273J Contemp Med Sci | Vol. 3, No. 11, Summer 2017: 273–277 Original aDepartment of Pharmacology & Therapeutics, Faculty of Medicine, University of Kufa, Iraq. bAl-Najaf Center for Cardiothoracic Surgery, Najaf, Iraq. cMinistry of Health & Environment, Al-Najaf Health Directorate, Iraq. dDiwaniya Teaching Hospital, Diwaniya, Iraq. eSchool of Medicine, University of Tasmania, TAS, Australia. Correspondence to Hayder Al-Aubaidy (email: h.alaubaidy@utas.edu.au). (Submitted: 13 May 2017 – Revised version received: 16 June 2017 – Accepted: 26 June 2017 – Published online: 26 September 2017) Objective This study highlights the protective effects of montelukast on myocardial ischemic reperfusion injury induced by cardiopulmonary bypass during valve replacement surgery. Methods A total of 60 patients with valvular disease undergoing elective valve surgery were enrolled in this randomized single-blinded study. Participants were divided into two main groups: Montelukast-treated group consisted of 30 patients who were given 10 mg montelukast sodium (Singulair®, MSD, USA) tablet, once daily at bedtime for 3 days before valve surgery. Control group consisted of 30 patients who underwent valve surgery without taking montelukast tablets. Blood samples were collected at following times (T 0 ; T 1 before aortic cross clamp; T 2 after aortic cross clamp; and T 3 24 h after the surgery), for measuring several inflammatory markers. Ejection fraction (EF) was measured before surgery and three months after surgery. Pulmonary functions were measured before and after the surgery in both study groups. Results There were significant increase in the levels of TNF-a, IL-6, a2 macroglobulin/creatinine ratio and CTnI, in the control group compared to the montelukast-treated group among different study times, (P < 0.05). In addition, the EF was significantly higher in the montelukast-treated group after the valve surgery, (P < 0.05). Levels of forced vital capacity (FVC), forced expiratory volume 1 (FEV 1 ), and FEV 1 /FVC ratio where significantly higher in the montelukast-treated group than the control group, (P < 0.05). Conclusion This study shows the benefits of using pre-surgical montelukast supplement in ameliorating the inflammatory process in patients undergoing cardiopulmonary bypass during valve replacement surgery. Keywords montelukast, mitral and aortic valve replacement surgery, ischemia reperfusion injury, interleukin-6, cardiac troponin 1, tumor necrotic factor-alpha, alpha 2 macroglobulin/creatinine, ejection fraction, forced vital capacity (FVC), forced expiratory volume in one second (FEV 1 ), FEV 1 /FVC ratio Introduction Cardiopulmonary bypass (CPB) is an important procedure, which is routinely performed as part of a classical cardiac surgery and support of life,1 but it is associated with injury that may induce pathological changes in the form of systemic inflamma- tory response syndrome (SIRS) or multiple organ dysfunction syndrome (MODS).2 SIRS remains as a distress in open-heart surgery, and lack of adequate patient screening is an ongoing problem.3,4 It is particularly noteworthy that SIRS is initiated by many factors including surgical trauma, reperfusion of ischemic organ and CPB.4 The CPB is the major factor for initiating SIRS since off-pump cardiac surgery has been shown to significantly reduce inflammatory response.5,6 Other related factors triggering the inflammatory response including hemodilution; electrolyte imbalance; pharmacological agents which are used during sur- gery; myocardial cardioplegic arrest; formation of heparin– protamine complex; and the release of endothelin and the expression of adhesion molecule on leukocyte and endothe- lium.5,6 There are evidences supporting that CPB can induce the activation of most of the body’s major host defensive pro- cesses, include the activation of various complements, coagula- tion factors, kinins, fibrinolysis, leukocytes, platelets and inflammatory cytokines.7 This study aims to evaluate the possible protective effects of montelukast as a selective cystienyl leukot- riene-1 receptor antagonist in the myocardial ischemic reperfu- sion injury induced by heart valve replacement surgery. Patients and Methods Sixty patients (23 males and 37 females) with valvular heart disease