimal growth is sustained chronically. Further concerns with this device include the potential for increased neointimal growth⁶ and the development of adverse edge effects, resulting in an increased frequency of non–target-lesion revascularization.⁷

The objectives of the present study were to analyze histologically neointimal suppression, healing responses, endothelialization, and edge effects at 6 and 12 months after ³²P ß-emitting stent implantation in normal rabbit iliac arteries.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
The protocol was approved by the Institutional Animal Care and Use Committee and conformed to the position of the American Heart Association on research animal use.

Stent Treatment Groups
BX stents (3.0x15 mm; Isostent, Inc) were rendered radioactive by established ion implantation techniques.⁸ A 6-, 24-, or 48-µCi or a nonradioactive control stent was randomly placed, under fluoroscopic guidance, in each iliac artery of male New Zealand White rabbits. At euthanasia, the iliac arteries were perfusion-fixed with 10% formalin. Animals received an injection of bromodeoxyuridine (BrdU) before euthanasia.⁵ The cumulative 6- and 12-month radiation dose at a tissue depth of 0.5 mm from the mid portion of the stent was 95 Gy for the 6-µCi stent, 381 Gy for the 24-µCi stent, and 763 Gy for the 48-µCi stent.

Angiographic Analysis
Prestenting, immediately poststenting, and preeuthanasia iliac artery lumen diameters were measured with digital calipers. The arterial diameter just proximal and distal to the stent was measured at the time of euthanasia to determine angiographic edge effects.

Tissue Processing
In brief, stented segments were embedded whole in methylmethacrylate as described previously.⁵ Four-micrometer sections from the proximal, middle, and distal portion of the stents were stained with hematoxylin-eosin and Movat pentachrome stains. A 3.0-mm arterial segment just proximal and distal to the stents was processed and stained to evaluate edge effects.

Morphometry
All histological sections were magnified and digitized with the observer blinded to the treatment group. Computerized morphometry (IPLab Spectrum software) was performed on stented segments to determine lumen area, area within the internal elastic lamina (IEL), neointimal area, percent luminal stenosis, neointimal thickness at and between each stent wire site, and adventitial thickness between each stent strut. To evaluate stent edge stenosis, the IEL area, external elastic lamina (EEL) area, and adventitial area were measured in the proximal and distal arterial edge segments. A negative remodeling index was defined as the ratio of the area within the outer boundary of the adventitia to the area within the EEL. This ratio normalizes the adventitial outer boundary to the vessel size (determined by the EEL), thus correcting for the expected increase in adventitia present in larger relative to smaller vessels. The maximal intimal thickness in the stent edges was measured.

To assess intimal cellular proliferation, mid sections were incubated with a mouse monoclonal anti-BrdU antibody, and BrdU-positive intimal cells were counted as a percent of total cells.⁵ Actin-positive intimal cells and inflammatory cells (neutrophils and macrophages) in midstent sections were counted from 8 randomly selected x400 fields, and intimal cell densities were calculated. Stains for fibrin were performed, and the percentage of the intima occupied by fibrin was measured.

Evaluation of Stent Endothelialization
Stented iliac arteries were processed for scanning electron microscopy (SEM) as described previously.⁵ The percent of the luminal surface that was endothelialized was determined from digitized photographs.

Statistical Analysis
Numerical data are presented as mean±SD. Continuous variables were compared with an ANOVA.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Thirty-six BX stents (6 µCi, n=10; 24 µCi, n=9; 48 µCi, n=9; nonradioactive controls, n=8) were deployed in 18 rabbits and used for light microscopy studies at 6 months. A total of 32 BX stents (6 µCi, n=7; 24 µCi, n=9; 48 µCi, n=8; nonradioactive controls, n=8) were deployed in 16 rabbits and used for light microscopy studies at 12 months. Twenty iliac artery stents (n=5 for each radioactive stent treatment group plus 5 control stents) were placed in 10 rabbits for endothelialization studies at 6 months and a similar number of stents and rabbits at 12 months. The vast majority of struts had injury scores of 0 or 1, with no differences among treatment groups.

