Inhibition of Arterial Restenosis Following Balloon Angioplasty

  • F. F. (Russ) Knapp
  • Ashutosh Dash


The availability of effective methods to treat and manage the restenotic phenomena which usually occur over time following arterial balloon angioplasty is a continual goal of interventional cardiology and radiology. Many technologies have been evaluated and many are still under investigation. The use of appropriately anatomically focused doses of ionizing radiation from intra-arterial sources is an effective strategy for inhibition of the smooth muscle cell proliferation which characterizes the restenotic milieu. Use of solid radioactive source is practiced in radiation oncology/interventional cardiology, while the use of unsealed radioactive sources (i.e., radiopharmaceuticals) has traditionally represented a partnership between nuclear medicine and interventional cardiology. This technology involves the use of radioactive liquid-filled balloons for radiation dose delivery to the vessel wall post angioplasty and has been referred to as intravascular radiation therapy (IVRT). In addition, stents coated with radioisotope agents have been evaluated, but the most effective approach has been the post-balloon angioplasty use of angioplasty balloons filled with beta-emitting radioactive liquid sources which was pioneered with the 188Re. Although this technology has worked very well in the coronary vessels, the introduction and current wide use of alternative nonradiation-based technologies with drug-eluting stents (DES) has overshadowed the use of radioisotopes for this application. However, the introduction of 188Re-liquid-filled balloons for restenosis therapy following angioplasty of the peripheral vessels represents a recent rejuvenation of this technology. This chapter reviews the basic concepts using radioactive liquid-filled balloons for arterial restenosis therapy.


Major Adverse Cardiac Event Radioactive Source Percutaneous Coronary Intervention Target Lesion Revascularization Restenosis Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Bonvini R, Baumgartner I, Do DD, et al. Late acute thrombotic occlusion after endovascular brachytherapy and stenting of femoropopliteal arteries. J Am Coll Cardiol. 2003;41:409–12.PubMedCrossRefGoogle Scholar
  2. Cervinka P, St'ásek J, Costa MA, et al. The “edge effect” after implantation of beta-emitting (55Co) stents with high initial activity. Acta Medica (Hradec Kralove). 2004;47(1):37–42.Google Scholar
  3. Chakroborthy S, Unni PR, Banerjee S, et al. Potential 166Ho radiopharmaceuticals for intravascular radiation therapy (IVRT)-1: [166Ho] holmium labeled ethylene dicysteine. Bucl Med Biol. 2001;28(3):309–17.CrossRefGoogle Scholar
  4. Cheneau E, Wu Z, Leborgne L, Ajani AE, et al. Additional stenting promotes intimal proliferation and compromises the results of intravascular radiation therapy: an intravascular ultrasound study. Am Heart J. 2003;146(1):142–5.PubMedCrossRefGoogle Scholar
  5. Das T, Banerjee S, Samuel G, et al. 188Re-ethylene dicysteine: a novel agent for possible use in endovascular radiation therapy. Nucl Med Commun. 2000;21(10):939–45.PubMedCrossRefGoogle Scholar
  6. Das T, Banerjee S, Samuel G, et al. [186,188Re]-Rhenium ethylene dicysteine (Re-EC): preparation and evaluation for possible use in endovascular brachytherapy. Nucl Med Biol. 2001;27:189–97.CrossRefGoogle Scholar
