Intracoronary β-Radiation Exacerbates Long-Term Neointima Formation in Balloon-Injured Pig Coronary Arteries

Coussement, Patrick; León, Héctor De; Ueno, Takayoshi; Salame, Mahomed Y.; King, Spencer B.; Chronos, Nicolas; Robinson, Keith A.

doi:10.1161/hc4401.098516

Cited by 26 publications

(15 citation statements)

References 32 publications

(30 reference statements)

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“…In contrast, with vascular brachytherapy, only 33% of the intimal surface of 6-Ci ␤-emitting stents is endothelialized at 3 months, and the degree of delayed healing with vascular radiation therapy is far greater (increased intimal fibrin deposition and inflammation) than that observed with everolimus in the present study. 17,25 To our knowledge, no other studies of drug-eluting stents have assessed the extent of stent endothelial coverage at 28 days by scanning electron microscopy. Even with a semiquantitative light microscopic method, the stent endothelialization score of porcine coronary arteries with sirolimuseluting stents was 2.9, corresponding to Ͻ75% stent surface endothelial coverage.…”

Section: Discussionmentioning

confidence: 99%

Oral Everolimus Inhibits In-Stent Neointimal Growth

et al. 2002

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Background— Rapamycin (sirolimus)-eluting stents are associated with reduced restenosis rates in animal studies and initial human trials. The present study evaluated whether orally administered everolimus (a macrolide of the same family as sirolimus) inhibits in-stent neointimal growth in rabbit iliac arteries. Methods and Results— New Zealand white rabbits were randomized to everolimus 1.5 mg/kg per day starting 3 days before stenting and reduced to 1 mg/kg per day from days 14 to 28 (group 1), everolimus 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days (group 2), or matching placebo for each group. Drugs were administered by oral gavage. Stents were deployed in both iliac arteries, and arteries were harvested 28 days after stenting. Group 1 everolimus-treated rabbits experienced weight loss and anorexia, which resolved after the everolimus dose was lowered on day 14. Group 2 animals were healthy for the duration of everolimus dosing. Both everolimus treatment groups significantly reduced in-stent neointimal growth (46% reduction and 42% reduction in intimal thickness in groups 1 and 2, respectively). In group 2 everolimus-treated animals, the neointima was healed or healing, characterized by stent struts covered by a thin neointima, overlying endothelial cells, and only small foci of fibrin. Scanning electron microscopy showed >80% stent surface endothelialization in group 2 everolimus-treated rabbits. Conclusions— Oral everolimus suppresses in-stent neointimal growth in the rabbit iliac artery. At a dose of 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days, everolimus was well tolerated and was associated with significant neointimal healing.

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Section: Discussionmentioning

confidence: 99%

Oral Everolimus Inhibits In-Stent Neointimal Growth

et al. 2002

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“…These findings corroborate previous animal studies in which the antiproliferative effect of irradiation was no longer observed at 6 months with 15 Gy. 19,20 Thus, higher doses may be necessary to prolong the effectiveness of irradiation over time. Interestingly, the present study did not find differences in the absolute and the rate of reendothelialization of the examined doses to support a longer duration of antiplatelet therapy for 30 Gy over 15 Gy.…”

Section: Cheneau Et Al Time Course Of Stent Endothelializationmentioning

confidence: 99%

Time Course of Stent Endothelialization After Intravascular Radiation Therapy in Rabbit Iliac Arteries

