title: Dose-dependent smooth muscle cell proliferation induced by thermal injury with pulsed infrared lasers.
abstract: BACKGROUND
  Recently, laser-heated and radio frequency-heated balloon angioplasty techniques have been proposed as a means to treat or minimize dissection and elastic recoil but have been associated with a high rate of clinical restenosis. Similarly, pulsed laser angioplasty techniques proposed to minimize thermal injury while ablating obstructing atheroma have failed to reduce clinical restenosis. Because "hot balloon" and pulsed laser angioplasty create both mechanical and thermal injury, it has been difficult to discern the cause of the smooth muscle cell (SMC) proliferation resulting in restenosis and whether such magnitude of proliferation is predictable and dose related. This study was undertaken to explore these issues.
  
  
  RESULTS
  Localized thermal lesions accompanying efficient ablation were created with a pulsed Tm:YAG laser in nine rabbit aortas, which consistently led to a focal proliferation of SMC that filled the ablated region by 4 weeks. Transcutaneous Ho:YAG pulsed laser irradiation at multiple independent sites of 24 central rabbit ear arteries without ablation led to brief approximately 30 degrees C thermal transients and thermal damage to the artery wall resulting in significant neointimal proliferation by 3 weeks and a mean cross-sectional narrowing of 59 +/- 17% at a dose of 390 mJ/mm2. Acute and chronic responses to varying total energy deposition were studied by histology after the rabbits were killed at 2 hours to 4 weeks. Arterial segments midway between laser injuries were unaffected and served as internal controls. Neointimal proliferation at 3 weeks after laser injury exhibited a clear dose dependence. Mean cross-sectional narrowing increased from 34 +/- 10% to 85 +/- 15% as laser fluence increased from 240 mJ/cm2 to 640 mJ/cm2 (r = 0.84). Similarly, cross-sectional narrowing caused by SMC neointimal proliferation increased from 20 +/- 10% to 77 +/- 17% for a fixed surface irradiation as the depth of the most superficial arterial media decreased from 600 microns to 330 microns (r = 0.94).
  
  
  CONCLUSIONS
  Thermal injury to the arterial wall is a potent stimulus for SMC proliferation and may necessitate reduction in laser or thermal energy used for angioplasty. Moreover, a dose-response relation exists between the degree of thermal injury and SMC proliferative response. Hence, this technique could be used as a practical model of restenosis suitable for screening therapies for inhibition of SMC proliferation.
authors.affiliation: National Center for Research Resources, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 20892.
authors.forename: P C
authors.initials: PC
authors.lastname: Douek
authors.forename: R
authors.initials: R
authors.lastname: Correa
authors.forename: R
authors.initials: R
authors.lastname: Neville
authors.forename: E F
authors.initials: EF
authors.lastname: Unger
authors.forename: M
authors.initials: M
authors.lastname: Shou
authors.forename: S
authors.initials: S
authors.lastname: Banai
authors.forename: V J
authors.initials: VJ
authors.lastname: Ferrans
authors.forename: S E
authors.initials: SE
authors.lastname: Epstein
authors.forename: M B
authors.initials: MB
authors.lastname: Leon
authors.forename: R F
authors.initials: RF
authors.lastname: Bonner
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology / Q000528:radiation effects; D001158:Arteries / Q000473:pathology / Q000528:radiation effects; D002056:Burns / Q000209:etiology / Q000473:pathology*; D002455:Cell Division / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004423:Ear / Q000098:blood supply; D007259:Infrared Rays; D053685:Laser Therapy / Q000009:adverse effects* / Q000379:methods; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000528:radiation effects*; D011817:Rabbits