  7. Dilcher C, Satler LF, Pichard AD. Intracoronary radiation therapy using a novel beta emitter for in-stent restenosis Tungsten WRIST. Cardiovasc Revasc Med. 2005;6(2):52–7.PubMedCrossRefGoogle Scholar
  8. Dinkelborg LM, Tepe G, Noll B, et al. 186Re-labeled stents for prophylaxis of restenosis: first animal results. J Nucl Med. 2000;41(Suppl):7P.Google Scholar
  9. Eigler N, Whiting J, Chernomorsky A, et al. RADIANTTM liquid isotope intravascular radiation therapy system. In: Proceedings, second annual symposium on radiotherapy to reduce restenosis. Sponsored by Scripps Clinic and Research Foundation, La Jolla, January 16–17, 1998.Google Scholar
  10. Grise MA, Massullo V, Jani S, et al. Five-year clinical follow-up after intracoronary radiation. Circulation. 2002;105:2737–40.PubMedCrossRefGoogle Scholar
  11. Hang CL, Fu M, Hsieh BT, et al. Intracoronary beta-irradiation with liquid rhenium-188 to prevent restenosis following pure balloon angioplasty: results from the TRIPPER-1 study. Chang Gung Med J. 2003a;26:98–106.PubMedGoogle Scholar
  12. Hang CL, Fu M, Hsieh BT, et al. Intracoronary beta-irradiation with liquid rhenium-188: results of the Taiwan radiation in prevention of post-pure balloon angioplasty restenosis study. Chest. 2003b;124:1284–93.PubMedCrossRefGoogle Scholar
  13. Hausleiter J, Li A, Knapp R, Eigler N, Whiting J. Low body exposure in cases of radioactive balloon leakage – a biodistribution and elimination study of rhenium-188 in pigs. J Amer Coll Cardiol. 1999;33(Suppl. A):4A.Google Scholar
  14. Hausleiter J, Li A, Makkar R, Berman D, et al. Leakage of a liquid 188Re-filled balloon system during intracoronary brachytherapy. A case report. Cardiovasc Radiat Med. 2001;2:7–10.PubMedCrossRefGoogle Scholar
  15. Herlein C, Kovacs A, Wolf GK, et al. A novel balloon angioplasty catheter impregnated with beta-particle emitting radioisotopes for vascular brachytherapy to prevent restenosis. Eur Heart J. 2000;21:2056–62.CrossRefGoogle Scholar
  16. Hoher M, Wohrle J, Wohlfrom M, et al. Intracoronary beta-irradiation with rhenium-188-filled balloon catheter: a randomized trial in patients with de novo and restenotic lesions. Circulation. 2003;107:3022–7.PubMedCrossRefGoogle Scholar
  17. Hong MK, Park SW, Moon DH, et al. Extra-stent vascular remodeling in in-stent restenosis after 188Re-MAG3 radiation therapy. Int J Cardiol. 2003a;92:187–91.PubMedCrossRefGoogle Scholar
  18. Hong MK, Park SW, Moon DH, et al. Intravascular ultrasound analysis of nonstented adjacent segments in diffuse in-stent restenosis treated with radiation therapy with a rhenium-188-filled balloon. Cather Cardiovasc Interven. 2003b;58:428–33.CrossRefGoogle Scholar
  19. Kim KI, Bae J, Kang HJ, et al. Three-year clinical follow-up results of intracoronary radiation therapy using a rhenium-188 DTPA-filled balloon system. Circ J. 2004;68:532–7.PubMedCrossRefGoogle Scholar
  20. Kim K, Bae J, Koo BK, et al. Long-term clinical outcomes of dissections after intracoronary beta-radiation with rhenium-188-diethylenetraimminepentaacetic acid-filled balloon system. Int J Cardiol. 2005;104:190–6.PubMedCrossRefGoogle Scholar
  21. Kim JH, Shin JH, Song H-Y, et al. Liquid 188Re-filled balloon dilation for the treatment of refractory benign airway strictures: preliminary experience. J Vasc Radiol. 2008;19:406–11.CrossRefGoogle Scholar
