HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) 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 Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tünerir, B. Articles by Aslan, R. Search for Related Content PubMed PubMed Citation Articles by Tünerir, B. Articles by Aslan, R.

Ann Thorac Surg 1999;68:2173-2176
© 1999 The Society of Thoracic Surgeons

---

Original Articles: Cardiovascular

Measurement of troponin T to detect cardioprotective effect of trimetazidine during coronary artery bypass grafting

Bülent Tünerir, MD^a, Ömer Çolak, MD^b, Özkan Alata, MD^b, Yavuz Beogul, MD^a, Tugrul Kural, MD^a, Recep Aslan, MD^a

^a Department of Cardiovascular and Thoracic Surgery, Osmangazi University Medical School and Research Hospital, Eskiehir, Turkey
^b Department of Biochemistry, Osmangazi University Medical School and Research Hospital, Eskiehir, Turkey

Address reprint requests to Dr Tünerir, Hasan Polatkan Bulvari, Akin Sitesi A Blok No. 122, D: 19, Eskiehir, 26120, Turkey
e-mail: utuneri1{at}akbank.com.tr

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. The aim of the present study was to evaluate potential myocardial protection by trimetazidine by measurement of the cardiac marker protein troponin T (TnT) during coronary bypass operations.

Methods. We conducted a double-blind, placebo-controlled study on 30 randomized patients who had aorta-coronary artery bypass operations. The TMZ group was composed of 15 patients and the placebo group of 15 patients in New York Heart Association class III or IV. Pretreatment was started 3 weeks preoperatively with trimetazidine (60 mg orally per day) or the placebo. In the trimetazidine TMZ group, there were 2 women and 13 men with a mean age of 57.1 ± 2.2 years and mean cross-clamp time of 44 ± 1.8 minutes. In the placebo group, there were 5 women and 10 men with a mean age of 58.4 ± 1.2 years and a mean cross-clamp time of 42 ± 2.4 minutes. Serial blood samples were collected before and after the operation, and serum concentrations of cardiac TnT were measured.

Results. The preoperative serum concentration of TnT was 0 to 0.39 ng/mL in all patients. The mean TnT levels were measured 5 minutes after completion of cardiopulmonary bypass (1.5 ± 0.3 ng/mL) and 12 (1.4 ± 0.1 ng/mL), 24 (0.9 ± 0.1 ng/mL), and 48 hours postoperatively (0.1 ± 0.1 ng/mL) in the trimetazidine group. Troponin T levels in the placebo group measured at the same time periods were 4.4 ± 0.4, 4.8 ± 0.7, 2.8 ± 0.4, and 0.7 ± 0.1 ng/mL. In the trimetazidine group, TnT levels were significantly less than those of the placebo group (p < 0.001). The levels of TnT were tested by creatine kinase-MB levels of both groups. Mean cardiac index was evaluated in all patients preoperatively and postoperatively. There was no significant difference in perioperative hemodynamics (blood pressure and cardiac index) between groups.

Conclusions. These results obtained by measurement of cardiac TnT suggested that pretreatment with trimetazidine reduces ischemic-reperfusion damage during coronary bypass operations but did not affect postoperative hemodynamics.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Reperfusion injury remains the most uncontrolled phenomenon during cardiac operations. There is no doubt that the benefit of reperfusion can cause serious arrhythmias, myovascular damage, new necrosis, mechanical stunning, and low cardiac output syndrome after cardiopulmonary bypass. Advances in cell biology of cardiomyocytes have been remarkable in recent years. However, it is still impossible to monitor all the events that occur in these cells, especially in relation to their function and dysfunction.

An anti-ischemic drug trimetazidine is a 1-(2,3,4 trimethoxybenzyl) piperazine dihydrochloride salt (C₁₄H₂₂O₃N₂, 2 HCl) that has cardioprotective effects without inducing any significant hemodynamic changes [1, 2]. Its anti-ischemic effect has been assessed both experimentally [3] and clinically [4, 5].

Cardiac troponin T (TnT) is one of the contractile proteins of the myocardium. Its release into the circulation indicates various degrees of myocardial cell damage. Determination of cardiac TnT provides the highest diagnostic efficiency for detecting myocardial cell necrosis [6].

