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Right arrow Myocardial protection

Ann Thorac Surg 2001;72:571-576
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Peroxynitrite formation from human myocardium after ischemia-reperfusion during open heart operation

Yoshitaka Hayashi, MDa, Yoshiki Sawa, MDa, Shigeaki Ohtake, MDa, Naoto Fukuyama, MDb, Hiroe Nakazawa, MDb, Hikaru Matsuda, MDa

a Department of Surgery, Course of Interventional Medicine (E1), Osaka University Graduate School of Medicine, Osaka, Japan
b Second Department of Physiology, Tokai University School of Medicine, Kanagawa, Japan

Accepted for publication March 27, 2001.

Address reprint requests to Dr Sawa, Department of Surgery, Course of Interventional Medicine (E1), Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
e-mail: sawa{at}surg1.med.osaka-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
Background. Current experimental studies have demonstrated that peroxynitrite (ONOO-) has both cytotoxic and cytoprotective effects on myocardial ischemia-reperfusion injury. However, even myocardial ONOO- formation has not yet been investigated in humans undergoing open heart operation. We measured plasma nitrotyrosine as an indicator of ONOO- formation during open heart operation and examined its association with myocardial ischemia-reperfusion injury.

Methods. Twenty adult patients undergoing mitral valve replacement under cardiopulmonary bypass between 1997 and 1998 were enrolled in this study (6 men and 14 women). Arterial blood (Ao) and coronary sinus effluent (CS) were obtained: (1) before the initiation of cardiopulmonary bypass, (2) just after aortic unclamping, (3) at 5 minutes, (4) at 10 minutes, (5) at 15 minutes, and (6) at 20 minutes after aortic unclamping.

Results. At every sampling point after reperfusion, plasma nitrate and nitrite was significantly lower in CS than in Ao, and the percentage ratio of nitrotyrosine to tyrosine (%NO2-Tyr; an index of ONOO- formation) was significantly higher in CS than in Ao. The CS-Ao difference in %NO2-Tyr, myocardium-derived ONOO-, reached its peak at 5 minutes after reperfusion (2.17 ± 0.74%), which was significantly correlated with the peak CS-Ao difference in plasma malondialdehyde, and with postoperative maximum creatine kinase-MB.

Conclusions. These results first demonstrate that ONOO- is produced from human myocardium after ischemia-reperfusion during open heart operation, and myocardium-derived ONOO- can be determined by the CS-Ao difference in %NO2-Tyr.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Recent experimental studies have demonstrated that supplement of nitric oxide (NO) donor attenuates myocardial ischemia-reperfusion injury and have suggested that the impairment of NO synthase (NOS) after a period of ischemia plays a crucial role in the development of myocardial ischemia-reperfusion injury [1, 2]. However, NO production as a whole increases during and after open heart operation [3, 4]. This is mainly because cardiopulmonary bypass (CPB) results in the mechanical stimulation of the vascular wall and blood contact with artificial surfaces of the bypass circuit, which activates endothelial-constitutive NOS (ecNOS) [3] and subsequently expresses inducible NOS (iNOS) [4]. On the other hand, ischemic myocardium produces a large amount of superoxide anion (O2-) during reperfusion [5]. O2- rapidly reacts with NO to form peroxynitrite (ONOO-) [6].

The roles of ONOO- in myocardial reperfusion injury remain controversial, and both cytoprotective and cytotoxic effects have been demonstrated in current experimental studies [7–10]. However, even myocardial ONOO- formation has not yet been investigated in humans undergoing open heart operation. It is partially because ONOO- has a very short half-life in vivo [6] and its plasma fraction is difficult to measure.

3-nitro-L-tyrosin (nitrotyrosine), which is generated by the nitration of L-tyrosine (tyrosine) residues by ONOO- [11], is considered to be a good marker for ONOO--induced tissue damage [12] because it is relatively stable and can be measured readily. Thus, we have measured nitrotyrosine formation as an indicator of ONOO- production in various clinical situations [13, 14].

