title: Cyclooxygenase-2 inhibitor treatment improves left ventricular function and mortality in a murine model of doxorubicin-induced heart failure.
abstract: BACKGROUND
  Progression of heart failure after initial myocardial injury is mediated in part by various redundant inflammatory mediators, including the widely expressed cyclooxygenase-2 (COX-2). Because COX-2 inhibitors are useful in treating many inflammation-mediated diseases, we asked whether COX-2 inhibition can attenuate heart failure progression.
  
  
  RESULTS
  Heart failure was experimentally induced in 100 mice by administration of doxorubicin (4 mg. kg(-1). wk(-1) for 6 weeks). Beginning at day 42, mice were fed daily with either COX-2 inhibitor-containing mice chow (n=50) or plain mice chow (controls; n=50). Left ventricular ejection fraction was evaluated as a measure of heart failure by a novel method of transthoracic echocardiography (with intravascular ultrasound catheters) at baseline and on days 42, 56, and 70. From baseline to study termination, left ventricular ejection fraction in COX-2 inhibitor-treated mice decreased significantly less than in control mice (9% versus 29%, P<0.01). Mortality was significantly lower for COX-2 inhibitor-treated mice than for control mice (18% versus 38%, P<0.01). These results were confirmed in a revalidation study in COX-2 inhibitor-treated mice (n=25) and controls (n=25). That study revealed that the hearts from control mice weighed roughly the same as hearts from COX-2 inhibitor-treated mice but showed more extensive signs of cardiomyopathy (as determined by pathological analysis by an independent, blinded observer) and higher levels of COX-2 proteins (as determined by immunoblotting [6442+/-1635 versus 4300+/-2408 arbitrary units, P<0.022]).
  
  
  CONCLUSIONS
  COX-2 inhibitors can attenuate the progression of heart failure in a murine model of doxorubicin-induced heart failure.
authors.affiliation: Department of Adult Cardiology, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Tex 77030, USA. rdelgado@pol.net
authors.forename: Reynolds M
authors.initials: RM
authors.lastname: Delgado
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Nawar
authors.forename: Aly M
authors.initials: AM
authors.lastname: Zewail
authors.forename: Biswajit
authors.initials: B
authors.lastname: Kar
authors.forename: William K
authors.initials: WK
authors.lastname: Vaughn
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Nena
authors.initials: N
authors.lastname: Aleksic
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: Kathleen
authors.initials: K
authors.lastname: McKay
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D004317:Doxorubicin / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use*; D006333:Heart Failure / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases; D015203:Reproducibility of Results; D016037:Single-Blind Method; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D018836:Inflammation Mediators; D007527:Isoenzymes; C102563:3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; D004317:Doxorubicin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases