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ORIGINAL ARTICLE
Year : 2019  |  Volume : 22  |  Issue : 7  |  Page : 997-1001

The postoperatıve effects of use of trimetazidine before the coronary artery bypass graft surgery


1 Department of Anesthesiology, Katip Çelebi University Atatürk Research and Training Hospital, İzmir, Turkey
2 Department of Biochemistry, Katip Çelebi University Atatürk Research and Training Hospital, İzmir, Turkey
3 Department of Cardiovascular Surgery, Katip Çelebi University Atatürk Research and Training Hospital, İzmir, Turkey
4 Department of Anesthesiology, Ege Şehir Hospital, İzmir, Turkey

Date of Acceptance14-Mar-2019
Date of Web Publication11-Jul-2019

Correspondence Address:
Dr. B E Golboyu
Katip Çelebi University Atatürk Research and Training Hospital, Department of Anesthesiology, İzmir; Atatürk Eğitim ve Araştırma Hastanesi Basın Sitesi, 35360 Karabaǧlar, İzmir
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_587_18

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   Abstract 

s
Background: In this study, postoperative cardiac functions were observed in patients undergoing coronary artery bypass grafting (CABG) surgery following preoperative administration of the anti-ischemic drug trimetazidine. Materıals and Methods: The study included a total of 50 CABG patients; 25 were administered with trimetazidine preoperatively and 25 did not receive trimetazidine. A retrospective evaluation was made of the parameters of age, gender, preoperative echocardiography (ECHO) results, cross-clamping durations, postoperative inotropic requirements, and postoperative 4th-h troponin-I levels and the groups were compared. Results: There was no statistically significant difference determined between the 2 groups in respect of the data of age, gender, comorbidity, preoperative ECHO signs [(ejection fraction (EF), left ventricle end systolic diameter (lvsd), left ventricle end diastolic diameter (lvdd), left atrium diameter (LA), and intraventricular septum thickness (IVS)], inotropic requirements, and postoperative troponin-I levels. In the control group, a positive correlation was determined between postoperative troponin-I levels and DM (r: 0.597, p: 0.002). There was no correlation determined in the trimetazidine group (r:-0.042, p: 0.844). Conclusion: The results of this study demonstrated a positive correlation between postoperative troponin-I levels and DM in the group not administered with trimetazidine. There was no such correlation determined in the group administered with trimetazidine. This result may suggest that DM may increase troponin-I levels in the absence of trimetazidine, and therefore that the drug may be cardioprotective in such cases. Further studies on more extensive patient populations are required to confirm these results.

Keywords: Coronary artery bypass grafting, diabetes mellitus, trimetazidine, troponin-I


How to cite this article:
Aksun M, Aksun S, Kestelli M, Kuru V, Tanyeli H F, Girgin S, Damar E, Golboyu B E, Karahan N. The postoperatıve effects of use of trimetazidine before the coronary artery bypass graft surgery. Niger J Clin Pract 2019;22:997-1001

How to cite this URL:
Aksun M, Aksun S, Kestelli M, Kuru V, Tanyeli H F, Girgin S, Damar E, Golboyu B E, Karahan N. The postoperatıve effects of use of trimetazidine before the coronary artery bypass graft surgery. Niger J Clin Pract [serial online] 2019 [cited 2019 Jul 22];22:997-1001. Available from: http://www.njcponline.com/text.asp?2019/22/7/997/262529




   Introduction Top


Ischemia and reperfusion injury is one of the most significant problems in cardiac surgery and may cause postoperative malignant arrhythmia, perioperative myocardial infarct, and reduced cardiac flow. Inspite scientific advances at the cellular level and the use of cardioprotective methods, it has still not yet been possible to completely prevent reperfusion damage.[1] Therefore, anti-ischemic drugs are used in addition to various cardioplegia methods, which are applied at the stage of cardiac surgery.

Trimetazidine (1-(2, 3, 4-Trimethoxybenzyl) piperazine) (TMZ) is an anti-ischemic drug that changes the metabolic function of the myocardium without affecting hemodynamic markers such as heart rate, systolic blood pressure, and myocardial oxygen consumption.[2]

With mitochondrial 3-ketoacyl CoA thiolase selective inhibition, TMZ reduces fatty acid oxidation and increases intracellular glucose and lactate consumption. As a result of this, the side-effects of oxidative stress related to free-fatty acid are reduced.[3] During ischemia, mitochondrial metabolism and cardiac performance increase.[4]

Cardiac troponin (cTn) function in myocardial contraction by regulating the calcium-related interaction of actin and myosin, and these regulatory proteins are found in the 3 sub-forms of cardiac troponin-T (cTn-T), cardiac troponin-I (cTn-I), and cardiac troponin-C (cTn-C). The sensitivity and specificity of cTn-T and cTn-I are similar to each other and are extremely high for myocardial injury.[5]

The aim of this study was to examine the postoperative effects on myocardial functions of preoperative administration of TMZ treatment.


   Materials and Methods Top


Approval for the study was granted by the Local Ethics Committee. This retrospective study included 50 patients who underwent elective coronary artery bypass grafting (CABG) surgery between December 2013 and April 2014 in Katip Çelebi University Atatürk Education and Research Hospital. Data were obtained from the hospital records and computer database. The patients were admitted to hospital 3 days preoperatively, and per oral 20 mg TMZ was administered to 25 patients as Group 1. There was no TMZ administered to the 25 patients in Group 2.

For each patient, a record was made for comparison of age, gender, comorbidities, preoperative echocardiography (ECHO) data [(ejection fraction (EF), left ventricle end systolic diameter (LVSD), left ventricle end diastolic diameter (LVDD), left atrium diameter (LA), and intraventricular septum (IVS) thickness], cross-clamp durations, cardiopulmonary bypass durations, duration of intensive care unit stay, postoperative inotrope requirement, and preoperative troponin-I and postoperative 4th-h troponin-I values.

The exclusion criteria were recent (<90 days) myocardial infarct, emergency surgery, procedures such as valve surgery additional to the CABG operation, the use of medical treatment (e.g., vitamins and cortisol) that could affect the antioxidant status, chronic renal failure, liver disease, and cases where the postoperative troponin-I level was not examined.

Statistical analysis

Statistical analyses of the data obtained in the study were performed using IBM SPSS v. 22 software at a confidence interval of 95%. In the comparison of categorical data between the groups, the Pearson Chi-square test, Fisher's exact test, and Chi-square trend analysis were applied. Depending on the conformity to a normal distribution, in the comparison of continuous data between 2 groups, the independent samples t test and the Mann-Whitney U-test were applied and in the comparison of more than 2 groups, the Kruskal-Wallis H test (post-hoc Bonferroni corrected Mann-Whitney U test). The Pearson correlation analysis was used to determine relationships between the variables. The logistic regression analysis was performed to determine the predictors of high troponin levels with statistically significant variables. A value of P < 0.05 was accepted as statistically significant.


   Results Top


There was no statistically significant difference determined between the groups with respect to age (Group 1: 65.96 ± 9.62 years; Group 2: 60.88 ± 9.3 years), gender, and comorbidities [hypertension, diabetes mellitus (DM), and chronic obstructive pulmonary disease] (P > 0.05) [Table 1].
Table 1: Distribution of patient gender and comorbidities

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There was no statistically significant difference was determined between the groups in respect of preoperative ECHO findings (EF, LVSd, LVDd, LA, and IVS), cross-clamp durations, or cardiopulmonary bypass duration (P < 0.05) [Table 2].
Table 2: Distribution of patient age and preoperative echocardiography findings

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There was no statistically significant difference determined between the groups with respect of the number of coronary artery anastomosis or use of pump removal inotrope (P > 0.05) [Table 3].
Table 3: Number of CABG and inotrope use

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In the postoperative period, there was no statistically significant difference observed in the extubation time or in the duration of intensive care unit stay.