ONOO- is a potent oxidant that directly oxidizes sulfhydryl groups at a 1,000-fold greater rate than does hydrogen peroxide [15], and it inhibits the function of various enzymes, including mitochondrial electron transport chain components [16]. Its protonated form, peroxynitrous acid (ONOOH), initiates lipid peroxidation and may contribute to the oxidation of plasma lipoprotein [17]. This is one of the cytotoxic effects of ONOO-, which may affect myocardial lipid peroxidation. In this study, we measured nitrotyrosine formation in the blood of patients undergoing open heart operation and examined the association with myocardial lipid peroxidation in order to elucidate whether ONOO- is produced from human myocardium after ischemia-reperfusion during open heart operation.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
Study population
Twenty patients who underwent elective mitral valve replacement under tepid-thermic CPB in our institution in 1997 and 1998 were enrolled in this study. Six were men and 14 were women, and their ages at operation ranged from 24 to 72 years with a mean of 58.5 ± 11.6 years. Eleven had mitral valve stenosis, 8 had mitral regurgitation, and 1 had both. All showed normal coronary arteries on coronary angiography, and none received nitroglycerin before, during, or after CPB for the duration of the study period. All patients gave their informed consent for this study, and we followed the guidelines of our internal review board.

The CPB circuit was composed of a centrifugal pump, a membrane oxygenator, an arterial filter, a venous reservoir, and tubing lines, which were primed without blood components. No components of the CPB circuit were heparin-coated. Heparin at a dose of 3 mg/kg was infused, and CPB was instituted in a routine fashion. Two venous cannulas were placed directly into the superior vena cava and the inferior vena cava, and an arterial cannula was positioned directly into the ascending aorta.

Anesthesia was induced and maintained with diazepam (0.4 mg/kg), fentanyl (50 µg/kg), and inhaled isoflurane via endotracheal intubation. To reduce CPB-induced inflammatory response, nafamostat mesilate (FUT-175; Torii Pharmaceutical, Co, Tokyo, Japan) [18] or aprotinin (Trasylol; Bayer Pharmaceutical, Co, Leverkusen, Germany) [19] was used. No steroids were used in any of the patients [20]. In cases of a first open heart operation (n = 13), nafamostat mesilate, which is a serine protease inhibitor, was added at a dose of 1 mg/kg into the venous reservoir at the initiation of CPB, and was administered continuously during CPB at a dose of 0.5 mg/kg/h. In cases of a redo open heart operation (n = 7), 300,000 units of aprotinin was added into the venous reservoir at the initiation of CPB.

CPB was controlled by {alpha}-stat management with blood-flow rates of 2.2 to 2.6 L/min/m2 to maintain mean arterial pressure between 60 and 80 mm Hg, using vasoactive agents such as chlorpromazine hydrochloride and norepinephrine if necessary. We measured the temperature of blood in the arterial line just after it passed through the heat exchanger and controlled it at 34°C.

The myocardial protection was performed systemically in the same way for all patients [21]. Cardiac arrest was achieved by aortic cross-clamping and an initial antegrade administration of cold blood cardioplegia solution (blood/crystalloid = 2:1, 16 mEq/L potassium and 0.8 to 1.0 mEq/L calcium) at a volume of 10 mL/kg body weight. Intermittent retrograde cardioplegia infusion (blood/crystalloid = 4:1) of 5 mL/kg body weight was done every 20 minutes. The temperature of the cardioplegia solution was measured in the cardioplegia line just after it passed through the heat exchanger and was maintained at 15 to 20°C. The myocardial temperature at the ventricular septum was monitored and maintained below 20°C by additional infusions of retrograde cardioplegia. Terminal warm blood cardioplegia, with or without depletion of leukocytes, was not applied in any of these patients [22].

Patient characteristics, including both preoperative and perioperative variables, are shown in Table 1.