The aim of the present double-blind, placebo controlled study was to evaluate the potential myocardial protective effects of trimetazidine pretreatment by measuring the cardiac marker protein TnT during coronary bypass operations.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Patients
Cardioplegic ischemic arrested heart during open heart operations is the best model of myocardial ischemia. A total of 30 patients with coronary artery disease who had elective aortocoronary bypass operations on two or three vessels were randomly assigned to trimetazidine or placebo. All patients were in New York Heart Association functional class III or IV. The study was approved by the ethics committee. All patients had been given information about the study protocol. Because of the its optimal dose and optimal time period of pretreatment, during the 3 weeks preoperatively, patients received trimetazidine orally 60 mg per day or a placebo [2, 7]. In the TMZ group, there were 15 patients (2 women and 13 men) with a mean age of 57.1 ± 2.2 years and a mean cross-clamp time of 44 ± 1.8 minutes. In the placebo group, there were 5 women and 10 men with a mean age of 58.4 ± 1.2 years and a mean cross-clamp time of 42 ± 2.4 minutes. The clinical characteristics of all patients are shown in Table 1. The groups had similar clinical characteristics. There was no difference in age or body surface area. Poor ventricular ejection fraction (< 35%) was found in 2 patients of the control group and 3 of the study group. Four patients in the TMZ group had had previous myocardial infarction (MI). However, 3 patients in the placebo group had had previous MI. There was no hospital mortality.

Hemodynamic measurements
Standard radial, central venous, and Swan-Ganz catheters were inserted preoperatively. Cardiac output and cardiac index were measured before and 30 minutes after CPB by using the thermodilution technique (Hemopro1; Spectramed Inc, Oxnard, CA).

Metabolic studies
Serial blood samples were collected preoperatively (venous), 5 minutes after completion of CPB (right atrium) and 12, 24, and 48 hours postoperatively (venous). Serum concentration levels of cardiac TnT were measured by a commercially available enzyme-linked immunosorbent assay kit (Enzymum Test System ES 22; Boehringer Mannheim, Mannheim, Germany) in collected samples. The enzyme activities were determined by continuous monitoring using ultraviolet methods in a Hitachi 911 analyzer (Hitachi Co, Japan). In the same time, serum creatine kinase-MB (CK-MB) activities were measured in these samples.

Statistical analysis
The data were expressed as mean ± standard error of the mean. The significance in the difference for these results in the two groups was determined using the unpaired Student’s t test and analysis of variance. A p value of 0.05 or less was considered significant.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
There were no differences in age or body-surface area between the two groups. The cross-clamping time and left ventricular ejection fraction did not differ statistically in the two groups (Table 1).

At all times after completion of CPB, the serum concentrations of TnT in both groups were significantly higher than those before CPB (p < 0.001). These data clearly showed that when the cross clamp is applied to the aorta the unfavorable ischemic effects of CPB are induced. The CK-MB levels of the both groups also supported these results (p < 0.001).

The preoperative serum concentration of TnT values increased postoperatively, peaked by 12 hours, and started to decline by 24 hours in the placebo group. In the TMZ group, they reached a peak by 5 minutes after completion of CPB and started to decline by 12 hours (Figs 1 and 2). Levels of serum cardiac TnT at several sampling times in the two groups are presented in Table 2. The preoperative serum concentrations of TnT were 0 to 0.39 ng/mL in all patients.

View larger version (16K): [in this window] [in a new window]   Fig 1. Comparison of the cardiac troponin T levels between the trimetazidine and placebo groups.

View larger version (16K): [in this window] [in a new window]   Fig 2. Comparison of the creatine kinase-MB levels between the trimetazidine and placebo groups.

Ischemia-reperfusion damage of the myocardium was also monitored by creatine phosphokinase-MB levels of both groups. Serum creatine kinase-MB activity reached peak values at 5 hours after completion of CPB and 12 hours postoperatively in most patients in the placebo group. However, its activity reached peak level at 5 minutes after completion of CPB in the TMZ group. There was no difference in CK-MB levels between the two groups preoperatively (p > 0.05). In the control group, mean CK-MB values were 118.8 ± 6.5 IU/L 5 minutes after completion of CPB, 111 ± 8.3 IU/L at 12 hours, 84 ± 8.5 IU/L at 24 hours, and 37.5 ± 2.9 IU/L at 48 hours postoperatively (p > 0.05). In the TMZ group, these values were 59.1 ± 5.7 (p < 0.001), 49.4 ± 5.3 (p < 0.001), 41.3 ± 4.5 (p < 0.001), and 30.5 ± 2.5 IU/L (p > 0.05). In the study group, CK-MB levels were less than those of the control group (Fig 2).

