Cyclooxygenase-2 Inhibitor Treatment Improves Left Ventricular Function and Mortality in a Murine Model of Doxorubicin-Induced Heart Failure

Reynolds M. Delgado, Mohamad A. Nawar, Aly M. Zewail, Biswajit Kar, William K. Vaughn, Kenneth K. Wu, Nena Aleksic, Natarajan Sivasubramanian, Kathleen McKay, Douglas L. Mann, James T. Willerson

Research output: Contribution to journalArticle

69 Scopus citations

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. Methods and 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.

Original languageEnglish
Pages (from-to)1428-1433
Number of pages6
JournalCirculation
Volume109
Issue number11
DOIs
StatePublished - Mar 23 2004
Externally publishedYes

Keywords

  • Heart failure
  • Imaging
  • Inhibitors

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    Delgado, R. M., Nawar, M. A., Zewail, A. M., Kar, B., Vaughn, W. K., Wu, K. K., Aleksic, N., Sivasubramanian, N., McKay, K., Mann, D. L., & Willerson, J. T. (2004). Cyclooxygenase-2 Inhibitor Treatment Improves Left Ventricular Function and Mortality in a Murine Model of Doxorubicin-Induced Heart Failure. Circulation, 109(11), 1428-1433. https://doi.org/10.1161/01.CIR.0000121354.34067.48