undergoing elective valve surgery were randomly included in this single-blinded clinical trial. The study was conducted at the Cardiothoracic Center, Al Sadir Medical City, Najaf, Iraq between April 2015 and December 2016. Par- ticipants were classified into two main study groups: Group 1 Montelukast-treated group (MK group) included 30 patients who underwent valve surgery (14 patients had a mitral valve replacement, MVR) and (16 patients had an aortic valve replacement, AVR). Participants in this group were given 10 mg montelukast sodium (Singulair®, MSD, USA) tablet, once daily at bed time for 3 days before valve surgery.8,9 Group 2 (Control group, C group) included 30 participants who underwent valve replacement surgery (17 patients had a mitral valve replacement, MVR) and (13 patients had an aortic valve replacement, AVR). Participants in this group had no montelukast supplement, and they were considered as controls. Blood samples were collected at following times, (T0 after anesthesia; T1 before aortic cross clamp; T2 after aortic cross clamp; T3 24 h after the valve replacement ISSN 2413-0516 Attenuation of acute systemic inflammatory response after valve surgery Najah R. Hadi,a Fadhil G. Al-Amran,b Alaa A. Naeem,c Ali F. Abd alsaheb,d Mohammed A. Alturfy,b Waleed K. Fakher,b Yaser Q. Majeed,b Nada R. Alharis,a Hayder A. Al-Aubaidy e 274 J Contemp Med Sci | Vol. 3, No. 11, Summer 2017: 273–277 Montelukast in myocardial ischemia Original Hayder Al-Aubaidy et al. surgery), for the measurements of the following inflamma- tory biomarkers (tumer necrotic factor alpha (TNF-a); Interleukin 6 (IL-6); Alpha 2 macroglobumin over creati- nine (a2 macroglobulin/creatinine) ratio and cardiac tro- ponin 1 (cTnI). For all participants, serum samples were separated and stored at −80°C until analysis. The determi- nation of cytokines was formed using an ELISA assay (Cloud-Clone Corp., USA). Bronchial wash was collected from each participants before the valve replacement surgery and after the completion of the operation in order to determine the levels of IL6 and TNFa. Echocardiography was also performed to determine the ejection fraction (EF) before the surgery and was repeated three months after the surgery. Pulmonary function test was undertaken 2 days before the surgery and 10 days after the surgery in order to evaluate the lung protective effects of montelukast in non-asthmatic participants to determine the levels of the forced vital capacity (FVC); forced expiratory volume 1 (FEV 1); and the FEV 1/FVC ratio as measured by Spirometer. Statistical Analysis Data were analyzed to determine the mean and standard error of the mean using statistical package for social sciences (SPSS) version 20 software for windows. The study used independent sample t-test, paired t-test and chi-squared test for categorical variables. A P-value of ≤0.05 was considered significant. Results Participants of the two study groups were comparable for age, gender and comorbidities (Table 1). Tumor necrotic Factor Alpha (TNF-`) Concentration Serum levels of TNF-a were significantly lower in the mon- telukast-treated group compared to the control group, (P < 0.05), at different study times: before anesthesia; before aortic cross clamp; after aortic cross clamp and 24 h after sur- gery as shown (Fig. 1). Interleukine 6 (IL6) Concentration The IL-6 levels were significantly (P < 0.05) lower in mon- telukast-treated group as compared to the control group at all study times (Fig. 2). Cardiac Troponin I (cTnI) The concentrations of cTnI were significantly lower in the montelukast-treated group compared to the control group at the all selected study times, (P < 0.05), (Fig. 3). Alpha 2 Macroglobulin/Creatinine Ratio (A2M/Cr) Similarly, the levels of the a2M/Cr ratio were significantly (P < 0.05) lower in the montelukast-treated groupy times (Fig. 4). Ejection Fraction (EF) The EF was significantly higher in the montelukast-treated group compared to the Control group after the valve replace- ment surgery, (P < 0.05), (Fig. 5). FEV 1 /FVC Ratio This study showed a non-significant difference in FEV1/FVC ratio between the two study groups before the valve replace- ment surgery. However, the ratio became statistically signifi- cant, (P < 0.05), in the montelukast-treated