  22. Knapp FF Jr, Guhlke S, Beets AL, et al. Rhenium-188 – attractive properties for intravascular brachytherapy for inhibition of coronary restenosis after PTCA. J Nucl Cardiol. 1997a;4:S-118.Google Scholar
  23. Knapp Jr FF, Guhlke S, Beets AL, et al. Intraarterial irradiation with rhenium-188 for inhibition of restenosis after PTCA – strategy and evaluation of species for rapid urinary excretion. J Nucl Med. 1997b;38:124P.Google Scholar
  24. Knapp Jr FF. Rhenium-188 – a generator-derived radioisotope for cancer therapy. Can Biother Radiopharm. 1998;13:337–49.Google Scholar
  25. Knapp FF Jr, Beets AL, Guhlke S, et al. Rhenium-188 liquid-filled balloons effectively inhibit restenosis in a swine coronary overstretch model – a simple new method bridging nuclear medicine and interventional cardiology. J Nucl Med. 1998b;39:48P.Google Scholar
  26. Knapp FF Jr, Beets AL, Mirzadeh S, Guhlke S. Use of a new tandem cation/anion exchange system with clinical-scale generators provides high specific volume solutions of technetium-99m and rhenium-188. In: Proceedings, international trends in radiopharmaceuticals for diagnosis and therapy, Lisbon, Portugal, March 30–April 3, 1998; 1998b.Google Scholar
  27. Knapp Jr FF, Guhlke S, Beets AL, et al. Endovascular beta irradiation for prevention of restenosis using solution radioisotopes: pharmacologic and dosimetric properties of rhenium-188 compounds. Cardiovasc Rad Med. 1999;1:86–97.CrossRefGoogle Scholar
  28. Knapp FF Jr, Spencer RH, Stabin M. Use of rhenium-188 liquid-filled balloons for inhibition of coronary restenosis after PTCA – a new opportunity for nuclear medicine. In: Radionuclides for myocardium - current status and future aspects. Mediterra-Publishers, Athens, Greece; 1999b. p. 61–72 (ISBN 960-85227-9-X).Google Scholar
  29. Knapp Jr FF, Spencer R, Kropp J. Intravascular radiation therapy with radioactive liquid-filled balloons for inhibition of restenosis after angioplasty – a new opportunity for nuclear medicine. J Nucl Med. 2001;42:1384–7.PubMedGoogle Scholar
  30. Kotzerke J, Gabelmann J, Hanke H. Recurrent renal artery stenosis – endovascular brachytherapy with a rhenium-188 filled balloon catheter. Rofo Fortschr Geg Rontgentr Neuen Bildgeb Verfahr. 2002;174:1176–178 (German).Google Scholar
  31. Krötz F, Schiele TM, Zahler S, et al. Sustained platelet activation following intracoronary beta irradiation. Am J Cardiol. 2002;90:1381–4.PubMedCrossRefGoogle Scholar
  32. Leissner GG, Wengenmair H, Sciuk J, et al. Endovascular brachytherapy (EVBT) with Rhenium-188 for restenosis prophylaxis after angioplasty of infrainguinal lesions: early experience. Rofo. 2011;183(8):735–42 (in German).PubMedCrossRefGoogle Scholar
  33. Lewis DM, Dollimore LA, Powell N, et al. Apparatus and methods for radiotherapy. US Patent 7011619; 2006.Google Scholar
  34. Liermann D, Bottcher HD, Kollath J, et al. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoropopliteal arteries. Cardiovasc Intervent Radiol. 1994;17:12–6.PubMedCrossRefGoogle Scholar
  35. Lin WY, Tsai SC, Hsieh BT, et al. Evaluation of three rhenium-188 candidates for intravascular radiation therapy with liquid-filled balloons to prevent restenosis. J Nucl Cardiol. 2000a;7(1):37–42.PubMedCrossRefGoogle Scholar