Angiographic Assessment
Iliac artery lumen diameters before and immediately after stent placement were similar in all stent treatment groups (data not shown). At euthanasia (6 and 12 months), stent lumen diameters were similar in all groups. All stents were angiographically patent at the time of euthanasia without aneurysm formation.

Histologic Morphometry
Morphometric data are shown in Table 1 (6- and 12-month analyses). At 6 months, compared with control stents, there was a >50% reduction in mean intimal thickness, mean neointimal area, and mean percent arterial stenosis by the 24- and 48-µCi stents. Mean intimal thickness and area and percent arterial stenosis were similar between 6-µCi and control stents. Compared with control stents, lumen area was increased 17% (P=0.02) by the 24-µCi stents. At 12 months, there was maintenance of the >50% reduction in intimal thickness, neointimal area, and percent arterial stenosis by the 24- and 48-µCi stents. Compared with control stents, lumen area was increased 17% (P=0.01) by the 24-µCi stents and 15% (P=0.075) by the 48-µCi stents.

View this table: [in this window] [in a new window]   Table 1. Morphometry at 6 and 12 Months

There was a significant dose-dependent increase in mean adventitial thickness for all radioactive stent groups compared with controls at both 6 and 12 months (Table 1). Intimal suppression at 6 and 12 months was maximal in the mid portion of the stents.

Morphological Evaluation
None of the stents was thrombotically occluded. The intima (neointima) in control stents was well developed at 6 and 12 months, consisting of smooth muscle cells (SMCs) in a proteoglycan/collagen matrix (Figure 1A, 12 months). The 6-µCi stents at 6 and 12 months (Figure 1B, 12 months) demonstrated a well-defined neointima, but compared with control stents, there was a relatively greater amount of proteoglycan-rich matrix with fewer SMCs. Clear evidence of delayed healing of the intima was present in the 24- and 48-µCi stent groups (Figure 1C and 1D, 12 months), characterized by a generally hypocellular intima containing fibrin and trapped erythrocytes around struts, with frequent inflammatory cells and incomplete endothelialization. SMCs were occasionally seen within the proteoglycan-rich hypocellular extracellular matrix, and there was medial thinning with medial SMC loss, especially beneath stent struts. The changes of delayed intimal healing were similar in the 24- and 48-µCi stents.

View larger version (130K): [in this window] [in a new window]   Figure 1. Iliac artery morphology at low-power and high-power (inset) 12 months after stent placement. Control stent is shown in panel A; collagen-rich neointima is present. No inhibition of neointimal growth is present with 6-µCi stent (B), and neointima contains greater concentration of proteoglycan (blue-green extracellular proteoglycan matrix). Significant reduction in neointimal thickness is present within 24-µCi (C) and 48-µCi (D) stents. Note increased adventitial thickness (arrows) associated with 6-, 24-, and 48-µCi stents. Movat pentachrome; bar=0.18 mm.

Intimal Fibrin, Cellularity, Proliferation, Atherosclerosis, and Endothelialization
Intimal fibrin deposits were significantly more common in arteries containing radioactive stents. At 6 months, fibrin deposits accounted for 0.01±0.02% of the total intimal area of the mid segment of control stents compared with 5.2±4.3% for 6-µCi stents (P<0.05), 38.3±27.6% for 24-µCi stents (P<0.03 versus control and P=0.03 versus 6 µCi), and 38.5±30.1% for 48-µCi stents (P<0.05 versus control and 6 µCi). At 12 months, intimal fibrin deposits (Figure 2, A through D) were not seen in the control stents and accounted for 0.61±0.97% of the intimal area within the 6-µCi stents compared with 12.1±7.1% for the 24-µCi stents (P=0.0007 versus control and P<0.003 versus 6 µCi) and 33.4±25.6% for the 48-µCi stents (P<0.006 versus control and P<0.02 versus 6 µCi).