There was no statistically significant difference determined between the groups with respect of preoperative troponin-I levels (Group 1: 0.05 ± 0.92, Group 2: 0.06 ± 0.07, p: 0.523), or postoperative troponin-I levels (Group 1: 8.64 ± 6.79, Group 2: 8.92 ± 10.38, p: 0.535) (P > 0.05) [Table 4].
Table 4: Troponin levels and perioperative characteristics

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A positive correlation was determined in the control group between postoperative cTn-I value and DM (r: 0.597, p: 0.002), and there was no correlation determined in the TMZ group between cTn-I and DM (r:–0.042, p: 0.844) [Table 5]. We've made logistic regression analysis of the effect of presence of diabetes on postoperative troponin I value [Table 6].
Table 5: Correlations of Group 1 and Group 2 with DM

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Table 6: Logistic regression analysis of the effect of presence of diabetes on postoperative troponin I value

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   Discussion Top


CABG is a basic and effective surgical method for cardiac coronary artery disease.[6] Ischemia reperfusion injury during and following CABG may lead to reversible and irreversible myocardial damage.[7] Although several methods have been developed to reduce this negative effect on the myocardial tissue, cardiac function disorders are still widely encountered.[8] Myocardium protective methods play a key role during CABG.[9]

TMZ is an anti-ischemic agent with a proven cardio-protective effect, which does not affect hemodynamic parameters.[10] In the cardiomyocyte cells, TMZ inhibits mitochondrial 3-ketoacyl CoA thiolase, which has a basic role in beta-oxidation. This inhibition of the cell metabolism changes from fatty acid oxidation to glucose oxidation, which is more effective in ATP production and oxygen consumption.[11]

In a double-blinded, placebo-controlled, in comparison with a placebo-treated group, a patient group treated with preoperative TMZ were determined to have significantly lower CTn-T values at 5 min, 12 h, and 24 h after Cardiopulmonary bypass. This demonstrated effective protection of the contractile function by reducing cTn-T destruction during ischemia-reperfusion in the myocardium without affecting the perioperative hemodynamic parameters.[12]

In a double-blind, controlled, prospective study, evaluation was made of groups treated and not treated with preoperative TMZ by examining the effect on myocardial damage of preoperative and postoperative serum creatinine kinase (CK), CK isoenzyme MB (CK-MB), myoglobulin, and cTn-T levels. The postoperative values of these parameters were determined to be significantly lower in the TMZ group. Thus, it was emphasized that the use of preoperative TMZ has a protective effect on the myocardium.[13]

A meta-analysis of 6 randomized, controlled studies investigating the myocardial protective effect of preoperative TMZ treatment in CABG patients, evaluated the postoperative levels of several blood biochemical markers that occur in myocardial damage, including CK, CK-MB, creatinine phosphokinase, cTn-T, and cTn-I. On the subject of postoperative cTn-I levels in circulation,[9] Xu et al. and Wang et al. reported two data results. In both studies, although no significant difference was determined in postoperative cTn-I levels, a statistically significant difference was determined in cTn-T levels.[14],[15]

In parallel with the results of Xu and Wang, in the current study, there was no statistically significant difference determined between the TMZ-treated group and the placebo group in the postoperative 4th h cTn-I levels. However, in the group not treated with preoperative TMZ, a statistically significant positive correlation was determined between the postoperative cTn-I value and DM, whereas no correlation was determined in the TMZ-treated group between cTn-I values and DM. This suggests that the presence of DM could have elevated the troponin-I values in the patient group not treated with TMZ, and in the group where TMZ was used, there was a protective effect.

DM, which is ranked as the 5th cause of deaths worldwide, has been related to coronary artery disease, is one of the commonly seen comorbidities and has been evaluated as a significant risk factor for coronary artery disease.[16],[17] It is possible that TMZ could have a role as a significant protective agent in this combination of DM and coronary artery disease.

Belardinelli et al. conducted a study to determine whether or not there was any recovery of left ventricular systolic function and myocardial perfusion with short-term TMZ treatment in diabetic patients with ischemic cardiomyopathy. One patient group was administered 20 mg TMZ for 3 months and the other group received a placebo for the same period. All the patients were scanned with single photon emission computed tomography at the start of the study and at the end of the 3rd month. A significant progression in systolic wall thickness and EF was determined at the end of the 3rd month in the TMZ-treated patients compared to the control group. In addition, the total exercise time was recorded as increased in the TMZ group.[18]

In a study that evaluating the metabolic effect of TMZ on the left ventricle in diabetic Cardiomyopathy patients, the patients with Type 2 DM and ischemic cardiomyopathy were randomized into 2 groups receiving 20 mg TMZ or placebo for 6 months. Evaluation was made with ECHO at the start of the study and at the end of 6 months. Basal LVED was determined to have increased in the placebo group and decreased in the TMZ group at the end of 6 months. When compared with the basal values, the left ventricle EF had increased in the TMZ group and there was no change in the placebo group.

