title: Hypercholesterolemia and chronic ischemia alter myocardial responses to selective cyclooxygenase-2 inhibition.
abstract: OBJECTIVE
  Cyclooxygenase-2 inhibitors have been implicated in adverse cardiac events. We hypothesize that hypercholesterolemia and ischemia may alter the myocardial response to the cyclooxygenase-2 inhibitor celecoxib.
  
  
  METHODS
  Yorkshire swine fed normal chow (CX, n = 6) or high-cholesterol diet (HCX, n = 6) underwent placement of an Ameroid constrictor on the left circumflex artery and were started on celecoxib (200 mg/day). After 7 weeks, ischemic and nonischemic myocardium was analyzed for thrombogenic ratio (thromboxane content divided by prostacyclin content), total protein oxidative stress, and expression of prostacyclin synthase, thromboxane synthase, myeloperoxidase, and superoxide dismutase. Cardiac function, tissue perfusion, and vessel density were measured.
  
  
  RESULTS
  HCX animals were significantly hypercholesterolemic compared with CX animals. Thrombogenic ratio was significantly higher in the HCX group than in the CX group, but prostacyclin and thromboxane synthase expression was similar in all tissues. Myocardial perfusion was decreased in the HCX group compared with the CX group. Total oxidative stress, myeloperoxidase, and superoxide dismutase were increased in ischemic tissue compared with nonischemic tissues, but there was no diet-induced difference between groups. There was no difference in capillary or arteriolar density between groups. Left ventricular contractility was greater in the HCX group than in the CX group, but there was no significant difference in heart rate, mean arterial pressure, or left ventricular pressure.
  
  
  CONCLUSIONS
  Hypercholesterolemic patients using celecoxib may be at higher risk for thrombotic events than those with normal cholesterol, but the relationship between dyslipidemia, ischemia, and cyclooxygenase-2 inhibition is likely much more complicated than originally thought.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Chu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Robich
authors.forename: Antonio
authors.initials: A
authors.lastname: Lassaletta
authors.forename: Thomas
authors.initials: T
authors.lastname: Burgess
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sellke
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D000068579:Celecoxib; D015897:Comorbidity; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D011464:Epoprostenol / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006937:Hypercholesterolemia / Q000453:epidemiology / Q000503:physiopathology*; D007150:Immunohistochemistry; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000453:epidemiology / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D013931:Thromboxanes / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D013931:Thromboxanes; D011464:Epoprostenol; D000068579:Celecoxib