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Ann Thorac Surg 1998;65:1296-1302
© 1998 The Society of Thoracic Surgeons

Intravenous Aspartate Infusion After a Coronary Operation: Effects on Myocardial Metabolism and Hemodynamic State

^a Department of Cardiothoracic Surgery, Linköping Heart Center, University Hospital, Linköping, Sweden
^b Department of Cardiothoracic Anesthesia, Linköping Heart Center, University Hospital, Linköping, Sweden
^c Department of Thoracic Physiology, Karolinska Hospital, Stockholm, Sweden

Accepted for publication December 14, 1997.

Address reprint requests to Dr Svedjeholm, Department of Cardiothoracic Surgery, University Hospital, SE-581 85 Linköping, Sweden
e-mail: (rolf.svedjeholm{at}thx.us.lio.se)

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. In a previous study glutamate infusion after coronary artery bypass grafting was associated with beneficial effects on myocardial metabolism and myocardial performance. It has been claimed that aspartate is more important than glutamate for the recovery of myocardial metabolism after cardioplegic arrest. Therefore, the metabolic and hemodynamic effects of aspartate were studied after coronary artery bypass grafting.

Methods. Fifty to 240 mL of a 0.1 mol/L aspartic acid solution was infused intravenously during 60 minutes in 10 patients early after coronary artery bypass grafting. Myocardial metabolism was studied using the coronary sinus catheter technique.

Results. Aspartate infusion caused a significant increase in the arterial levels of both aspartate and glutamate. This was associated with a significant increase in myocardial uptake of aspartate and a decrease in myocardial uptake of glutamate. Myocardial exchange of other substrates remained unaffected. There were no changes in hemodynamic state except an increase of heart rate and pulmonary vascular resistance.

Conclusions. Interactions with glutamate metabolism, compatible with competitive inhibition of myocardial glutamate uptake, which may have outweighed potential effects of aspartate, were observed. Recognition of these amino acid interactions is important as they are used together as additives in cardioplegic solutions.

	Introduction

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Amino acids, particularly glutamate and aspartate, have been suggested to be important for the recovery of the oxidative metabolism of the heart after ischemia [1–3]. In a previous study intravenous glutamate infusion early after coronary artery bypass grafting (CABG) was associated with beneficial effects on the metabolic state of the heart and improved myocardial performance [4]. On the basis of these data from the isolated rat heart it has been claimed that aspartate may be more important than glutamate for the recovery of myocardial metabolism after cardioplegic arrest [5]. However, little is known about the myocardial requirements of aspartate or the effects of aspartate in humans.

The aim of this study was to investigate whether intravenous aspartate infusion can enhance myocardial aspartate uptake, to get an approximate idea of how much aspartate is required, and to determine whether increased uptake of aspartate is associated with improved myocardial metabolism and function after CABG.

	Material and methods

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Patients
Ten male patients with stable angina pectoris and well preserved left ventricular function, admitted for elective CABG, were included in the study. None of the patients had diabetes mellitus or other major metabolic disorder. Demographic data are as follows: number of patients, 10; age (years), 61 ± 2; weight (kg), 83 ± 4; body surface area (m²), 2.02 ± 0.05; left ventricular ejection fraction, 0.61 ± 0.01; number of grafted vessels, 4.0 ± 0.3; aortic cross-clamp time (minutes), 47 ± 5; cardiopulmonary bypass time (minutes), 91 ± 8; and aspartate aminotransferase day 1 (µkat/L), 2.03 ± 0.22.

Study protocol
The patients were studied starting 1 to 2 hours after completion of operation. Ten patients were given an infusion of 50 to 240 mL of 0.1 mol/L L-aspartic acid during 1 hour. The infusion rates in individual patients are given in Figure 1. No control group was studied as the investigation was carried out as a pilot and data from controls in a previous study using the same experimental setup had demonstrated stable hemodynamic and metabolic conditions during the study period.

View larger version (23K): [in this window] [in a new window]   Fig 1. Arterial aspartate level in individual patients according to whole blood analyses (µmol/L) in the basal state (0), during aspartate infusion (60), and 30 minutes after discontinuation of aspartate (90'). The samples for whole blood analysis of aspartate from one patient who received aspartate 12.5 mg/kg body weight/hour were lost by accident. The infusion rates of aspartate (mg/kg body weight per hour) in the remaining 9 patients are given with the legend to case plots.