group as compared to the Control group (Fig. 6). Correlation Between IL-6 and FEV 1 /FVC Ratio There was a significant negative correlation between the IL-6 in the bronchial wash and FEV1/FVC ratio, (r = −0.675, P < 0.001), for all participants (Fig. 7). Correlation Between TNF-` and FEV 1 /FVC Ratio Similarly, these was a significant negative correlation between the levels of TNF-a in bronchial wash and the FEV 1/FVC ratio, (r = −0.708, P < 0.001), (Fig. 8). Table 1. Demographic characteristics of the participants included in this study. Data are represented as mean ± standard error of mean. P considered to be significant at or below 0.05. Variable MK group (N = 30) C group (N = 30) Age/years 48.93 ± 1.68 48.43 ± 1.94 Gender (Male/Female) 13 (43.3%)/17 (56.7%) 10 (33.3%)/20 (66.7%) Body mass index (kg/m2) 27.1 ± 3.9 26.1 ± 2.6 Smoking/non smoking 20/10 21/9 Fasting plasma glucose (mmol/l) 5.2 ± 1.7 5.7 ± 2.3 Hypertensive 6 7 Systolic blood pressure (mm Hg) 145.5 ± 15 143.7 ± 16.8 Diastolic blood pressure (mmHg) 86.8 ± 14 86.5 ± 11.4 Heart rate (beats/min) 85.6 ± 17.5 84.3 ± 12.6 Blood urea (mg/dl) 26.2 ± 8.5 27.5 ± 9 Serum creatinine (mg/dl) 0.78 ± 0.09 0.72 ± 0.1 *significant difference between the two study groups at any time at P equal or less than 0.050. Fig. 1 TNF-` concentration at different study times into two groups; montelukast-treated group and control group. Hayder Al-Aubaidy et al. 275J Contemp Med Sci | Vol. 3, No. 11, Summer 2017: 273–277 Original Montelukast in myocardial ischemia Fig. 2 IL-6 concentration at different study times into two groups; montelukast-treated group and control group. Fig. 3 CTnI concentration at different study times into two groups; montelukast-treated group and control group. Fig. 4 `2M/Cr concentration at different study times into two groups; montelukast-treated group and control group. Fig. 5 Ejection fraction before and after valve surgery in montelukast-treated group and control group. Fig. 6 FEV 1 /FVC before and after valve surgery in montelukast- treated group and control group. Discussion Leukotrienes (LTs) are defined as bioactive proinflamma- tory molecules that are produced by the 5-lipoxygenase pathway from arachidonic acid metabolism in many cells, including epithelial cells, fibroblasts, myoblasts, smooth muscle cells, basophils, eosinophils, neutrophils, mac- rophages, and lymphocytes. They play potent inflammatory roles in human body response.10 These cytokines, particu- larly TNF-a, are early regulators of the immune response and can induce the release of secondary cytokines, such as IL-6 and TNF-a, which provokes neutrophil-mediated tissue injury by acting on endothelial cells and other neu- trophils.10 This study focussed on the anti-inflammatory effects of specific cytokines, (TNF-a and IL-6), in amelio- rating the inflammatory response after elective heart valve surgery. Both levels of these cytokines were significantly lower, (at all times), in the montelukast-treated groups as compared to the Control group, P < 0.05, (Figs 1 and 2). This proves the importance of using anti-inflammatory 276 J Contemp Med Sci | Vol. 3, No. 11, Summer 2017: 273–277 Montelukast in myocardial ischemia Original Hayder Al-Aubaidy et al. Fig. 7 Correlation between IL-6 and FEV 1 /FVC. Fig. 8 Correlation between TNF-` and FEV 1 /FVC. supplements prior to any invasive heart surgery to reduce the inflamatory result and improves the outcomes.11,12 Our findings also indicated that montelukast is able to reduce the levels of cTnI (Fig. 3). This is in agreement with the previous studies and confirm that montelukast, at high doses, might have cardioprotective effects during endotoxemia attrib- uted to its antioxidant and anti-inflammatory properties.13,14 It is also effective in reducing levels of lipopolysaccharides (LPS)- induced heart injury and decreasing malondialdehyde (MDA) levels, one of LPS-end products.13 Malondialdehyde (MDA) also has a potent role in inflammation, and it can increase the antioxidant glutathione (GSH) contents in heart tissue.13 Medical treatment with montelukast supplements was also beneficial in increasing the percentage of the EF among the montelukast-treated group as compareed to the Control group (Fig. 5). 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