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  		Table 1. Cardiopulmonary Bypass Data From the 20 Study Patients

 
Measurements
Arterial blood from aortic root (Ao) and coronary sinus effluent blood (CS) were obtained simultaneously: (1) before the initiation of CPB, (2) just after aortic unclamping, (3) at 5 minutes, (4) at 10 minutes, (5) at 15 minutes, and (6) at 20 minutes after aortic unclamping. We measured plasma levels of nitrate and nitrite, nitrotyrosine and tyrosine, and malondialdehyde (MDA) at each of these time points.

Plasma nitrate and nitrite was measured as a marker of NO production. The obtained plasma fraction was diluted 1:1 with nitrite and nitrate-free distilled water. Subsequently, 400 µL of diluted plasma was ultrafiltered at 2000 g (Ultrafree MC microcentrifuge device, UFC3 LGC; Millipore, Bedford, MA). The filtrates were analyzed by an automated procedure based on the Griess reaction [23].

We measured nitrotyrosine formation as an indicator of ONOO- production using a high-pressure liquid chromatography (HPLC) method previously described [14]. The plasma filtrates were hydrolyzed for 24 hours, and the supernatant was analyzed by HPLC with a C-18 reverse-phase column (Jasco, Tokyo, Japan); peak concentrations were measured with an ultraviolet detector set at 274 nm (UV-970; Jasco). The peak was identified on the basis of the retention time of authentic nitrotyrosine or tyrosine. ONOO- production was measured as the formation of nitrotyrosine from tyrosine and expressed as the percentage ratio of nitrotyrosine to tyrosine (nitrotyrosine/tyrosine + nitrotyrosine x 100%; %NO2-Tyr). The difference in %NO2-Tyr between CS and Ao (%NO2-Tyr:CS-Ao) was used as an index of ONOO- produced from myocardium [14].

Malondialdehyde (MDA) reflects both autooxidation and oxygen radical-mediated peroxidation of unsaturated fatty acids, and the difference in MDA between CS and Ao (MDA:CS-Ao) has been generally used as an index of myocardial lipid peroxidation [24]. Thus, we measured the levels of MDA in Ao and CS using the ion-pairing HPLC method Lazzarino and associates previously described [24]. Briefly, the obtained plasma fraction was acidified with 60% perchloric acid to break off the Schiff’s base potentially formed by the interaction of MDA and amino acid or amino groups of protein. The extracts were neutralized and used for direct HPLC analysis of MDA.

Postoperatively, arterial blood was obtained every 6 hours, and plasma creatine kinase-MB (CK-MB) was measured by immunoinhibition assay. The peak level during the first 24 postoperative hours (max CK-MB) was used as a marker of myocardial injury [25].

Statistical analysis
All data are expressed as mean ± standard deviation. Comparisons between groups (Ao and CS) were analyzed by paired Student’s t test. Repeated-measures analysis of variance was used to test the time-dependent changes. The Pearson’s correlation coefficient test and a linear regression analysis were performed between the peak level of %NO2-Tyr:CS-Ao and other parameters: CPB time, aortic cross-clamping (ACC) time, the peak level of MDA:CS-Ao, and the max CK-MB. All analyses were performed with the Statview v5.0 statistical package (Abacus Concepts Inc, Berkeley, CA). A p value less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
Clinical outcome
All patients in this study tolerated the surgical procedures and survived without any complications.

Plasma nitrate and nitrite
There were significant time-dependent changes in plasma nitrate and nitrite levels (NOx) in Ao and CS (p < 0.0001, analysis of variance, treatment effect). At every sampling point after aortic unclamping, NOx in both Ao and CS were significantly higher than before CPB, and NOx in CS was significantly lower than that in Ao (Table 2).