Blood samples for free fatty acid analysis were taken in the basal state and at 60 and 90 minutes. Hemodynamic measurements were performed in the basal state, at 30, 60, and 90 minutes. Mainly because of accidental loss of all samples for whole blood analysis of aspartate from 1 patient (patient 2), data for whole blood aspartate were 90% complete at 0, 20, and 90 minutes; 80% complete at 10 and 30 minutes; and 70% complete at 60 minutes. Plasma analyses of aspartate were 100% complete at both 0 and 60 minutes. The remaining data on glutamate, alanine glucose, lactate, and free fatty acids were 100% complete with the exception of flux values at 60 minutes for alanine, lactate, and glucose that were 90% complete.

Catheterization procedure and hemodynamic measurements
The final midcoronary position of the coronary sinus catheter (CCS-7U-90B, Webster Labs, Inc, Altadena, CA) was checked by fluoroscopy and measurement of oxygen saturation [6]. Coronary sinus blood flow (CF 300A, Webster Labs) was determined by retrograde thermodilution technique and the mean value calculated from three measurements.

Biochemical analyses
Whole blood samples were immediately deproteinized with ice-cold perchloric acid [7]. After centrifugation the protein-free extracts were deep-frozen to -70°C. Analysis of aspartate was done fluorometrically by a modified method according to Lowry and Passoneau [8]. The reagents used were 50 mmol/L imidazole-hydrochloride buffer, pH 7.0, 25 mmol/L alpha-ketoglutarate, 5 mmol/L of reduced nicotinamide adenine dinucleotide, and 5 µg/mL malic dehydrogenase (from porcine heart). Briefly, 20 µL of each sample was added to 1,000 µL of reagent and the initial readings were made. The reaction was started by adding glutamate oxalacetic transaminase (10 µg/mL, type I, from porcine heart). Thereafter the samples were incubated in room temperature until the reaction was completed (30 minutes) and the final readings were made. The concentration of aspartate was calculated from measured standard curves, and the mean of duplicate values was used. Glutamate concentration was determined fluorometrically by an adapted glutamate dehydrogenase method [9]. D-Glucose, lactate, and alanine concentrations were also determined fluorometrically [4].

Plasma samples were deproteinized with sulfosalicylic acid and stored at -70°C until analysis. Plasma aspartate and glutamate were analyzed with a conventional amino acid analyzer (Beckman system 6300; Beckman Instruments, Inc, Palo Alto, CA) and the eluted amino acids determined by the ninhydrin-hydantin reaction with S-2-aminoethyl-L-cysteine as internal standard. Free fatty acids were analyzed according to Ho [10].

Both whole blood and plasma analyses were done batchwise, care being taken that corresponding arterial and venous samples were analyzed simultaneously. Oxygen saturation and hemoglobin concentrations were measured in an OSM3 oximeter (Radiometer, Copenhagen, Denmark).

Statistical methods
Statistical analyses were performed with a computerized statistical package (Statistica 5.1; StatSoft, Inc, Tulsa, OK). Because of the small sample sizes nonparametric tests were used for comparisons, the Wilcoxon test for paired observations and the Mann-Whitney U test for unpaired observations. The Spearman rank method was used for analysis of correlation. To overcome the problem with dropped data and to reduce the risk for overinterpretation due to serial measurements, the mean value of summary measures in individual patients during aspartate infusion was also calculated and compared with the basal state using the Wilcoxon test [11]. Statistical significance was defined as a probability value less than 0.05. Data are presented as mean ± standard error of the mean.

Calculations and definitions
Oxygen consumption of the heart was estimated as the product of arterial–coronary sinus blood oxygen content difference and coronary sinus blood flow. Oxygen content of the blood (mmol/L) was calculated according to the formula:

Myocardial flux of glucose, lactate, and alanine was calculated as the product of arterial–coronary sinus blood concentration difference and coronary sinus blood flow. Myocardial flux of free fatty acids was calculated as the product of arterial–coronary sinus plasma concentration difference and coronary sinus plasma flow. Myocardial flux of aspartate and glutamate were calculated based on whole blood analyses and plasma analyses.