et al. 2003

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Background— Late total occlusion after vascular brachytherapy (VBT) continues to be a serious complication. Delayed reendothelialization was suggested as a pivotal cause, but the time course for complete healing is unknown. Methods and Results— Seventy-two rabbit iliac arteries underwent stent implantation and were treated with γ-radiation using 192 Ir. The prescribed doses were 0 Gy (controls, n=24 arteries), 15 Gy (n=24), or 30 Gy (n=24) at 2 mm. Animals were killed at 1 month (n=24), 3 months (n=24), or 6 months (n=24) and were analyzed for histomorphometry or scanning electron microscopy. Intimal area was reduced after VBT at 3 months with 15 and 30 Gy (0.66±0.07 and 0.66±0.04 mm 2 , respectively) compared with controls (1.01±0.11 mm 2 , P <0.05) and at 6 months with 30 Gy (0.75±0.09 versus 1.28±0.26 mm 2 in controls, P <0.01). Intimal area was similar at 6 months between 15 Gy and controls. At 1 month, 92±4% of the control stented segment was covered with endothelial cells, whereas only 37±4% and 37±8% was covered in the 15- and 30-Gy arteries, respectively. Similarly, at 3 and 6 months, there was a difference in the extent of reendothelialized areas (at 3 months, 95±2%, 32±12%, and 29±13%; and at 6 months, 98±2%, 40±8%, and 35±12% in control, 15-Gy, and 30-Gy arteries, respectively). Excess platelets and leukocytes were seen in irradiated arteries without complete coverage of endothelium. Conclusions— Reendothelialization after VBT is not completed at 6 months after VBT. Special care with prolonged antiplatelet therapy should be considered beyond that time point.

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“…The 2 most important issues have been late thrombosis and delayed restenosis, which may be caused by delayed endothelial regeneration and aggravated inflammatory cell infiltration. [3][4][5] Presently, no adjuvant therapy is available for modulating the disturbed healing process after intravascular radiation therapy.…”

mentioning

confidence: 99%

Mobilized Endothelial Progenitor Cells by Granulocyte-Macrophage Colony-Stimulating Factor Accelerate Reendothelialization and Reduce Vascular Inflammation After Intravascular Radiation

Cho

Kim²,

Lee³

et al. 2003

Circulation

165

105

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Background-Endothelial progenitor cells (EPCs) play a pivotal role in repair and regeneration of damaged vessels. We investigated the role of mobilized EPCs in the healing process after intravascular radiation therapy. Methods and Results-One iliac artery of hypercholesterolemic rabbits was subjected to balloon injury and intravascular radiation with a Re-188 balloon and the contralateral iliac artery to balloon injury only. Rabbits received granulocytemacrophage colony-stimulating factor (recombinant human GM-CSF) (60 g/d subcutaneously) daily for 1 week, either 7 days before the angioplasty or at the time of angioplasty. Control rabbits received human albumin. GM-CSF significantly increased the double-positive (CD31ϩ and KDRϩ) fraction in peripheral blood monocytes and showed a higher number of EPCs than albumin after culture and, furthermore, enhanced migration and incorporation of EPCs. In the albumin group, intravascular radiation therapy reduced neointimal hyperplasia but delayed reendothelialization and aggravated monocyte infiltration. GM-CSF treatment significantly accelerated the reendothelialization and inhibited monocyte infiltration (reendothelialization index, 81Ϯ13% in the GM-CSF radiation [nϭ7] versus 30Ϯ11% in the control radiation [nϭ9] at 2 weeks, PϽ0.01). GM-CSF treatment produced an additional significant reduction in neointimal formation at 14 and 28 days after injury in the intravascular radiation groups (intima to media ratio, 0.14Ϯ0.11 in the GM-CSF radiation [nϭ5] versus 0.36Ϯ0.07 in the control radiation [nϭ5] at 4 weeks, PϽ0.01). Conclusions-GM-CSF treatment mobilizes EPCs, accelerates reendothelialization, and reduces monocytes infiltration after intravascular radiation therapy, suggesting that stem cell mobilization is a promising strategy for enhancing the vascular healing process after cytotoxic angioplasty. (Circulation. 2003;108:2918-2925.)

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Intracoronary β-Radiation Exacerbates Long-Term Neointima Formation in Balloon-Injured Pig Coronary Arteries

Cited by 26 publications

References 32 publications

Oral Everolimus Inhibits In-Stent Neointimal Growth

Oral Everolimus Inhibits In-Stent Neointimal Growth

Time Course of Stent Endothelialization After Intravascular Radiation Therapy in Rabbit Iliac Arteries

Mobilized Endothelial Progenitor Cells by Granulocyte-Macrophage Colony-Stimulating Factor Accelerate Reendothelialization and Reduce Vascular Inflammation After Intravascular Radiation

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