View larger version (64K): [in this window] [in a new window]   Figure 2. Dose-dependent increase in intimal fibrin deposition (brownish-red reaction product) and cell proliferation (brownish-red stained nuclei) 12 months after deployment of control (A and E), 6-µCi (B and F), 24-µCi (C and G), and 48-µCi (D and H) stents. A through D, Anti-fibrin antibody staining with hematoxylin counterstain, bar=0.15 mm; E-H, anti-BrdU antibody staining with hematoxylin counterstain, bar=0.02 mm.

Levels of cell proliferation were elevated in all radioactive stents at 6 and 12 months versus controls (Table 2 and Figure 2, E through H). Total intimal cell density and SMC density were substantially reduced in the high-activity stents at 6 and 12 months (Table 2), but of the cells present, there were greater numbers of inflammatory cells (Figure 3, A through D). Focal atherosclerotic change, consisting of intimal collections of foam cells with or without cholesterol clefts and focal calcification, was observed in the intima of one 6-µCi stent, one 24-µCi stent, and three 48-µCi stents at 6 months and one 24-µCi stent and four 48-µCi stents at 12 months (Figure 3E).

View this table: [in this window] [in a new window]   Table 2. Intimal Cell Density and Cell Proliferation (BrdU-Labeling Index) at 6 and 12 Months

View larger version (59K): [in this window] [in a new window]   Figure 3. Intimal cellularity at 12 months. Control stent intima (A) consists of numerous spindle-shaped SMCs. Six-microcurie stent intima (B) is relatively hypocellular and contains occasional mononuclear cells. Intima within 24- and 48-µCi stents (C and D, respectively) contains rare spindle-shaped cells and frequent inflammatory cells with focal collections of red blood cells and fibrin. E, Focal atherosclerosis with large needle-shaped cholesterol clefts (arrows) with focal foam cells within 48-µCi stent. Hematoxylin-eosin; bar=0.05 mm in A through D, 0.11 mm in E.

The absence of complete healing was confirmed by SEM. At 6 months, only 57.8±4.8% and 42.4±4.4% of the intimal surface was endothelialized in the 24- and 48-µCi stents, respectively, compared with 87.4±5.3% for 6-µCi stents and 99.6±0.4% for control stents (P<0.005). Endothelialization remained incomplete even at 12 months with these higher-radioactivity stents: 71.6±5.3% and 75.0±3.7% of the 24- and 48-µCi stent surface was endothelialized, respectively. In the 24- and 48-µCi stents, endothelialization was present at the ends of the stents, and the central portion of the stents was only partially endothelialized with focally adherent inflammatory cells and platelets (Figure 4).

View larger version (172K): [in this window] [in a new window]   Figure 4. Low-power SEM of control stent (A) and 48-µCi stent (B) at 12 months. Entire control stent is endothelialized, whereas 48-µCi stent is endothelialized at ends (* in B). Parts of central portion of 48-µCi stent are nonendothelialized, and bare or partially covered struts are present. Transition zone between endothelialization and nonendothelialization is outlined in B and shown at medium power in C. Two areas are further magnified (arrow and box in C corresponding to D and E, respectively) to show adherent platelets and inflammatory cells on partially endothelialized (D) and nonendothelialized (E) parts of stent. Bars=0.5 mm in A and B, 0.1 mm in C, 0.01 mm in D and E.

Edge Effects
At 12 months (Table 3), all radioactive stent groups had significantly greater maximal intimal thickness versus controls in the distal nonstented edge segment, with a smaller lumen diameter, increased percent stenosis, and increased negative remodeling index in the 24- and 48-µCi groups (Figure 5). The IEL and EEL areas were smallest in the 48-µCi stents. Adverse edge effects were present but slightly less marked in the proximal nonstented arterial segment (Table 3). At 6 months (data not shown), maximal intimal thickness in the distal nonstented arterial segment was significantly greater (P<0.03) in the 48-µCi group than in controls, and angiographic lumen diameter was smallest in the 48-µCi group (P0.04 versus other groups). The negative remodeling index was significantly greater in the 48-µCi stents compared with controls. In the proximal nonstented edge segment, there were trends (P<0.10) toward a smaller lumen diameter, greater percent stenosis, and a greater negative remodeling index in the 48-µCi stents compared with controls.