A release of substrates was defined as a flux value significantly (p < 0.05) less than zero. An uptake of substrates was defined as a flux value significantly (p < 0.05) greater than zero. The term basal state refers to measurements done immediately before the start of aspartate infusion. Hemodynamic parameters were calculated from standard formulas.

Ethical aspects
The study was performed according to the principles of the Helsinki Declaration of Human Rights, and was approved by the ethics committee for medical research at the University Hospital of Linköping. Informed consent was obtained from each patient.

Clinical management
Clinical management has been described in detail previously [4]. Cardiopulmonary bypass was conducted with a membrane oxygenator and a roller pump generating nonpulsatile flow. A crystalloid fluid containing no glucose or lactate (Ringer’s acetate) was used with the addition of mannitol for priming the extracorporeal circuit. Moderate hemodilution (hematocrit, 25%) and moderate hypothermia (30 to 32°C) was used. Antegrade delivery of St. Thomas cold crystalloid cardioplegic solution was used for myocardial protection. None of the patients received blood during the study period or later in the postoperative course. Shed mediastinal blood was routinely retransfused after operation. According to clinical routines nitroglycerin, and if necessary nitroprusside, was used to prevent postoperative hypertension of more than 150 mm Hg.

	Results

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Clinical course
The postoperative course was uneventful and no side effects of the infusions were seen. None of the patients required inotropic support. None of the patients displayed electrocardiographic or enzymatic signs of perioperative myocardial infarction.

Hemodynamic parameters
There was no change in cardiac index or left ventricular stroke work index during aspartate infusion. The only statistically significant hemodynamic changes during aspartate infusion validated by summary measures were minor to moderate increases in heart rate and pulmonary vascular resistance index. These changes persisted after stopping the infusion (Table 1). There was no significant change in myocardial oxygen uptake or coronary sinus blood flow during the study period.

During aspartate infusion the increase in arterial level of aspartate correlated with the infusion rate (r = 0.48; p < 0.01) and there was also a correlation between arterial aspartate and aortocoronary sinus difference of aspartate (Fig 2; r = 0.66; p < 0.001).

View larger version (15K): [in this window] [in a new window]   Fig 2. Arterial aspartate (whole blood) versus aortocoronary sinus (A-CS) difference of aspartate (whole blood) during the entire study period (0 to 90 minutes). (r = Spearman rank correlation coefficient.)

Glutamate
During aspartate infusion arterial glutamate (whole blood) level increased from 171 ± 7 (basal state) to 231 ± 12 µmol/L at 60 minutes (p < 0.01). In the basal state there was a significant myocardial uptake of glutamate (2.6 ± 0.6 µmol/min; p < 0.01) that was significantly reduced after 10, 20, and 60 minutes of aspartate infusion. Thirty minutes after stopping the aspartate infusion glutamate uptake had returned to preinfusion levels (3.1 ± 0.4 µmol/min).

During aspartate infusion arterial plasma glutamate increased from 104 ± 14 µmol/L (basal state) to 194 ± 24 µmol/L at 60 minutes (p < 0.01), whereas myocardial glutamate uptake from plasma decreased from 4.4 ± 0.7 µmol/min (basal state) to 2.5 ± 0.6 µmol/min at 60 minutes (p < 0.05). Thirty minutes after stopping the aspartate infusion glutamate uptake had returned to preinfusion levels (4.6 ± 0.7 µmol/min).

Myocardial glutamate uptake correlated with plasma glutamate in the basal state (r = 0.54; p = 0.11) and at 90 minutes (r = 0.73; p < 0.05) but not during aspartate infusion. However, there was an inverse relationship between myocardial glutamate uptake from plasma and arterial plasma aspartate (Fig 3; r = -0.67; p < 0.05) after 60 minutes of aspartate infusion. Also, there was an inverse relationship between arterial plasma aspartate and the proportion of glutamate in the total myocardial glutamate + aspartate uptake (r = -0.65; p < 0.05). Arterial plasma glutamate correlated with arterial plasma aspartate after 60 minutes of aspartate infusion (Fig 4; r = 0.81; p < 0.01).