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  		Table 2. Changes in Plasma Nitrate and Nitrite and the Percentage Ratio of Nitrotyrosine to Tyrosine in the Arterial Blood and Coronary Sinus Effluent

 
Nitrotyrosine (peroxynitrite) formation
Nitrotyrosine was not detected in the supernatant obtained before CPB in either Ao or CS, but was detected after aortic unclamping in both Ao and CS. There were significant time-dependent changes in %NO2-Tyr in Ao and CS (p < 0.0001, analysis of variance, treatment effect), and %NO2-Tyr was significantly higher in CS than in Ao at every sampling point after reperfusion (Table 2). %NO2-Tyr:CS-Ao reached its peak at 5 minutes after reperfusion (Fig 1). There was a significant correlation between the peak %NO2-Tyr:CS-Ao and CPB time (correlation = 0.761, p < 0.0001), and between the peak %NO2-Tyr:CS-Ao and ACC time (correlation = 0.868, p < 0.0001). The scattergrams and the results of a linear regression analysis are shown in Figure 2.



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  		Fig 1. The CS-Ao difference in %NO2-Tyr (%NO2-Tyr: CS-Ao) before CPB and after myocardial reperfusion. Data are expressed as mean ± SD. **p < 0.01 vs value of last sampling point. (Ao = aortic root; CPB = cardiopulmonary bypass; CS = coronary sinus.)

 


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  		Fig 2. There is a significant correlation between (A) the peak CS-Ao difference in %NO2-Tyr and CPB time (%NO2-Tyr = -0.272 + 0.014 x CPB time, r2 = 0.579 [slope = 0.014, SE = 0.003, p < 0.0001]), and (B) the peak CS-Ao difference in %NO2-Tyr and ACC time (%NO2-Tyr = -0.159 + 0.019 x ACC time, r2 = 0.753 [slope = 0.019, SE = 0.003, p < 0.0001]). (ACC = aortic cross-clamping time; Ao = aorta; CPB = cardiopulmonary bypass; CS = coronary sinus).

 
Malondialdehyde
Malondialdehyde (MDA) was not detected in the plasma fraction obtained before CPB in either Ao or CS, but was detected after aortic unclamping in both Ao and CS. There were significant time-dependent changes in MDA:CS-Ao (p < 0.0001, analysis of variance, treatment effect), and MDA:CS-Ao reached its peak at 5 minutes after reperfusion, similar to the pattern of %NO2-Tyr:CS-Ao (just after aortic unclamping, 1.89 ± 0.72 µmol/L; at 5 minutes, 2.35 ± 0.97 µmol/L; at 10 minutes, 2.03 ± 0.83 µmol/L; at 15 minutes, 1.32 ± 0.57 µmol/L; and at 20 minutes, 0.92 ± 0.46 µmol/L). There was a significant correlation between the peak %NO2-Tyr:CS-Ao and the peak MDA:CS-Ao (correlation = 0.822, p < 0.0001). The scattergrams and the results of a linear regression analysis are shown in Figure 3.



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  		Fig 3. Relation between the peak CS-Ao difference in %NO2-Tyr and the peak CS-Ao difference in MDA. (MDA = -0.004 + 1.08 x %NO2-Tyr, r2 = 0.676 [slope = 1.080, SE = 0.176, p < 0.0001]). (Ao = aortic root; CS = coronary sinus; MDA = malondialdehyde.)

 
Maximum 24-hour postoperative CK-MB
The maximum CK-MB was 15.8 ± 7.6 IU/L, and there was a significant correlation between the peak %NO2-Tyr:CS-Ao and maximum CK-MB (correlation = 0.786, p < 0.0001). The scattergrams and the results of a linear regression analysis are shown in Figure 4.



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  		Fig 4. Relation between the peak CS-Ao difference in %NO2-Tyr and maximum value of CK-MB. (max CK-MB = -1.759 + 8.076 x %NO2-Tyr, r2 = 0.618 [slope = 8.076, SE = 1.496, p < 0.0001]). (ACC = aortic cross-clamping time; Ao = aorta; CK-MB = creatinine kinase-MB; CS = coronary sinus).