Diabetic CMP patients have disrupted myocardial glucose distribution and impaired distal distribution of coronary atherosclerosis. TMZ, which is an anti-ischemic metabolic agent, increases the use of myocardial glucose inspite the inhibition of fatty acid oxidation. With the addition of TMZ to standard medical treatment for diabetic patients with ischemic heart disease, beneficial effects have been determined on left ventricle volume and EF in comparison with placebo and the effect has been associated with the effect of TMZ on cardiac glucose use.[19]

Although there are many studies in literature related to TMZ treatment of diabetic patients with comorbid coronary artery disease, there are very few references related to TMZ treatment of diabetic patients undergoing CABG. In the current study, although the results have shown that TMZ could be used as a cardioprotective agent, especially in DM patients.


   Limitations Top


Our study was performed in a small number of patient populations because of the limited number of patients using preoperative TMZ. In our clinic, troponin is not routinely examined before CABG surgery. We believe that comparing preoperative troponin values with postoperative results will give more reliable results. Furthermore, the retrospective design of our study was the most important limiting factor. We believe that prospective studies with a larger patient population will yield more meaningful results.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86:580-8.  Back to cited text no. 4
    
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Adams JE 3rd, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s?. Circulation 1993;88:750-63.  Back to cited text no. 5
    
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ZhangN, LeiJ, LiuQ, HuangW, Xiao H, Han LeiH. The effectiveness of preoperative trimetazidine on myocardial preservation in coronary artery bypass graft patients: A systematic review and meta-analysis. Cardiology 2015;131:86-96.  Back to cited text no. 9
    
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Lopaschuk GD, Barr R, Thomas PD, Dyck JR. Beneficial effects of trimetazidine in ex vivo working ischemichearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme a thiolase. Circ Res 2003;93:e33-7.  Back to cited text no. 10
    
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Chrusciel P, Rysz J, Banach M. Defining the role of trimetazidine in the treatment of cardiovascular disorders: Some insights on its role in heart failure and peripheral artery disease. Drugs 2014;74: 971-80.  Back to cited text no. 11
    
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Tünerir B, Colak O, Alataş O, Beşoǧul Y, Kural T, Aslan R. Measurement of troponin T to detect cardioprotective effect of trimetazidine during coronary artery bypass grafting. Ann Thorac Surg 1999;68:2173-6.  Back to cited text no. 12
    
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Iskesen I, Kurdal AT, Eserdag M, Cerrahoglu M, Sirin BH. Trimetazidine may protect the myocardium during cardiac surgery. Heart Surg Forum 2009;12:175-9.  Back to cited text no. 13
    
14.
Xu P, Wen B, Jiao Z, Liu C, Zhao W. The cardioprotective effects of trimetazidine during off-pump coronary artery bypass grafting. Henan Med Res 2014;23:29-31.  Back to cited text no. 14
    
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Wang H, Hu D, Jia S. The cardioprotective efficacy of TMZ during coronary artery bypass graft surgery. Chin J Med Guide 2003;5:017.  Back to cited text no. 15
    
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Wang CC, Reusch JE. Diabetes and cardiovascular disease: Changing the focus from glycemic control to improving long-term survival. Am J Cardiol2012;110:58-68B.  Back to cited text no. 16
    
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Chiha M, Njeim M, Chedrawy EG. Diabetes and coronary heart disease: A risk factor for the global epidemic. Int J Hypertens2012;2012:697240.  Back to cited text no. 17
    
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Belardinelli R, Cianci G, Gigli M, Mazzanti M, Lacalaprice F. Effects of trimetazidineon myocardial perfusion and left ventricular systolic function in type 2 diabetic patients with ischemic cardiomyopathy. J Cardiovasc Pharmacol2008;51:611-5.  Back to cited text no. 18
    
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Rosano GM, Vitale C, Sposato B, Mercuro G, Fini M. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: A double blind placebo controlled study. Cardiovasc Diabetol2003;28;2:16.  Back to cited text no. 19
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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