In the study group, the mean cardiac index (CI) was 2.38 ± 0.12 L/m² per minute preoperatively and 2.41 ± 0.02 L/m² per minute postoperatively. These values in the control group were 2.27 ± 0.07 and 2.31 ± 0.11 L/m² per minute, respectively. When hemodynamic data were compared, there were no significant differences in mean arterial pressure and cardiac index between groups.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Despite surgical and pharmacologic advances in myocardial preservation, myocardial reperfusion damage remains the most uncontrolled aspect of cardiac operations. Reperfusion is frequently accompanied by various symptoms grouped under the heading of reperfusion syndrome or reperfusion injury [8]. Functional recovery therefore is not immediate, but usually appears after a period of contractile dysfunction (myocardial stunning) lasting for several hours or even days after the start of reperfusion. The cellular mechanisms underlying the reperfusion syndrome might involve depletion of high-energy phosphates, over production of oxygen-derived free radicals, damage of cell membrane and mitochondria, calcium accumulation in myocardium, and acidosis [2–4]. Numerous pharmacologic studies have attempted to detect or limit such reperfusion injury and consequently prevent stunning and reperfusion-induced arrhythmias [1–4, 9].

In the past several decades, serum levels of cardiac enzymes and isoenzymes have become the final arbiters by which myocardial damage is diagnosed or excluded. Because conventionally used enzymes are neither perfectly sensitive nor specific, there is a need for a new sensitive and specific marker of myocardial damage. With the development of a new one-step enzyme immunoassay for cardiac TnT by Katus and coworkers [10], a much more cardiac specific and sensitive method for detection of perioperative myocardial ischemic injury is now available. Cardiac troponin T, a myofibrillar protein present in the contractile apparatus, is composed of two myofilaments, a thick one consisting of myosin and thin one composed of actin, tropomyosin, and troponin. Troponin is a protein complex consisting of three subunits, troponin T, troponin I, and troponin C. Troponin T is a regulatory protein that helps the heart muscle contract. It can be differentiated by immunologic methods from its skeletal-muscle isoform. An enzyme immunoassay specific for cardiac TnT is now available in a commercial kit for routine use [10]. Troponin T measurements, however, are also highly sensitive in the diagnosis of myocardial injury and accurately detect even small amounts of myocardial necrosis [11]. Troponin T levels start to increase a few hours after the onset of myocardial damage and remain increased for several days [12]. For this reason, in the present study, we measured serum cardiac TnT levels to detect the cytoprotective effect of TMZ during ischemia and reperfusion. The best model of myocardial ischemia and reperfusion is the cardioplegic ischemic-arrested heart during open heart operation. All study patients received preoperative oral TMZ for myocardial protection against the reperfusion injury.

A number of experimental and clinical studies [1, 3, 7] in this field have shown that TMZ exerts direct anti-ischemic effects, limiting calcium accumulation and acidosis, inflammation, and oxygen-derived free radical production after reperfusion. Although these metabolic effects are not clear, recently there have been reports of mitochondrial protection against oxidative stress damage [13]. Lavanchy and associates [14] showed that adenosine triphosphate and phosphocreatine levels in hearts treated with TMZ were significantly superior to those in the control hearts during reperfusion. Trimetazidine prevents depletion of high-energy phosphates, reduces acidosis, and enhances phosphorylation activity of the mitochondria from the beginning of reperfusion, thus allowing resumption of oxidative phosphorylation and resynthesis of phosphocreatine [1, 13]. Maridonneau-Parini and Harpey [15] reported that TMZ protects against oxygen free radical damage to the cell membrane. Guarnieri and colleagues [16] demonstrated that TMZ reduced superoxide production by mitochondria. Ruiz-Meana and associates [17] reported that preincubation of cardiomyocytes with TMZ did not prevent rigor contracture induced by metabolic inhibition or hypercontracture during subsequent reoxygenation, but did improve sarcolemmal resistance to reoxygenation-induced mechanical stress. Such studies could help to explain the beneficial effects of TMZ during ischemia-reperfusion injury. Fabiani and associates [7] measured CK-MB, myoglobin, malondialdehyde (MDA) levels, and hemodynamic variables to detect the cardioprotective effect of TMZ in patients who had coronary artery bypass grafting. They found that pretreatment with TMZ had a cardioprotective effect but did not improve postoperative hemodynamics.

In the present study, we found significantly lower cardiac TnT levels in the TMZ pretreatment group than in the placebo group (p < 0.001). We demonstrated the anti-ischemic effect of TMZ by using a new cardiospecific marker, cardiac TnT, for reperfusion injury. However, we cannot explain its anti-ischemic cellular mechanism on the basis of our data.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

