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(Circulation. 1999;99:1892-1897.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Myocardial Lactate Metabolism in Fetal and Newborn Lambs
Presented in part at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 13–16, 1995, and at the Annual Scientific Session of the Society for Pediatric Research, May 1996, and published in abstract form (Circulation. 1995;92[suppl I]:I-770).
From the Division of Pediatric Cardiology, Department of Pediatrics, Beatrix Children's Hospital and Groningen Utrecht Institute for Drug Exploration, Groningen, Netherlands.
Correspondence to J.R.G. Kuipers, Division of Pediatric Cardiology, Beatrix Children's Hospital, PO Box 30.001, 9700 RB, Groningen. E-mail j.r.g.kuipers{at}med.rug.nl
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Abstract |
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Background—Around birth, myocardial substrate supply changes from carbohydrates before birth to primarily fatty acids after birth. Parallel to these changes, the myocardium is expected to switch from the use of primarily lactate before birth to fatty acids thereafter. However, myocardial lactate uptake and oxidation around birth has not been measured in vivo.
Methods and Results—We measured myocardial lactate uptake, oxidation, and release with infusion of [1-13C]lactate and myocardial flux of fatty acids and glucose in chronically instrumented fetal and newborn (1 to 15 days) lambs. Myocardial lactate oxidation was the same in newborn (81.7±14.7 µmol · min-1 · 100 g-1, n=11) as in fetal lambs (60.7±26.7 µmol · min-1 · 100 g-1, n=7). Lactate uptake was also the same in newborn as in fetal lambs. Lactate uptake was higher than lactate flux, indicating lactate release simultaneously with uptake. In the newborn lambs, lactate uptake declined with age. Lactate uptake was strongly related to lactate supply, whereas lactate oxidation was not. The supply of fatty acids or glucose did not interfere with lactate uptake, but the flux of fatty acids was inversely related to lactate oxidation.
Conclusions—We show that lactate is an important energy source for the myocardium before birth as well as in the first 2 weeks after birth in lambs. We also show that there is release of lactate by the myocardium simultaneously with uptake of lactate. Furthermore, we show that lactate oxidation may be attenuated by fatty acids but not by glucose, probably at the level of pyruvate dehydrogenase.
Key Words: metabolism • lactate • blood flow • isotopes • fetus
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Introduction |
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Fatty acids are the major energy source for the myocardium in the adult,1 whereas lactate has been suggested to be the major energy source for the myocardium in the fetus.2 3 However, the alleged role of lactate as an energy source for the fetal myocardium was based on experiments in which only the flux of lactate across the myocardium was measured. The lactate flux is the product of myocardial blood flow times the net arteriovenous concentration difference of lactate across the myocardium. This difference reflects the balance between uptake and release of lactate. Lactate release simultaneously with uptake has previously been found in the myocardium of human adults4 ; this phenomenon may have obscured the role of lactate as an energy substrate for the fetal myocardium.
The role of lactate as an energy substrate for the myocardium during the transition from fetal to neonatal life is still a matter of dispute. Fisher et al5 suggested that lactate would be replaced by fatty acids in newborn lambs. They studied newborn lambs ranging in age from 4 to 25 days. However, from a study in newborn lambs ranging in age from 1 to 4 days, we proposed that lactate could remain an important energy source for the myocardium in the first week after birth.3 Previous studies in isolated heart preparations showed a limited capacity of the myocardium of the newborn to oxidize fatty acids6 7 and suggested that glycolysis may be the major energy source for the myocardium of the newborn.8 However, these studies in isolated heart preparations used different sets of substrates in a wide range of concentrations. The differences in experimental setup have led to a wide variation in myocardial substrate supply. This variation may have influenced myocardial lactate uptake in these studies, because the myocardium in the adult is generally thought to be an omnivore.9 The flux of lactate is inversely related to the arterial concentration of free fatty acids in human adults.10 Alternatively, a rise in arterial concentration of lactate can inhibit the uptake and oxidation of fatty acids11 12 13 in isolated hearts.
The aim of this study was, first, to determine the importance of lactate as an energy substrate for the myocardium before birth as well as in the first weeks after birth. Therefore, we measured myocardial lactate oxidation with the use of [1-13C]lactate as a tracer in chronically instrumented fetal and newborn lambs. Second, we wanted to distinguish between the actual and the net lactate uptake by the fetal and newborn myocardium in vivo. For that purpose, we measured lactate flux, uptake, and release in the myocardium with the use of [1-13C]lactate. Third, we wanted to study the influence of the supply of alternative substrates on lactate uptake and oxidation. Therefore, we also measured the myocardial supply and flux of glucose, free fatty acids, and ketone bodies. We hypothesized that lactate is the major energy substrate for the heart before birth and that lactate oxidation decreases after birth. Furthermore, we hypothesized that the expected decrease will be due partly to a decrease in supply and partly to the increase in supply of alternative substrates, eg fatty acids and glucose. As far as we know, this study is the first in which myocardial lactate uptake and oxidation were measured in vivo before and shortly after birth.
