Skip to main content
SpringerLink
Log in

Adventitial response to intravascular brachytherapy in a rabbit model of restenosis

Die Rolle der Adventitia nach intravaskulärer Brachytherapie in einem Kaninchen-Restenosemodell

  • Original Article
  • Published:
Wiener Klinische Wochenschrift Aims and scope Submit manuscript

Zusammenfassung

Einleitung

Schwere koronare Ereignisse (MACE) treten spät nach vaskulärer Brachytherapie häufiger auf als bei Kontrollpatienten. Wir untersuchten Veränderungen in der Adventitia nach intravaskulärer Bestrahlung in einem Kaninchenmodell, da expansives Remodeling mit einer schlechten Prognose nach Gefäßinterventionen verbunden ist.

Methodik

Bei zwanzig normolipidämischen Kaninchen wurde eine Ballondilatation in beiden Aa. iliacae externae durchgeführt. In einem Gefäß wurde anschließend randomisiert eine Bestrahlung mit einer 90Y-Quelle (15 Gy oder 30 Gy in 0,5 mm Tiefe in der Gefäßwand) durchgeführt. Nach vier Wochen wurden an den autoptisch entnommenen Gefäßen morphometrische Messungen durchgeführt und die Zelldichte und der Kollagengehalt bestimmt. Mit Ki67 wurden proliferierende, mit TUNEL apoptotische Zellen nachgewiesen. Ein Proliferations-bzw. Apoptoseindex wurde als Anzahl der jeweils positiven Zellen pro Gesamtzellzahl × 100 angegeben.

Ergebnisse

Die Neointimafläche reduzierte sich auf 0,27±0,3 mm2 nach Bestrahlung gegenüber 0,55±0,2 mm2 bei Kontrollgefäßen (p=0,007), während die Adventitiafläche von 0,62±0,3 mm2 auf 0,87±0,3 mm2 zunahm (p=0,02). Die Bestrahlung verringerte den Proliferations-(0,95±2,6 vs. 3,73±4,7, p=0,026) sowie den Apoptoseindex (0,006±0,02 vs. 0,107±0,2, p=0,03) in der Neointima, aber nicht in den übrigen Gefäßschichten. Der Kollagengehalt und das arterielle Remodeling unterschieden sich nicht zwischen den Gruppen. Hinsichtlich keines Parameters gab es signifikante Unterschiede zwischen der 15 Gy- und der 30 Gy-Gruppe, obwohl die Verdickung der Adventitia in der Hochdosisgruppe ausgeprägter war.

Schlussfolgerung

Intravaskuläre Betabestrahlung nach Ballonangioplastie bei normolipidämischen Kaninchen ist mit einer Zunahme der Neoadventitia und einer Abnahme der Neointima assoziert. Ein Zusammenhang mit der vermehrten Inzidenz von MACE nach vaskulärer Brachytherapie kann daher angenommen werden.

Summary

Background

The incidence of late major adverse cardiac events (MACE) after coronary brachytherapy is higher than in controls. Because expansive remodeling has been shown to correlate with poor clinical outcome after vascular interventions, we studied adventitial changes after intravascular irradiation in a rabbit model.

Methods

Twenty normolipidemic rabbits underwent balloon injury in both external iliac arteries. One artery ws assigned for subsequent irradiation with a90Y source (15 Gy or 30 Gy at 0,5 mm in the vessel wall). After four weeks morphometric measurements were made and cell density and collagen amount determined. Staining for Ki67 identified proliferating cells; apoptotic cells were identified by TUNEL staining. Proliferative and apoptotic indices were calculated as the number of respective positive cells/total cell count ×100.

Results

The neointimal area decreased to 0.27±0.3 mm2 after irradiation compared with 0.55±0.2 mm2 in controls (p=0.007), whereas adventitial area increased from 0.62±0.3 mm2 to 0.87±0.3 mm2 (p=0.02). Irradiation reduced both the proliferative (0.95±2.6 vs. 3.73±4.7, p=0.026) and apoptotic (0.006±0.02 vs. 0.107±0.2, p=0.03) indices in the neointima, but not in the other arterial-wall layers. Collagen amount and arterial remodeling did not differ between the groups. There was no difference between 15 and 30 Gy in any of the parameters, although adventitial thickening was more pronounced in the high-dose group.

