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Journal of Cardiovascular Pharmacology:
doi: 10.1097/FJC.0b013e31804a5e50
Short Communication

Improvement of Cardiac Function With Parecoxib, A Cyclo-oxygenase-2 Inhibitor, in a Rat Model of Ischemic Heart Failure

Abbate, Antonio MD*; Salloum, Fadi N PhD*; Ockaili, Ramzi A MD*; Fowler, Alpha A III MD*; Biondi-Zoccai, Giuseppe G L MD†; Straino, Stefania BS*‡; Lipinski, Michael J MD*; Baldi, Alfonso MD§; Crea, Filippo MD¶; Biasucci, Luigi M MD¶; Vetrovec, George W MD*; Kukreja, Rakesh C PhD*

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From the *Virginia Commonwealth University Pauley Heart Center, Richmond, VA; †Department of Cardiology, Universita' di Torino, Turin, Italy; ‡Department of Cardiovascular Science, Istituto Dermopatico dell'Immacolata, Rome, Italy; §Department of Biochemistry and Biophysics “F. Cedrangolo,” Section of Pathologic Anatomy, Second University of Naples, Naples, Italy; and ¶Institute of Cardiology, Catholic University, Rome, Italy.

A. Abbate and F.N. Salloum contributed equally to the realization of this study.

Reprints: Antonio Abbate, MD, Assistant Professor of Medicine, VCU Pauley Heart Center, 10025 Bellona Court, Richmond, VA, 23233 (e-mail: abbatea@yahoo.com).

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Abstract

Objective: To assess changes in cardiac function in animals with ischemic congestive heart failure (CHF) treated with a selective cyclo-oxygenase-2 (COX-2) inhibitor.

Background: In patients with CHF, COX-2 expression was associated with features of worsening failure. However, evidence of beneficial or detrimental functional effects of COX-2 inhibition in ischemic CHF is lacking.

Methods: Thirty male Wistar rats underwent coronary ligation and were allowed to recover for 12 months. Five sham-operated animals were used as controls. After 12 months, six surviving animals underwent baseline echocardiogram to measure end-diastolic diameter (EDD), end-systolic diameters (ESD), fractional shortening (FS), and anterior and posterior diastolic and systolic wall thicknesses. The animals were thereafter treated by daily intraperitoneal parecoxib injections (0.75 mg/kg) for 7 days. On day 7, a repeat echocardiogram was performed.

Results: When compared to baseline, repeat echocardiography after 7 days of parecoxib treatment showed no changes in the EDD (9.4 ± 0.4 mm vs. 9.4 ± 0.3 mm, P = 0.9), a significant reduction of ESD (5.5 ± 0.8 mm vs. 6.4 ± 0.3 mm, P = 0.028), and a significant improvement in the FS (43 ± 3% vs. 32 ± 5%, P = 0.027). Improvement of FS was associated with a significant change in systolic thickness in the infarct zone (3.6 ± 0.4 mm vs. 3.0 ± 0.1 mm, P = 0.046), whereas no significant changes in systolic thickness in the remote area were observed.

Conclusions: Administration of parecoxib in ischemic CHF provides functional improvement of the peri-infarct myocardium. This finding may prove useful in improving quality of life and, perhaps, survival in patients with ischemic heart disease.

Cyclo-oxygenase-2 (COX-2) is the enzyme that catalyzes the conversion of arachidonic acid to prostaglandin H2. A great interest in COX-2 has developed over the years because of its central role in inflammation and because of the benefits of specific COX-2 inhibitors in chronic rheumatologic diseases. However, only recently has interest increased concerning the role of COX-2 in heart disease. Two separate lines of research have highlighted the role of COX-2 in ischemic heart disease. First, several experimental papers have looked at the role of COX-2 in the response of the myocardium to ischemia and reperfusion.1-3 Second, population studies and randomised controlled studies have shown that the use of COX-2 was associated with increased incidence of acute myocardial infarction (AMI),4 likely due to an effect not on the myocardium itself but rather on the platelets and/or the endothelium. Better understanding of the role of COX-2 may therefore provide insights in the cause of acute myocardial ischemia and also in the tissue response to ischemia. Considering the latter scenario, several investigators have looked at COX-2 inhibition in experimental models of myocardial ischemia.

Although many have reliably shown that COX-2 contributes to the beneficial effects of late preconditioning in ischemia-reperfusions,1 many others have shown that COX-2 inhibition is beneficial in models of prolonged ischemia such as those of permanent infarct-related artery occlusion.2,3,5 In two retrospective studies on patients with congestive heart failure (CHF), COX-2 expression was found in myocytes and associated with features of worsening failure.6,7 However, evidence of beneficial or detrimental functional effects of COX-2 inhibition in ischemic CHF is lacking. The aim of this study was to assess potential changes in cardiac function in animals with ischemic CHF treated with parecoxib, a selective COX-2 inhibitor.