View larger version (18K): [in this window] [in a new window]   Fig 3. Arterial plasma aspartate versus myocardial glutamate uptake from plasma after 60 minutes of aspartate infusion. (r = Spearman rank correlation coefficient.)

View larger version (18K): [in this window] [in a new window]   Fig 4. Arterial plasma aspartate versus arterial plasma glutamate after 60 minutes of aspartate infusion. (r = Spearman rank correlation coefficient.)

Lactate
There was no myocardial uptake or release of lactate in the basal state and no significant change during aspartate infusion. Arterial lactate level remained essentially unaffected during aspartate infusion.

Myocardial lactate uptake correlated with myocardial aspartate uptake during aspartate infusion at 20 minutes (r = 0.73; p < 0.05), 30 minutes (r = 0.55; p = 0.12), and 60 minutes (r = 0.89; p < 0.01).

Glucose
There was no myocardial uptake of glucose in the basal state and no significant change during aspartate infusion. Arterial blood glucose remained unchanged during aspartate infusion.

Free fatty acids
There was a significant myocardial uptake of free fatty acids in the basal state (10.6 ± 2.0 µmol/min), but no significant change during the study period. Arterial level did not change during the study period.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Intravenous infusions of amino acids provide an alternative to amino acid-enhanced cardioplegic reperfusion solutions. Both glutamate and aspartate are reported to improve myocardial tolerance to ischemia and to improve the recovery of oxidative metabolism after ischemia in animals [1–3]. Data from the isolated rat heart suggest that aspartate may enhance myocardial recovery after cardioplegic arrest more effectively than glutamate [5]. In the present study intravenous aspartate infusion after CABG was associated with a dose-dependent increase of both arterial aspartate level and myocardial uptake of aspartate. In contrast to findings after glutamate infusion in the same setting [4], no positive effect of aspartate on myocardial metabolism and function could be demonstrated. However, considerable interactions with glutamate metabolism were observed, which may have outweighed the effects of aspartate.

Aspartate and glutamate were analyzed in both plasma and whole blood. The reason for this is that erythrocyte content of glutamate, and aspartate in particular, is considerably higher than in plasma. Therefore, plasma analysis may underestimate the flux of these amino acids [12]. On the other hand, plasma analyses are more reliable as exchange of amino acids mainly concerns the plasma fraction and extraction rate of these amino acids from plasma is high [13]. In contrast, whole blood analyses of aspartate measure small changes in large concentrations. In the present study, plasma aspartate constituted less than 4% of whole blood aspartate before starting the aspartate infusion and less than 10% of whole blood aspartate 30 minutes after stopping the infusion (see Table 2). In fact, 9 of 11 whole blood samples that failed to detect an uptake of aspartate were obtained either in the basal state or after the infusion had been stopped. A better agreement between plasma and whole blood analyses was found during aspartate infusion as it primarily influenced the plasma fraction, with a 46-fold increase, thus reducing the concentration discrepancy between the plasma and erythrocyte fraction. The fact that both plasma and whole blood analyses demonstrated similar changes in aspartate and glutamate kinetics during aspartate infusion supports the validity of the findings.

Myocardial aspartate uptake was enhanced as a consequence of increasing arterial levels during aspartate infusion. Increasing arterial plasma levels of aspartate also influenced the metabolism of glutamate. Myocardial glutamate uptake in the postischemic heart is normally dependent on arterial levels [14]. During aspartate infusion, however, there was a decrease in myocardial glutamate uptake in spite of increased arterial glutamate levels. To explain this finding, amino acid transport in the cardiomyocytes (and other tissues) have to be considered. In the rat heart aspartate and glutamate compete for the same Na⁺-dependent amino acid carrier [15]. In humans the arterial plasma aspartate level is very low and mainly glutamate is taken up by the ischemic and postischemic heart [14, 16, 17]. If, however, the plasma level of aspartate is markedly increased as in the present study, competitive inhibition of glutamate uptake could occur. A similar effect in other tissues, such as skeletal muscle, would lead to elevated arterial glutamate levels as a consequence of reduced glutamate uptake. This hypothesis, thus, explains both the elevated arterial glutamate level and the reduced myocardial glutamate uptake during aspartate infusion. Accordingly, a positive correlation between arterial plasma aspartate and arterial plasma glutamate was observed during aspartate infusion (see Fig 4). Further support for this theory was provided by the inverse relationship between arterial plasma aspartate and myocardial glutamate uptake during aspartate infusion (see Fig 3), and the inverse relationship between arterial plasma aspartate and the proportion of glutamate in the total glutamate + aspartate uptake. However, although competitive inhibition of glutamate uptake by aspartate can explain these findings, other metabolic interactions between aspartate and glutamate may have contributed. The clinical significance of reduced myocardial glutamate uptake in this setting is not known, but it cannot be excluded that the effects of aspartate may have been outweighed by impeded myocardial glutamate uptake.