View this table: [in this window] [in a new window]   Table 3. Distal and Proximal Stent Edge Effects at 12 Months

View larger version (84K): [in this window] [in a new window]   Figure 5. Edge effects at 12 months. Arterial segment distal to control stent (A and B) and 48-µCi stent (C and D) are shown. Adventitia is thin (adv), and there is minimal intimal thickening (arrowhead) distal to control stent (B). Distal to 48-µCi stent, there is eccentric, proteoglycan-rich intimal thickening (arrows) with negative remodeling characterized by increased adventitial thickness (adv) and smaller area enclosed within IEL (A and C). Movat pentachrome; bars=0.13 mm in A and C, 0.06 mm in B and D.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This is the longest and largest experimental study that confirms long-term suppression of in-stent neointimal growth with ³²P ß-emitting stents. Concerns raised about whether the intimal suppression seen at 3 months would be maintained appear to be allayed by the current 6- and 12-month data. Furthermore, this modality appeared to be safe and well tolerated in this animal model, and there were no cases of late occlusive stent thrombosis. However, numerous observations indicate persistent delayed healing of the intimal surface: incomplete stent endothelialization, intimal fibrin deposition, ongoing cellular proliferation, and inflammation. SEM clearly showed impaired endothelialization out to 1 year, in contrast to previous studies in which complete endothelialization was suggested after only limited analysis.⁹ These data provide morphological insights into the initial results seen with the use of ß-emitting radioactive stents in humans.

Mechanisms of Delayed Healing and Endothelialization
Reestablishment of an intact endothelium is believed to be a critical factor in limiting the neointimal expansion that produces restenosis.^{10 11} After endothelial denudation, endothelialization proceeds, via cell migration and proliferation, from the edges of the denuded segment toward the center.¹² Migration of endothelial cells from branch vessels and vasa vasorum toward the center of the stent is another source for intimal reendothelialization. One month after nonradioactive stent deployment in rabbits, the neointima is fully healed, stent endothelialization is complete, and intimal SMC proliferation is at low levels.^{13 14} However, in the present study, healing and endothelialization remain far from complete out to 1 year after placement of 24- and 48-µCi stents despite extremely low levels of radioactivity—levels below which biologic activity might not be expected to be present. For example, the radioactivity present on the 24-µCi stent fell below 0.1 µCi on day 129. The radiation delivered may have had its desired effect of producing lethal DNA damage to the local SMCs and endothelial cells during cell division. It is uncertain whether the remaining SMCs and endothelial cells within the stent and at the stent margins have sufficient proliferative potential to ever completely "heal" the intimal surface. Adventitial fibrosis and radiation-induced damage to branch vessels and vasa vasorum may deplete the pool of cells necessary to restore a complete endothelial lining. Furthermore, injury to the arterial wall may interfere with endothelial cell and SMC migration and adhesion even if cell proliferation continues. Presently, no long-term animal study has demonstrated a brachytherapy regimen (beta or gamma, stent or wire) that both effectively inhibits neointimal growth and results in complete healing. In humans, the timing of complete intimal healing remains to be established.

An intact endothelial lining also plays an antithrombotic role, and one can postulate that impaired endothelialization may be responsible for the persistent intimal fibrin deposition observed out to 12 months in the present study. Incomplete endothelialization and lumen thrombus are likely to be a feature of other methods of arterial brachytherapy; Salame et al¹⁵ showed impaired endothelialization, persistent intramural hemorrhage, and increased platelet recruitment 1 month after overstretch balloon injury and ⁹⁰Y/Sr brachytherapy utilizing a catheter-based system. Concerns regarding a persistently prothrombotic lumen surface have led to the practice of long-term antiplatelet therapy in patients treated with coronary brachytherapy. This recommendation followed the reported 6.6% incidence of sudden thrombotic events 2 to 15 months after PTCA in patients treated with intracoronary ß-radiation.¹⁶ The incompletely endothelialized intima with persistent fibrin deposition, observed in the present study, may be an important substrate for late thrombosis.

