title: Dose-dependent coronary artery intimal thickening after local delivery of the anti-oxidant tetradecylthioacetic acid from stents.
abstract: OBJECTIVE
  To examine the in vitro uptake and elution of the anti-oxidant tetradecylthioacetic acid (TTA) from phosphorylcholine (PC)-coated stents, and the in vivo uptake, retention, inflammatory response and histomorphometric changes after overstretch injury of the porcine coronary artery.
  
  
  METHODS
  PC-coated stents were loaded in one of three different concentrations of TTA (87, 174 and 347 mmol/L, i.e. 25, 50 and 100 mg/mL) and randomized versus PC-coated stents to the right coronary or left circumflex artery (18 pigs). Uptake of TTA into the coronary wall from the 347 mmol/L concentration was measured after 3 h and 24 h, 7 days, 14 days and 28 days (two pigs at each time point).
  
  
  RESULTS
  In vitro, TTA was successfully loaded onto the stents and elution was nearly complete after 48 h. In vivo, TTA could be demonstrated in the vessel wall for up to 4 weeks. Percent area stenosis was significantly higher in the TTA group, 35.2+/-20.9% versus 27.5+/-17.0% (p=0.03). Dose-related comparison showed increased intimal thickness, 0.66+/-0.53 mm versus 0.29+/-0.26 mm (p=0.008) and intimal area, 2.83+/-1.61 mm2 versus 1.58+/-0.91 mm2 (p=0.004) for the 347 mmol/L TTA versus controls. There was a significantly positive relationship between the TTA-loading dose and both intimal area (B=0.69, p=0.01) and maximal intimal thickness (B=0.17, p=0.02). The pro-inflammatory precursor arachidonic acid increased four-fold in the arterial wall of the TTA group, while the anti-inflammatory fatty acid index, calculated as (docosapentaenoic acid+docosahexaenoic acid+dihomo-linolenic acid)/arachidonic acid, was suppressed to 0.65+/-0.27 compared to 1.13+/-0.23 in control vessels (p<0.001).
  
  
  CONCLUSIONS
  TTA caused a dose-dependent intimal thickening and reduced anti-inflammatory fatty acid index. Contrary to expectations, TTA seems unsuitable as stent coating.
authors.affiliation: Department of Heart Disease, Haukeland University Hospital, N-5021 Bergen, Norway. karel.kuiper@helse-bergen.no
authors.forename: Karel K J
authors.initials: KK
authors.lastname: Kuiper
authors.forename: Mohamed
authors.initials: M
authors.lastname: Salem
authors.forename: Oddrun Anita
authors.initials: OA
authors.lastname: Gudbrandsen
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Muna
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Berge
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Nordrehaug
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D020099:Coated Materials, Biocompatible / Q000378:metabolism; D023903:Coronary Restenosis; D003331:Coronary Vessels / Q000293:injuries / Q000473:pathology*; D004867:Equipment Design; D005227:Fatty Acids / Q000378:metabolism; D007249:Inflammation; D011897:Random Allocation; D015607:Stents; D013440:Sulfides / Q000008:administration & dosage / Q000737:chemistry*; D013552:Swine; D013997:Time Factors; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D000975:Antioxidants; D020099:Coated Materials, Biocompatible; D005227:Fatty Acids; D013440:Sulfides; D016718:Arachidonic Acid; C062078:1-(carboxymethylthio)tetradecane