  36. Lin WY, Hsieh JF, Tsai SC, et al. A comprehensive study of thyroid and gastric uptake of 188Re-perrhenate in endovascular irradiation using liquid-filled balloons to prevent restenosis. Nucl Med Biol. 2000b;27:83–7.PubMedCrossRefGoogle Scholar
  37. McGoron AJ, Kassing WM, Thomas SR, et al. Intravascular irradiation using Re-186 liquid-filled balloon catheters: correlation between experimental and theoretical studies. Cardiovasc Radiat Med. 1999;1(4):368–75.PubMedCrossRefGoogle Scholar
  38. Moura A, Yamada A, Hauer D, et al. Samarium-153 for intravascular irradiation therapy with liquid-filled balloons to prevent restenosis: acute and long term results in hypercholesterolemic rabbit restenosis model. Cardiovasc Radiat Med. 2001;2(2):69–74.PubMedCrossRefGoogle Scholar
  39. Nowak B, Meyer JMA, Goergen T, et al. Dosimetry of a 188Rhenium-labeled self-expanding stent for endovascular brachytherapy in peripheral arteries. Cardiovasc Rad Med. 2001;2:246–53.CrossRefGoogle Scholar
  40. Pokrajac B, Kirisits C, Schmid R, et al. Beta endovascular brachytherapy using CO2-filled centering catheter for treatment of recurrent superficial femoropopliteal artery disease. Cardiovasc Revasc Med. 2009;10(3):162–5.PubMedCrossRefGoogle Scholar
  41. Reynen K, Kockeritz U, Kropp J, et al. Intracoronary radiotherapy with a Re-188 liquid-filled PTCA balloon system in in-stent restenosis: acute and long-term angiographic results, as well as 1-year clinical follow-up. Int J Cardiol. 2004;95:29–34.PubMedCrossRefGoogle Scholar
  42. Reynen K, Kropp J, Koeckerits U, et al. Intracoronary radiotherapy with a 188Rhenium liquid-filled angioplasty balloon system in In-stent restenosis: a single-center, prospective, randomized, placebo-controlled, double-blind evaluation. Coron Artery Dis. 2006;17:371–7.PubMedCrossRefGoogle Scholar
  43. Schaart DR, Bos AJ, Winkelman AJ, Clarijs MC. The radial depth-dose distribution of a 188W/188Re beta line source measured with novel, ultra-thin TLDs in a PMMA phantom: comparison with Monte Carlo simulations. Phys Med Biol. 2002;47:3605–27.PubMedCrossRefGoogle Scholar
  44. Schopohl B, Liermann D, Jülling L, et al. Ir-192 endovascular brachytherapy for avoidance of intimal hyperplasia after percutaneous transluminal angioplasty and stent implantation in peripheral vessels: 6 years of experience. Int J Radiation Oncology Biol Phys. 1996;36:835–40.CrossRefGoogle Scholar
  45. Stabin MG, Konijnenberg M, Knapp Jr FF, Spencer RH. Monte Carlo modeling of radiation dose distributions in intravascular radiation therapy. Med Phys. 2000;27:1088–92.CrossRefGoogle Scholar
  46. Stoll H-P, Hutchins GD, Winkle WL, Nguyen AT, Hou D, Appledorn CR, Romeike B, March KL. Liquid-filled balloon brachytherapy with 68Ga is effective and safe because of the short 60-minute half-life. Circulation. 2001a;103:1793–8.PubMedCrossRefGoogle Scholar
  47. Stoll HP, Hutchins GD, Winkle WL, et al. Advantages of short-lived positron-emitting radioisotopes for intracoronary radiation therapy with liquid-filled balloons to prevent restenosis. J Nucl Med. 2001b;42(9):1375–82.PubMedGoogle Scholar
  48. Waksman R, Bhargava B, Saucedo JF, et al. Yttrium-90 delivered via a centering catheter and afterloader, given both before and after stent implantation, inhibits neointima formation in porcine coronary arteries. Cardiovasc Radiat Med. 2000;2(1):11–7.PubMedCrossRefGoogle Scholar