Current knowledge indicates that glutamate is of particular importance for the ischemic and postischemic human heart [14, 16, 18], whereas similar data for aspartate are lacking. Arterial plasma levels of glutamate are much higher than aspartate levels, suggesting a physiologically more important role for glutamate. In ischemic heart disease and after CABG the human heart preferably extracts glutamate [14, 16, 18]. Furthermore, glutamate administration has been shown to improve myocardial tolerance to ischemia in coronary patients and to improve the metabolic and hemodynamic state of the heart in cardiac failure after cardiac operations [19–21]. In contrast to the present study, intravenous glutamate was associated with beneficial effects on myocardial metabolism and performance in the same experimental setup after CABG [4].

However, it would be premature to dismiss aspartate as a potentially useful substrate for the ischemic or postischemic human heart based on this pilot study. In a previous study, control patients in the same experimental setup demonstrated stable myocardial metabolism and hemodynamics during the study period with the exception of a decrease in myocardial lactate uptake [4]. Thus, aspartate may have prevented a decrease of lactate extraction and this is supported by the positive correlations between myocardial lactate uptake and myocardial aspartate uptake.

The dosage of aspartate also deserves consideration. In the present study aspartate infusion was associated with a dose-dependent increase in arterial aspartate. Furthermore, myocardial aspartate uptake correlated with arterial levels. However, the number of patients were too few and the dose range too small to detect a level at which myocardial aspartate uptake was saturated. Therefore, the dosage of aspartate may have been suboptimal in some patients. Opposed to this, there was no correlation between dosage of aspartate and change in myocardial performance.

Patient selection and the timing of the study were not ideal. Further studies on aspartate in humans should be performed during early reperfusion or during cardioplegic arrest, and preferably in high-risk patients who may be more likely to benefit from metabolic intervention. However, the present results demonstrate that exogenous aspartate administration can enhance myocardial aspartate uptake, and attract attention to the metabolic interactions with glutamate. Recognition of these amino acid interactions are important as they are used together as additives in cardioplegic solutions. The salutary effects of combining these amino acids, demonstrated in animals, need to be confirmed in humans. If so, it remains to be determined whether the current 1:1 proportion used in cardioplegic solutions is ideal or if it should be modified.

To conclude, the present results demonstrate that administration of aspartate in humans can enhance myocardial uptake of aspartate. Intravenous aspartate infusion after CABG was associated with a dose-dependent increase of both arterial aspartate level and myocardial uptake of aspartate. In contrast to findings after glutamate infusion in the same setting, no positive effect of aspartate on myocardial metabolism and function could be demonstrated. However, considerable interactions with glutamate metabolism, compatible with competitive inhibition of myocardial glutamate uptake, which may have outweighed potential effects of aspartate were observed. Recognition of these amino acid interactions are important as they are used together as additives in cardioplegic solutions. The salutary effects of aspartate demonstrated in animals remain to be confirmed in humans.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The original work described in this article was supported by grants from the Swedish Heart Lung Foundation, The Swedish Medical Research Council (project no. 04139), The Swedish Society of Medicine, Östergötlands Läns Landsting, Linköping Heart Center and the University of Linköping.

	References

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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 Author home page(s): Ingemar Vanhanen Rolf Svedjeholm Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vanhanen, I. Articles by Svedjeholm, R. Search for Related Content PubMed PubMed Citation Articles by Vanhanen, I. Articles by Svedjeholm, R.