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METHODS

Male Wistar rats (10 weeks of age, weighing 350-500 g) underwent coronary ligation. The surgical procedures were performed on day 1 by two skilled operators (FNS and RAO) as it has previously been described.5 Briefly, rats under anesthesia (pentobarbital 50-70 mg/kg) underwent surgical opening of the chest and ligation of the proximal left coronary artery. Thirty animals that had survived surgery were allowed to recover for 12 months. Five sham-operated rats were available for comparison (Group 1). Of the 30 animals, only 6 (20%) survived up to 12 months (Group 2). All animals underwent transthoracic echocardiography under light anesthesia (pentobarbital 30-50 mg/kg).The chest was shaved and the rat was placed supine. An echocardiography system equipped with 15-MHz phase-array transducer (Hewlett-Packard) was used. The transducer was positioned on the left anterior side of the chest. The heart was first imaged in the two-dimensional mode in the parasternal long- and short-axis views of the left ventricle (LV). Based on these views, the M-mode cursor was positioned perpendicular to the ventricular septum and posterior wall. According to the American Society of Echocardiography recommendations,8 M-mode images were then obtained at the level of the papillary muscles below the mitral valve tip. End-diastolic diameter (EDD) and end-systolic diameter (ESD) were measured using a parasternal short-axis view by M-mode at the level of the tip of the papillary muscles. The fractional shortening (FS) was calculated as (EDD - ESD)/EDD. Anterior wall diastolic thickness (AWDT), anterior wall systolic thickness (AWST), posterior wall diastolic thickness (PWDT), and posterior wall systolic thickness (PWST) were also measured. The LV mass was estimated using the following formula (((EDD + AWDT + PWDT)3 - (EDD)3 × 0.8 × 1.04) + 0.6) / 1000.

The animals were thereafter treated with a soluble COX-2 inhibitor, parecoxib (0.75 mg/kg intraperitoneal) daily for 7 days. On day 7, 1 hour after treatment, a repeat echocardiogram was obtained. All animals therefore underwent echocardiogram before and after treatment (groups 2A and 2B, respectively).

The present study complies with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH publication No. 85-23, revised in 1996).

Statistical analysis was performed using the SPSS 11.0 package for Windows. Continuous variables are expressed as mean and standard error; t test for paired and for unpaired data was used when appropriate.

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RESULTS

All six animals in group 2 survived the 7-day treatment, and all animals experienced diarrhea during the treatment. Body weight was unchanged after 7 days. Two animals however died shortly after the repeat echocardiogram, likely due to the stress of anesthesia.

When compared to sham-operated controls (group 1), echocardiography at baseline (group 2A) showed greater EDD (9.4 ± 0.3 mm vs. 6.0 ± 0.1 mm, P < 0.001), greater ESD (6.4 ± 0.3 mm vs. 2.2 ± 0.1 mm, P < 0.001), and smaller fractional shortening (32 ± 5% vs. 65 ± 1%, P < 0.001). Systolic thickness of the anterior wall (infarct site) was also reduced (3.0 ± 0.1 mm vs. 3.5 ± 0.1 mm, P < 0.001), whereas systolic thickness in the posterior wall (remote site) was greater (3.8 ± 0.3 mm vs. 3.5 ± 0.1 mm, P = 0.01). Estimated LV mass in group 2A was 1572 ± 32 g (P < 0.001 vs. group 1, 780 ± 21 g).

When compared to baseline (group 2A), repeat echocardiography after 7 days of parecoxib treatment (group B) showed no changes in the EDD (9.4 ± 0.4 mm vs. 9.4 ± 0.3 mm, P = 0.9), a significant reduction of ESD (5.5 ± 0.8 mm vs. 6.4 ± 0.3 mm, P = 0.028), and a significant improvement in the FS (43 ± 3% vs. 32 ± 5%, P = 0.027). Improvement of FS was associated with a significant change in systolic thickness in the infarct zone (3.6 ± 0.4 mm vs. 3.0 ± 0.1 mm, P = 0.046), whereas no significant changes in systolic thickness in the remote area were observed (3.8 ± 0.3 mm vs. 3.9 ± 0.3 mm, P = 0.62). No significant changes were found in the estimated LV mass (1572 ± 32 g vs. 1648 ± 42 g, P = 0.2) (Figure 1).

Figure 1
Figure 1
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DISCUSSION

This study shows for the first time a functional improvement with administration of parecoxib, a selective COX-2 inhibitor, in an animal model of ischemic CHF.