Animal Models of ß-Emitting Stents
To date, rabbit, porcine, and canine arteries have been used to study these brachytherapy devices. Rabbit studies have consistently yielded intimal suppression at 3 months.^{5 9} Before the present study, few long-term data were available, and 2 studies showed no intimal suppression with radioactive stents placed in dogs¹⁷ and pigs.⁶

The results of the present study suggest the rabbit iliac artery may be the superior animal model to study responses likely to be seen in humans. In the recently reported Milan Dose-Response Study⁷ of ³²P ß-emitting stents, there was a dose-dependent reduction in pure intrastent restenosis rates at 6-month follow-up: 16%, 3%, and 0% in arteries treated with 0.75- to 3.0-µCi, 3.0- to 6.0-µCi, or 6.0- to 12.0-µCi stents, respectively. The authors noted near-complete inhibition of neointimal growth, at stent activities >3 µCi, in the mid portion of the stent, with increased tissue ingrowth toward the stent margins. This impressive intimal suppression was similar to that seen in the present study out to 1 year with 24- and 48-µCi stents. Furthermore, the mechanism of edge restenosis in the present study involved the combined effects of intimal growth and negative remodeling, similar to data derived from intravascular ultrasound studies in the restenosis cases of human radioactive stent implants.⁷

Atherosclerosis
In-stent atherosclerotic lesions observed in a minority of the stents at 6 and 12 months were an unexpected finding in normal rabbit arteries, a model that does not develop atherosclerosis in the absence of hypercholesterolemia. Radiation therapy–induced accelerated atherosclerosis is a recognized complication in long-term surviving patients treated with external-beam radiation (XRT).¹⁸ The latency period for this complication is typically >10 years.¹⁹ One cannot extrapolate the data in the present study to suggest that accelerated atherosclerosis is likely to occur in patients treated with ß-emitting stents. On the other hand, patients who develop significant radiation-induced accelerated atherosclerosis presumably had no or minimal coronary disease before the initiation of XRT, in contrast to coronary brachytherapy patients who already have advanced atherosclerosis. Therefore, any latent tendency toward atherosclerosis progression by coronary brachytherapy could have negative clinical consequences.

Study Limitations
The major finding of the present study is the demonstration of incomplete intimal healing concurrent with intimal growth suppression by radioactive stents. However, only selected stent activities were examined (6, 24, and 48 µCi). Additionally, results from radioactive stent deployment in normal peripheral arteries may differ from stent placement in atherosclerotic epicardial coronary arteries.

Conclusions
At 12 months, ³²P ß-emitting stents show a treatment effect consisting of reduced intimal thickness and area, increased lumen area, and reduced luminal percent stenosis. However, impaired intimal healing persists, characterized by late luminal fibrin deposition, inflammation, incomplete endothelialization of the stent surface, and ongoing cellular proliferation. Neointimal growth and negative arterial remodeling contribute to stent edge effects. The finding of incomplete healing strongly supports the use of prolonged antithrombotic therapy. Longer-term follow-up studies are needed to assess the significance of atherosclerotic change.

	Acknowledgments

 
This study was supported by a grant from Isostent, Inc, Belmont, Calif.

	Footnotes

 
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense.

Received June 22, 2000; revision received October 17, 2000; accepted October 18, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Wardeh AJ, Kay IP, Sabate M, et al. ß-Particle-emitting radioactive stent implantation: a safety and feasibility study. Circulation. 1999;100:1684–1689.[Abstract/Free Full Text]

2. Teirstein PS, Massullo V, Jani S, et al. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation. 2000;101:360–365.[Abstract/Free Full Text]

3. Waksman R, White RL, Chan RC, et al. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation. 2000;101:2165–2171.[Abstract/Free Full Text]

4. Carter AJ, Laird JR, Bailey LR, et al. Effects of endovascular radiation from a ß-particle-emitting stent in a porcine coronary restenosis model: a dose-response study. Circulation. 1996;94:2364–2368.[Abstract/Free Full Text]