1. Harpey C., Clauser P., Labrid C., Freyria J.L., Poirier J.P. Trimetazidine, a cellular anti-ischemic agent. Cardiovasc Drug Rev 1988;6:292-312.
2. Detry J.M., Sellier P., Pennaforte S., et al. Trimetazidine. Br J Clin Pharmacol 1994;37:279-288.[Medline]
3. Lavanchy N., Martin J., Rossi A. Anti-ischemic effects of trimetazidine; 31 P-NM5 spectroscopy in the isolated rat heart. Arch Intern Pharmacodyn Ther 1987;286:97-110.
4. Kober G., Buck T., Sievert H., Vallbracht C. Myocardial protection during percutaneous transluminal coronary angioplasty. Eur Heart J 1992;13:1109-1115.[Abstract/Free Full Text]
5. Bricaud H., Brottier L., Barat J.L., Combe C., Boussens B., Bonnet J. Cardioprotective effect of trimetazidine in severe ischemic cardiomypathy. Cardiovasc Drugs Ther 1990;4(Suppl 4):861-865.
6. Triggiani M., Simeone F., Gallorini C., et al. Measurement of cardiac troponin T and myosin to detect perioperative myocardial damage during coronary surgery. Cardiovasc Surg 1994;2:441-445.[Medline]
7. Fabiani J.N., Ponzio O., Emerie I., et al. Cardioprotective effect of trimetazidine during coronary artery graft surgery. J Cardiovasc Surg 1992;33:486-491.[Medline]
8. Aslan R., Tünerir B., Dernek S., et al. The factors effecting complement activation in open heart surgery. J Cardiovasc Surg 1992;33:754-760.[Medline]
9. Dernek S., Tünerir B., Sevin B., Aslan R., Uyguç Ö., Kural T. The effects of methylprednisolone on complement, immunoglobulins and pulmonary neutrophill sequestration during cardiopulmonary bypass. Cardiovasc Surg 1999;7:414-418.[Medline]
10. Katus H.A., Loser S., Hallermayer K., et al. Development and in vitro characterization of a new immunoassay of cardiac troponin T. Clin Chem 1992;38:386-393.[Abstract/Free Full Text]
11. Mair P., Mair J., Seibt I., et al. Cardiac troponin T. J Cardiothorac Vasc Anesth 1993;7:674-678.[Medline]
12. Mair J., Dienstl F., Puschendorf B. Cardiac troponin T in diagnosis of myocardial injury. Crit Rev Clin Lab Sci 1992;29:31-57.[Medline]
13. Veitch K., Maisin L., Hue L. Trimetazidine effects on the damage to mitochondrial functions caused by ischemia and reperfusion. Am J Cardiol 1995;76:25-30.
14. Lavanchy N., Martin J., Rossi A. Trimetazidine preservation of the energy potential of the myocardium during ischemia and reperfusion. Phosphorus NMR spectroscopy study of the isolated heart. Presse Med 1986;15:1758-1761.
15. Maridonneau-Parini I., Harpey C. Trimetazidine protects the human red blood cell against oxygen free radical damage. Cardiovasc Drugs Ther 1990;4:818-819.
16. Guarnieri C., Finelli C., Zini M., Muscari C. Effects of trimetazidine on the calcium transport and oxidative phosphorylation of isolated rat heart mitochondria. Basic Res Cardiol 1997;92:90-95.[Medline]
17. Ruiz-Meana R.M., Garcia-Dorado G.D., Julia M., Gonzalez M.A., Inserte J., Soler-Soler J. Pre-treatment with trimetazidine increases sarcolemmal mechanical resistance in reoxygenated myocytes. Cardiovasc Res 1996;32:587-592.[Medline]

This article has been cited by other articles:

				T. Doenst, H. Bugger, M. Schwarzer, G. Faerber, M. A. Borger, and F. W. Mohr Three good reasons for heart surgeons to understand cardiac metabolism Eur J Cardiothorac Surg, May 1, 2008; 33(5): 862 - 871. [Abstract] [Full Text] [PDF]

				D. Abramov, M. Abu-Tailakh, M. Frieger, A. Ganiel, D. Tuvbin, and A. Wolak Plasma Troponin Levels After Cardiac Surgery vs After Myocardial Infarction Asian Cardiovasc Thorac Ann, December 1, 2006; 14(6): 530 - 535. [Abstract] [Full Text] [PDF]

				F. Eefting, B. Rensing, J. Wigman, W. J. Pannekoek, W. M. Liu, M. J. Cramer, D. J Lips, and P. A Doevendans Role of apoptosis in reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 414 - 426. [Abstract] [Full Text] [PDF]

				N. Danchin Recent advances in cardioprotection during myocardial revascularization procedures: benefit of a metabolic intervention Eur. Heart J. Suppl., November 1, 2001; 3(suppl_O): O21 - O25. [Abstract] [PDF]

This Article Abstract Full Text (PDF) 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 Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tünerir, B. Articles by Aslan, R. Search for Related Content PubMed PubMed Citation Articles by Tünerir, B. Articles by Aslan, R.