  49. Waksman R, Ajani AE, White RL, et al. Two-year follow-up after beta and gamma intracoronary radiation therapy for patients with diffuse in-stent restenosis. Am J Cardiol. 2001;88:425–8.PubMedCrossRefGoogle Scholar
  50. Waksman R, McEwan PE, Moore TI, et al. PhotoPoint photodynamic therapy promotes stabilization of atherosclerotic plaques and inhibits plaque progression. J Am Coll Cardiol. 2008;52(12):1024–32.PubMedCrossRefGoogle Scholar
  51. Walichiewicz S, Petelenz B, Wilczek K, et al. 32P liquid sources – comparison of the effectiveness of postangioplasty versus poststenting intravascular brachytherapy in hypercholesterolemic rabbits. Adjunctly implanted titanium stent does not attenuate the effect of endovascular irradiation. Cardiovasc Radiat Med. 2003;4(2):64–8.PubMedCrossRefGoogle Scholar
  52. Walichiewicz S, Wilczek K, Petelenz B, et al. Post-dilation intravascular brachytherapy trials on hypercholesterolemic rabbits using 32P-phosphate solution in angioplasty balloons. Cardiovasc Intervent Radiol. 2004;27(1):42–50.PubMedCrossRefGoogle Scholar
  53. Weinberger J, Knapp Jr FF. Use of liquid-filled balloons for coronary irradiation, Chapter 45. In: Waksman R, editor. Vascular brachytherapy. 2nd ed. Armonk: Futura Publishing Co., Inc.; 1999. p. 521–35. ISBN 0-87993-4131.Google Scholar
  54. Weinberger J, Knapp Jr FF. Use of liquid-filled balloons for coronary irradiation. In: Waksman R, editor. Vascular brachytherapy. 3rd ed. Armonk: Futura Publishing Co., Inc.; 2002. p. 753–90.Google Scholar
  55. Weinberger J, Giedd KN, Simon AD, et al. Radioactive beta-emitting solution-filled balloon treatment prevents porcine coronary restenosis. Cardiovasc Rad Med. 1999;1:252–6.CrossRefGoogle Scholar
  56. Wilczek K, Walichiewicz S, Petelenz B, et al. Post-stenting intravascular brachytherapy trials on hypercholesterolemic rabbits using 32P liquid sources: implications for prevention of in-stent restenosis. Cardiovasc Intervent Radiol. 2002;25(4):307–13.PubMedCrossRefGoogle Scholar
  57. Wohlgemuth WA, Leissner G, Wegenmair H, et al. Endovascular brachytherapy in the femoropopliteal segment using 192Ir and 188Re. Cardiovasc Intervent Radiol. 2008;31:698–708.PubMedCrossRefGoogle Scholar
  58. Wohlgemuth WA, Leissner G, Wengenmair H, et al. Endovascular brachytherapy with (192)Ir and (188)Re to treat de novo and recurrent infrainguinal restenoses. J Cardiovasc Surg (Torino). 2010;51(4):573–8.Google Scholar
  59. Wuu CA, Schiff PB, Marylanski M, et al. 3D Dosimetry study of 188Re liquid balloon for intravascular brachytherapy using bang polymer gel dosimeters. Radiat Prot Dosimetry. 2002;99:397–400.PubMedCrossRefGoogle Scholar
  60. Wuu CS, Schiff P, Maryanski MJ, et al. Dosimetry study of Re-188 liquid-filled balloon for intravascular brachytherapy using polymer gel dosimeters and laser-beam optical CT scanner. Med Phys. 2003;30:132–7.PubMedCrossRefGoogle Scholar
  61. Zamora PO, Osaki S, Som P, et al. Radiolabeling brachytherapy sources with Re-188 through chelating microfilms: stents. J Biomed Mater Res. 2000;53(3):244–51.PubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2016

Authors and Affiliations

  • F. F. (Russ) Knapp
    • 1
  • Ashutosh Dash
    • 2
  1. 1.Nuclear Security and Isotope DivisionOak Ridge National LaboratoryOAK RIDGEUSA
  2. 2.Isotope Production and Applications DivisionBhabha Atomic Research CentreMumbaiIndia

Personalised recommendations