5. Farb A, Tang AL, Shroff S, et al. Neointimal responses 3 months after ³²P ß-emitting stent placement. Int J Radiat Oncol Biol Phys. 2000;48:889–898.[Medline] [Order article via Infotrieve]

6. Carter AJ, Scott D, Bailey LR, et al. Dose-response effects of ³²P radioactive stents in an atherosclerotic porcine coronary model. Circulation. 1999;100:1548–1554.[Abstract/Free Full Text]

7. Albiero R, Adamian M, Kobayashi N, et al. Short- and intermediate-term results of ³²P radioactive ß-emitting stent implantation in patients with coronary artery disease: the Milan Dose-Response Study. Circulation. 2000;101:18–26.[Abstract/Free Full Text]

8. Carter AJ, Laird JR. Experimental results with endovascular irradiation via a radioactive stent. Int J Radiat Oncol Biol Phys. 1996;36:797–803.[Medline] [Order article via Infotrieve]

9. Hehrlein C, Stintz M, Kinscherf R, et al. Pure ß-particle-emitting stents inhibit neointima formation in rabbits. Circulation. 1996;93:641–645.[Abstract/Free Full Text]

10. Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after arterial injury, I: smooth muscle growth in the absence of endothelium. Lab Invest. 1983;49:327–333.[Medline] [Order article via Infotrieve]

11. Asahara T, Bauters C, Pastore C, et al. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation. 1995;91:2793–2801.[Abstract/Free Full Text]

12. Reidy MA, Clowes AW, Schwartz SM. Endothelial regeneration, V: inhibition of endothelial regrowth in arteries of rat and rabbit. Lab Invest. 1983;49:569–575.[Medline] [Order article via Infotrieve]

13. Van Belle E, Maillard L, Tio FO, et al. Accelerated endothelialization by local delivery of recombinant human vascular endothelial growth factor reduces in-stent intimal formation. Biochem Biophys Res Commun. 1997;235:311–316.[Medline] [Order article via Infotrieve]

14. Bai H, Masuda J, Sawa Y, et al. Neointima formation after vascular stent implantation: spatial and chronological distribution of smooth muscle cell proliferation and phenotypic modulation. Arterioscler Thromb. 1994;14:1846–1853.[Abstract/Free Full Text]

15. Salame MY, Verheye S, Mulkey SP, et al. The effect of endovascular irradiation on platelet recruitment at sites of balloon angioplasty in pig coronary arteries. Circulation. 2000;101:1087–1090.[Abstract/Free Full Text]

16. Costa MA, Sabate M, van der Giessen WJ, et al. Late coronary occlusion after intracoronary brachytherapy. Circulation. 1999;100:789–792.[Abstract/Free Full Text]

17. Taylor AJ, Gorman PD, Farb A, et al. Long-term coronary vascular responses to ³²P ß-particle-emitting stents in a canine model. Circulation. 1999;100:2366–2372.[Abstract/Free Full Text]

18. Stewart JR, Fajardo LF, Gillette SM, et al. Radiation injury to the heart. Int J Radiat Oncol Biol Phys. 1995;31:1205–1211.[Medline] [Order article via Infotrieve]

19. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA. 1993;270:1949–1955. [Abstract/Free Full Text]

This article has been cited by other articles:

				F. Sera, M. Awata, M. Uematsu, J.-i. Kotani, S. Nanto, and S. Nagata Optimal Stent-Sizing With Intravascular Ultrasound Contributes to Complete Neointimal Coverage After Sirolimus-Eluting Stent Implantation Assessed by Angioscopy J. Am. Coll. Cardiol. Intv., October 1, 2009; 2(10): 989 - 994. [Abstract] [Full Text] [PDF]

				A. V. Finn, G. Nakazawa, M. Joner, F. D. Kolodgie, E. K. Mont, H. K. Gold, and R. Virmani Vascular Responses to Drug Eluting Stents: Importance of Delayed Healing Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1500 - 1510. [Abstract] [Full Text] [PDF]