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
We measured the plasma concentration of nitrotyrosine during open heart operation, and considered the CS-Ao difference in %NO2-Tyr as myocardial-derived ONOO- formation. Although there are some limitations to elucidate ONOO- formation and clarify its cytological role in myocardial ischemia-reperfusion injury, the present study design may resolve them.

Myocardium is subjected to ischemia during aortic cross-clamping, whereas other organs are supplied with oxygenated blood by CPB. In the development of CPB-induced inflammatory response, abnormal release of free radicals [26] and enhanced NO production are induced [3, 4], which can react with each other to form ONOO-. On the other hand, several current studies demonstrated another pathway to form nitrotyrosine that we considered as an indicator of ONOO- production. For example, Eiserich and associates have suggested that nitrite, a major end product of NO, can also promote tyrosine nitration in the presence of myeloperoxidase in polymorphonuclear neutrophils [27], and Faymonville and associates demonstrated that myeloperoxidase is a marker of neutrophil activation during CPB [28]. In the present study, nitrotyrosine was also detected in Ao, and the amount of nitrotyrosine in CS may be affected by CPB-induced nitrotyrosine production. However, the CS-Ao difference in %NO2-Tyr is not affected by CPB-induced free radicals and myeloperoxidase, and it is supposed to relatively well reflect myocardium-derived ONOO- production.

In the present study, the lowest NO in CS and the highest CS-Ao difference in %NO2-Tyr were observed at 5 minutes after myocardial reperfusion, and the peak CS-Ao difference in %NO2-Tyr was correlated with the peak CS-Ao difference in MDA and the postoperative maximum plasma CK-MB level. These findings may suggest that the degree of myocardial ischemia-reperfusion injury is determined soon after myocardial reperfusion. In a myocardial-ischemia model using isolated rat hearts, Tsao and coworkers demonstrated that endothelial damage occurred very early after reperfusion [29], with which our results are nearly consistent.

Lipid peroxidation is one of the cytotoxic effects of ONOO- [8], but ONOO- has various cytotoxic effects other than lipid peroxidation. Landino and associates, for example, demonstrated that ONOO- stimulates the cyclooxygenase activities of prostaglandin endoperoxide synthases [30]. Prostaglandin is thought to be one of the CPB-induced chemotactic mediators [26], participating in enhancing myocardial injury after open heart operations [31, 32]. On the other hand, the cytoprotective effects of ONOO- have been demonstrated [9, 10], and ONOO- is considered to be bioconverted to nitrosoglutathione by interactions with glutathione in a blood environment [10]. The present study has demonstrated that the peak CS-Ao difference in %NO2-Tyr was correlated with the degree of myocardial ischemia-reperfusion injury. However, these results suggest that ONOO- production may be an adaptive response to myocardial ischemia-reperfusion injury, and do not necessarily elucidate that ONOO- plays a cytotoxic role in the development of myocardial ischemia-reperfusion injury. The cytological effects of ONOO- on the development of myocardial ischemia-reperfusion injury during open heart operation remains controversial, and further studies are needed to elucidate the role of ONOO- in myocardial ischemia-reperfusion injury during open heart operation.

There has been no clinical investigation about ONOO- formation despite its various cytological effects on myocardial ischemia-reperfusion injury under experimental situations. It remains unclear whether ONOO- should be supplied or eliminated for attenuating myocardial ischemia-reperfusion injury. The present study first investigated ONOO- formation in humans undergoing open heart operation. Although this method of measuring ONOO- may be useful only in the evaluation of perioperative myocardial injury at present, it seems applicable to elucidating the cytological effect of myocardium-derived ONOO- during open heart operation.

In summary, we demonstrated clinically for the first time that ONOO- was produced from human myocardium after ischemia-reperfusion during open heart operation by the measurement of plasma nitrotyrosine in Ao and CS. Although the cytological role of ONOO- in myocardial ischemia-reperfusion injury remains unclear, myocardium-derived ONOO- can be determined by the CS-Ao difference in %NO2-Tyr.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

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