Conclusions

In normolipidemic rabbits, intravascular beta-irradiation after balloon angioplasty is associated with an increase in neoadventitia and a reduction of neointima. It is conceivable that this phenomenon may contribute to the increased incidence of late MACE after vascular brachytherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Salame M, Verheye S, Crocker I, et al (2001) Intracoronary radiation therapy. Eur Heart J 22: 629–647

    Article  PubMed  CAS  Google Scholar 

  2. Nikol S, Hofling B (1995) Regulation of smooth muscle cell proliferation and its possible role in preventing restenosis post-angioplasty. Wien Klin Wochenschr 107: 379–389

    PubMed  CAS  Google Scholar 

  3. Gottsauner-Wolf M, Moliterno D, Lincoff A, et al. (1996) Restenosis — an open file. Clin Cardiol 19: 347–356

    Article  PubMed  CAS  Google Scholar 

  4. Grise, M, Massullo V, Jani S, et al (2002) Five-year clinical follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 105: 2737–2740

    Article  PubMed  Google Scholar 

  5. Regar E, Kozuma K, Sianos G, et al (2002) Routine intracoronary beta-irradiation. Acute and one year outcome in patients at high risk of recurrence of stenosis. Eur Heart J 23: 1038–1044

    Article  PubMed  CAS  Google Scholar 

  6. Waksman R, Rodriguez JC, Robinson KA, et al (1997) Effect of intravascular irradiation on cell proliferation, apoptosis, and vascular remodeling after balloon overstretch injury of porcine coronary arteries. Circulation 96: 1944–1952

    PubMed  CAS  Google Scholar 

  7. Verin V, Popowski Y, Bochaton-Piallat M, et al (2000) Intraarterial beta irradiation induces smooth muscle cell apoptosis and reduces medial cellularity in a hypercholesterolemic rabbit restenosis model. Int J Radiation Oncology Biol Phys 46: 661–670

    CAS  Google Scholar 

  8. Shi Y, O’Brien JE, Fard A, et al (1996) Adventitial my ofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation 94: 1655–1664

    PubMed  CAS  Google Scholar 

  9. Staab ME, Srivatsa SS, Lerman A, et al (1997) Arterial remodeling after experimental percutaneous injury is highly dependent on adventitial injury and histopathology. Int J Cardiol 58: 31–40

    Article  PubMed  CAS  Google Scholar 

  10. Dangas G, Mintz G, Mehran R, et al (1999) Preintervention arterial remodeling as an independent predictor of target-lesion revascularization after nonstent coronary intervention. An analysis of 777 lesions with intravascular ultrasound imaging. Circulation 99: 3149–3154

    PubMed  CAS  Google Scholar 

  11. Kay I, Sabate M, Costa M, et al (2000) Positive geometric vascular remodeling is seen after catheter-based, radiation followed by conventional stent implantation, but not after radioactive stent implantation. Circulation 102: 1434–1439

    PubMed  CAS  Google Scholar 

  12. Wexberg P, Kirisits C, Gyongyosi M, et al (2002) Vascular morphometric changes after radioactive stent implantation: a dose-response analysis. J Am Coll Cardiol 39: 400–407

    Article  PubMed  Google Scholar 

  13. Mück K, Schmidt W, Wexberg P, et al (2000) Design and dosimetry of a novel 90Y beta source to prevent restenosis after angioplasty. Int J Radiation Oncology Biol Phys 46: 249–255

    Article  Google Scholar 

  14. Pötter R, van Limbergen E, Dries W, et al (2001) Recommendations of the EVA GEC ESTRO Working group: prescribing, recording, and reporting in endovascular brachytherapy. Quality assurance, equipment, personnel and education. Radiother Oncol 59: 339–360

    Article  PubMed  Google Scholar 

  15. Farb A, Shroff S, John M, et al (2001) Late arterial responses (6 and 12 months) after 32P β-emitting stent placement. Sustained intimal suppression with incomplete healing. Circulation 103: 1912–1919

    PubMed  CAS  Google Scholar 

  16. Sheehan J (1944) Foam cell plaques in the intima of irradiated small arteries (100–500 microns in external diameter). Arch Pathol 37: 297–303

    Google Scholar 

  17. Sinzinger H, Kritz H (1995) Gamma irradiation is not a novel approach to inhitibit neointimal hyperplasia after arterial injury. Stroke 26: 903–904

    PubMed  CAS  Google Scholar 

  18. Brenner D, Miller R, Hall E (1996) The radiobiology of intravascular irradiation. Int J Radiat Oncol Biol Phys 36: 805–810