The use of COX-2 inhibitors in animal models of AMI due to coronary ligation demonstrated beneficial effects in terms of more favourable remodelling.2,3,5 However, COX-2 inhibitors have yet to be tested in ischemic CHF models. Saito et al6 were the first to demonstrate COX-2 expression in the myocardium of patient with CHF. In an autopsy study of patients that died after an acute myocardial infarction, we showed that COX-2 expression in the myocardium was associated with greater cardiomyocyte apoptosis and features of worsening failure.7 In accordance with the hypothesis that COX-2 may mediate ischemic damage to the myocardium, two groups independently have shown functional benefits of COX-2 inhibition in animal models of AMI.2,3 In the current study, we allowed animals to survive 12 months after surgery in order to test the role of COX-2 inhibition in a chronic rather than acute model of ischemia. Previous studies have indeed shown that COX-2 expression persists in the region bordering the infarct (and not in the remote areas) for months after the initial ischemic event, supporting the concept of persistent or recurrent ischemia in the zone bordering infarct.7,9 Despite its loss of function, the viability of the zone bordering the infarct is demonstrated by the recovery of function after revascularization, a concept referred to as hibernating myocardium. Baker et al10 reported COX-2 expression in hibernating myocardium and have suggested that COX-2 may mediate hibernation. In our study, we tested the hypothesis that inhibiting COX-2 might influence functional performance of the peri-infarct region, and found that contractility was significantly improved after 7 days of treatment with parecoxib.

Functional improvement by COX-2 inhibitors in a model of nonischemic heart failure has already been shown and was paired with a significant reduction in mortality.11

Major limitations of this study, however, are the small number of cases, the lack of a control group, and the uncertainty of whether the functional improvement obtained would translate into an overall improvement in prognosis. The finding that a functional improvement was paired with favorable outcome in studies of acute myocardial infarction models is reassuring, although not conclusive. Another limitation is the unknown mechanism by which COX-2 inhibition affects contractility and the lack of demonstration of parecoxib administration on myocardial COX-2 expression and activity. Further studies are necessary to investigate the nature of this effect. Given such limitations, the results of this study should be considered hypothesis-generating rather conclusive remarks.

In conclusion, parecoxib administration in ischemic CHF provides functional improvement of the peri-infarct myocardium. This finding may prove useful in improving quality of life and, perhaps, survival in patients with ischemic heart disease.

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ACKNOWLEDGMENTS

The authors wish to thank Dr. Daniele Santini (University Campus Bio-Medico, Rome, Italy) for critically discussing the data, and Dr. Vera Di Trocchio (Virginia Commonwealth University, Richmond, VA) for her writing, editorial, and graphical support. Parecoxib used in the experiments was kindly provided by Pfizer Italia at no cost.

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REFERENCES

1. Shinmura K, Xuan YT, Tang XL, et al. Inducible nitric oxide synthase modulates cyclo-oxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning. Circ Res. 2002;90:602-608.

2. Saito T, Rodger IW, Hu F, et al. Inhibition of COX pathway in experimental myocardial infarction. J Mol Cell Cardiol. 2004;37:71-77.

3. Lapointe MC, Mendez M, Leung A, et al. Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in mouse. Am J Physiol Heart Circ Physiol. 2003;286:H1416-1424.

4. Wong D, Wang M, Cheng Y, et al. Cardiovascular hazard and non-steroidal anti-inflammatory drugs. Curr Opin Pharmacol. 2005;5:204-210.

5. Abbate A, Limana F, Capogrossi MC, et al. Cyclo-oxygenase-2 (COX-2) inhibition reduces apoptosis in acute myocardial infarction. Apoptosis. 2006;11:1061-1064.

6. Saito T, Giaid A. Cyclooxygenase 2 and nuclear factor-kappaB in myocardium of end-stage human heart failure. Circulation. 1999;5:222-227.

7. Abbate A, Santini D, Biondi-Zoccai GGL, et al. Cyclooxygenase-2 (COX-2) expression at site of recent myocardial infarction: friend or foe? Heart. 2004;90:440-443.

8. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2:358-367.

9. Abbate A, Bussani R, Biondi-Zoccai GGL, et al. Infarct-related artery occlusion, tissue markers of ischaemia, and increased apoptosis in the peri-infarct viable myocardium. Eur Heart J. 2005;26:2039-2045.

10. Baker CSR, Dutka DP, Pagano D, et al. Immunocytochemical evidence for inducible nitric oxide synthase and cyclooxygenase-2 expression with nitrotyrosine formation in human hibernating myocardium. Bas Res Cardiol. 2002;97:409-415.

11. Delgado RM, Nawar MA, Zewail AM, et al. Cyclooxygenase-2 inhibitor treatment improves left ventricular function and mortality in a murine model of doxorubicin-induced heart failure. Circulation. 2004;109:1428-1433.

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Keywords:

heart failure; cyclo-oxygenase-2; ischemic heart disease

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