				C. Deiner, E. Shagdarsuren, P. L. Schwimmbeck, P. Rosenthal, C. Loddenkemper, U. Rauch, M. Pauschinger, R. Dietz, H.-P. Schultheiss, R. Dechend, et al. Nf-{kappa}b and AP-1 activation is associated with late lumen loss after porcine coronary angioplasty and antiproliferative beta-irradiation Cardiovasc Res, July 1, 2007; 75(1): 195 - 204. [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]

				R. Kishore, C. Luedemann, E. Bord, D. Goukassian, and D. W. Losordo Tumor Necrosis Factor-Mediated E2F1 Suppression in Endothelial Cells: Differential Requirement of c-Jun N-Terminal Kinase and p38 Mitogen-Activated Protein Kinase Signal Transduction Pathways Circ. Res., November 14, 2003; 93(10): 932 - 940. [Abstract] [Full Text] [PDF]

				A. Farb, A. P. Burke, F. D. Kolodgie, and R. Virmani Pathological Mechanisms of Fatal Late Coronary Stent Thrombosis in Humans Circulation, October 7, 2003; 108(14): 1701 - 1706. [Abstract] [Full Text] [PDF]

				A. Lafont Basic aspects of plaque vulnerability Heart, October 1, 2003; 89(10): 1262 - 1267. [Full Text] [PDF]

				D. A. Goukassian, R. Kishore, K. Krasinski, C. Dolan, C. Luedemann, Y.-s. Yoon, M. Kearney, A. Hanley, H. Ma, T. Asahara, et al. Engineering the Response to Vascular Injury: Divergent Effects of Deregulated E2F1 Expression on Vascular Smooth Muscle Cells and Endothelial Cells Result in Endothelial Recovery and Inhibition of Neointimal Growth Circ. Res., July 25, 2003; 93(2): 162 - 169. [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]

				E. Cheneau, M. C. John, J. Fournadjiev, R. C. Chan, H.-S. Kim, L. Leborgne, R. Pakala, H. Yazdi, A. E. Ajani, R. Virmani, et al. Time Course of Stent Endothelialization After Intravascular Radiation Therapy in Rabbit Iliac Arteries Circulation, April 29, 2003; 107(16): 2153 - 2158. [Abstract] [Full Text] [PDF]

				R Virmani, F D Kolodgie, A Farb, and A Lafont Drug eluting stents: are human and animal studies comparable? Heart, February 1, 2003; 89(2): 133 - 138. [Abstract] [Full Text] [PDF]

				A. Finkelstein, R. Makkar, T. M. Doherty, V. R. Vegesna, P. Tripathi, M. Liu, J. Bergman, M. Fishbein, J. Hausleiter, K. Takizawa, et al. Increased Expression of Macrophage Colony-Stimulating Factor After Coronary Artery Balloon Injury Is Inhibited by Intracoronary Brachytherapy Circulation, May 21, 2002; 105(20): 2411 - 2415. [Abstract] [Full Text] [PDF]

				P. Wexberg, C. Kirisits, M. Gyongyosi, M. Gottsauner-Wolf, M. Ploner, B. Pokrajac, R. Potter, and D. Glogar Vascular morphometric changes after radioactivestent implantation: a dose-response analysis J. Am. Coll. Cardiol., February 6, 2002; 39(3): 400 - 407. [Abstract] [Full Text] [PDF]

				T. A. Fischell and R. Virmani Intracoronary Brachytherapy in the Porcine Model: A Different Animal Circulation, November 13, 2001; 104(20): 2388 - 2390. [Full Text] [PDF]

				P. K. Coussement, H. de Leon, T. Ueno, M. Y. Salame, S. B. King III, N. A.F. Chronos, and K. A. Robinson Intracoronary {beta}-Radiation Exacerbates Long-Term Neointima Formation in Balloon-Injured Pig Coronary Arteries Circulation, November 13, 2001; 104(20): 2459 - 2464. [Abstract] [Full Text] [PDF]

This Article Abstract 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 Farb, A. Articles by Virmani, R. Search for Related Content PubMed PubMed Citation Articles by Farb, A. Articles by Virmani, R. Related Collections Restenosis Catheter-based coronary interventions: stents