This Article Full Text Full Text (PDF) All Versions of this Article: 109/11/1428    most recent 01.CIR.0000121354.34067.48v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Delgado, R. M. Articles by Willerson, J. T. Search for Related Content PubMed PubMed Citation Articles by Delgado, R. M., III Articles by Willerson, J. T. Related Collections Congestive Cardiovascular Pharmacology Echocardiography Animal models of human disease

(Circulation. 2004;109:1428-1433.)
© 2004 American Heart Association, Inc.

Basic Science Reports

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

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

From the Department of Adult Cardiology, Texas Heart Institute at St. Luke’s Episcopal Hospital (R.M.D., M.A.N., A.M.Z., B.K., W.K.V., K.M., J.T.W.), Houston, Tex; Winters Center for Cardiovascular Medicine, Baylor College of Medicine (N.S., D.L.M.), Houston, Tex; and The University of Texas Medical School at Houston (K.K.W., N.A., J.T.W.), Houston, Tex.

Reprint requests to Reynolds M. Delgado III, MD, St. Luke’s Episcopal Hospital, 6624 Fannin, Suite 2420, Houston, TX 77030. E-mail rdelgado{at}pol.net

Received March 27, 2003; revision received October 30, 2003; accepted November 13, 2003.

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.

Key Words: heart failure • inhibitors • imaging

This article has been cited by other articles:

				M. A Frias, S. Somers, C. Gerber-Wicht, L. H Opie, S. Lecour, and U. Lang The PGE2-Stat3 interaction in doxorubicin-induced myocardial apoptosis Cardiovasc Res, July 9, 2008; (2008) cvn171v2. [Abstract] [Full Text] [PDF]

				M. Esaki, G. Takemura, K.-i. Kosai, T. Takahashi, S. Miyata, L. Li, K. Goto, R. Maruyama, H. Okada, H. Kanamori, et al. Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H1048 - H1057. [Abstract] [Full Text] [PDF]

				C.-c. Huang, P.-C. Chen, C.-W. Huang, and J. Yu Aristolochic Acid Induces Heart Failure in Zebrafish Embryos That is Mediated by Inflammation Toxicol. Sci., December 1, 2007; 100(2): 486 - 494. [Abstract] [Full Text] [PDF]

				P. Mukhopadhyay, S. Batkai, M. Rajesh, N. Czifra, J. Harvey-White, G. Hasko, Z. Zsengeller, N. P. Gerard, L. Liaudet, G. Kunos, et al. Pharmacological Inhibition of CB1 Cannabinoid Receptor Protects Against Doxorubicin-Induced Cardiotoxicity J. Am. Coll. Cardiol., August 7, 2007; 50(6): 528 - 536. [Abstract] [Full Text] [PDF]

				L. Timmers, J. P.G. Sluijter, C. W.J. Verlaan, P. Steendijk, M. J. Cramer, M. Emons, C. Strijder, P. F. Grundeman, S. K. Sze, L. Hua, et al. Cyclooxygenase-2 Inhibition Increases Mortality, Enhances Left Ventricular Remodeling, and Impairs Systolic Function After Myocardial Infarction in the Pig Circulation, January 23, 2007; 115(3): 326 - 332. [Abstract] [Full Text] [PDF]

				J. Wohlschlaeger, K. J. Schmitz, J. Palatty, A. Takeda, N. Takeda, C. Vahlhaus, B. Levkau, J. Stypmann, C. Schmid, K. W. Schmid, et al. Roles of cyclooxygenase-2 and phosphorylated Akt ( T hr308) in cardiac hypertrophy regression mediated by left-ventricular unloading J. Thorac. Cardiovasc. Surg., January 1, 2007; 133(1): 37 - 43. [Abstract] [Full Text] [PDF]

				T. G. Neilan, G. A. Doherty, G. Chen, C. Deflandre, H. McAllister, R. K. Butler, S. E. McClelland, E. Kay, L. R. Ballou, and D. J. Fitzgerald Disruption of COX-2 modulates gene expression and the cardiac injury response to doxorubicin Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H532 - H536. [Abstract] [Full Text] [PDF]

				P. G. Horan, M. F. McMullin, and P. P. McKeown Anthracycline cardiotoxicity Eur. Heart J., May 2, 2006; 27(10): 1137 - 1138. [Full Text] [PDF]

				S. Mitchell, A. Ota, W. Foster, B. Zhang, Z. Fang, S. Patel, S. F. Nelson, S. Horvath, and Y. Wang Distinct gene expression profiles in adult mouse heart following targeted MAP kinase activation Physiol Genomics, March 13, 2006; 25(1): 50 - 59. [Abstract] [Full Text] [PDF]

				L. Li, G. Takemura, Y. Li, S. Miyata, M. Esaki, H. Okada, H. Kanamori, N. C. Khai, R. Maruyama, A. Ogino, et al. Preventive Effect of Erythropoietin on Cardiac Dysfunction in Doxorubicin-Induced Cardiomyopathy Circulation, January 31, 2006; 113(4): 535 - 543. [Abstract] [Full Text] [PDF]

				K. K. Wu, J.-Y. Liou, and K. Cieslik Transcriptional Control of COX-2 via C/EBP{beta} Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 679 - 685. [Abstract] [Full Text] [PDF]

				N. Goren, J. Cuenca, P. Martin-Sanz, and L. Bosca Attenuation of NF-{kappa}B signalling in rat cardiomyocytes at birth restricts the induction of inflammatory genes Cardiovasc Res, November 1, 2004; 64(2): 289 - 297. [Abstract] [Full Text] [PDF]