    Article  PubMed  CAS  Google Scholar 

  19. Wexberg P, Gottsauner-Wolf M, Sulzbacher I, et al. (2001) Fatal late coronary thrombosis after implantation of a radioactive stent: post-mortem angiography and histologic findings — case, report. Radiology 220: 142–144

    PubMed  CAS  Google Scholar 

  20. Salame M, Verheye S, Mulkey S, et al. (2000) The effect of endovascular irradiation on platelet recruitment at sites of balloon angioplasty in pig coronary arteries. Circulation 101: 1087–1090

    PubMed  CAS  Google Scholar 

  21. Costa M, Sabate M, van der Giessen W, et al (1999) Late coronary occlusion after intracoronary brachytherapy. Circulation 100: 789–792

    PubMed  CAS  Google Scholar 

  22. Waksman R, Ajani A, White R, et al (2001) Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis. Washington Radiation for In-Stent Restenosis Trials plus 6 months of clopidogrel (WRIST PLUS). Circulation 103: 2332–2335

    PubMed  CAS  Google Scholar 

  23. Isner J, Kearney M, Bortman S, et al (1995) Apoptosis in human atherosclerosis and restenosis. Circulation 91: 2703–2711

    PubMed  CAS  Google Scholar 

  24. Durand E, Mallat Z, Addad F, et al (2002) Time course of apoptosis and cell proliferation and their relationship to arterial remodeling and restenosis after angioplasty in an atherosclerotic rabbit model. J Am Coll Cardiol 39: 1680–1685

    Article  PubMed  Google Scholar 

  25. Kollum M, Cottin Y, Chan R, et al (2001) Delayed re-endothelialization and T-cell infiltration following intracoronary radiation therapy in the porcine model. Int J Radiation Oncology Biol Phys 50: 495–501

    Article  CAS  Google Scholar 

  26. Condado J, Waksman R, Gurdiel O, et al (1997) Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 96: 727–732

    PubMed  CAS  Google Scholar 

  27. Maeng M, Olesen P, Emmertsen N, et al (2001) Time course of vascular remodeling, formation of neointima and formation of neoadventitia after angioplasty in a porcine model. Coron Art Dis 12: 285–293

    Article  CAS  Google Scholar 

  28. Verin V, Popowski Y, Urban P, et al (1995) Intra-arterial beta irradiation prevents neointimal hyerplasia in a hypercholesterolemic rabbit restenosis model. Circulation 92: 2284–2290

    PubMed  CAS  Google Scholar 

  29. Rubin P, Williams J, Riggs P, et al (1998) Cellular and molecular mechanisms of radiation inhibition of restenosis. Part I: role of the macrophage and platelet-derived growth factor. Int J Radiat Oncol Biol Phys 40: 929–941

    Article  PubMed  CAS  Google Scholar 

  30. Sata M, Saiura A, Kunisato A, et al (2002) Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nature Med 8: 403–409

    Article  PubMed  CAS  Google Scholar 

  31. Gold R, Schmied M, Giegerich G, et al (1994) Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques. Lab Invest 72: 611–613

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Division of Internal Medicine II, Universitätsklinik für Innere Medizin II, Abteilung für Kardiologie, Währinger Gürtel 18-20, A-1090, Vienna, Austria

    Paul Wexberg, Martin Osranek, Franz Weidinger, Gerald Maurer & Michael Gottsauner-Wolf

  2. Institute for Biomedical Research, University of Vienna, Vienna, Austria

    Ursula Windberger

  3. Department of Pathology, University of Vienna, Vienna, Austria

    Susanna Lang

  4. Austrian Research Center, Seibersdorf, Austria

    Konrad Mück

Authors
  1. Paul Wexberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Konrad Mück
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ursula Windberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susanna Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martin Osranek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Franz Weidinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gerald Maurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Gottsauner-Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul Wexberg.

Additional information

This study was supported by a grant from the Ludwig Boltzmann Institute for Cardiovascular Research, and the “Jubiläumsfonds der Oesterreichischen Nationalbank”, Vienna, Austria.

Deceased.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wexberg, P., Mück, K., Windberger, U. et al. Adventitial response to intravascular brachytherapy in a rabbit model of restenosis. Wien Klin Wochenschr 116, 190–195 (2004). https://doi.org/10.1007/BF03040486

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03040486

Schlüsselwörter

Key words

Search

Navigation