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Methods |
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We studied 8 fetal lambs at 126 to 127 days of gestation and 14 newborn lambs with ages ranging from 1 to 15 days after birth. If >1 study was performed in an animal, there was at least 1 day between the 2 studies. Surgical and experimental procedures were approved by the animal research committee of the University of Groningen.
Surgical Procedure
The fetal and newborn lambs were instrumented as described
previously.3 The fetal lambs were instrumented at 124 to
125 days of gestation (term is 145 days). In the fetal lambs, we
inserted polyvinyl catheters (ID, 0.3 mm; OD, 0.5 mm) into
the ascending aorta, superior vena cava, coronary sinus, left
atrium, carotid artery, and jugular vein and into the amniotic cavity
for zero pressure reference. We instrumented 2 of the lambs in utero
and delivered them by cesarean section at 139 days of gestation. The
other newborn lambs were instrumented within the first 2 days after
birth. In the newborn lambs, we inserted catheters into the ascending
aorta, coronary sinus, pulmonary artery, vena cava, and
left atrium. We studied the lambs at least 2 days after surgery.
Experimental Protocol
On the day of the study, we gave the animals 60 to 90 minutes to
get accustomed to the study room. We weighed the newborn lambs and
placed them in a sling. We removed heparin from the catheters at least
1 hour before blood samples were taken. Heart rate and blood pressures
were recorded every 5 minutes throughout the experiment. We infused
[1-13C]lactate into the caval vein at a priming
dose rate of 15 mg/kg in 10 minutes and at a continuous rate of 0.15
mg · kg-1 ·
min-1 thereafter. The dose needed for the fetal
lambs was calculated assuming a body weight of 3 kg. Before the start
of the infusion, there was no difference in natural abundance of
[1-13C]lactate between the studies. A steady
state of arterial 13C enrichment of
lactate is reached after 30 minutes of infusion.14 After
30 and 45 minutes of infusion, we withdrew blood samples
simultaneously from the ascending aorta and
coronary sinus for the determination of lactate concentration,
13C enrichment of lactate,
CO2 concentration, 13C
enrichment of CO2, oxygen saturation, hemoglobin
concentration, hematocrit, pH, PCO2,
PO2, and
HCO3- concentration and
concentrations of glucose, free fatty acids, ß-OH-butyrate, and
acetoacetate. Immediately after collection of these samples, we
injected radioactive microspheres labeled with either
141Ce, 113Sn,
103Ru, or 95Nb (New England
Nuclear-Trac, DuPont Biotechnology Systems) into the left atrium in
both fetal and newborn lambs. Simultaneously, we withdrew a
reference sample from the aortic catheter with a pump (Harvard
Apparatus) for 1.25 minutes at a rate of 4.5 to 6 mL/min
into a preweighed heparinized syringe.
Measurements
Heart rate was obtained from the blood pressure signal. We
measured aortic, atrial, and amniotic pressures with Baxter pressure
transducers (Baxter Medical) and recorded them on a thermal array
recorder (Nihon Kohden). We corrected fetal blood pressures using
amniotic fluid pressure as zero pressure reference. Oxygen saturation
was determined in duplicate with a hemoximeter (OSM-2, Radiometer) and
hemoglobin concentration with a hemoglobin photometer (Hemocue AB).
Hematocrit was measured in duplicate by the microcapillary method. We
determined pH, PCO2,
PO2, and
HCO3- concentrations with a
blood gas analyzer (ABL-2, Radiometer). Blood flow to the
myocardium was determined with radionuclide-labeled
microspheres (15 µm in diameter) as described
previously. 3 Organ blood flows were calculated with the
aid of a computer program and were expressed in mL ·
min-1 · 100 g wet
wt-1.
The blood collected for the determination of substrate concentrations was transferred immediately to a tube containing a dash of NaF (25 mg), mixed, and kept in ice. The concentrations of glucose, lactate, pyruvate, ß-hydroxybutyrate, and acetoacetate were determined in duplicate in whole blood by enzymatic methods as described previously.3 The concentrations of free fatty acids were determined in duplicate in plasma as described previously.3 Plasma concentrations were converted to blood concentrations through multiplication with the following factor: [100-hematocrit (%)]/100.
For the determination of the 13C enrichment of lactate, we extracted lactate from the plasma as described previously.14 We determined the isotope ratio of the lactate derivative by gas chromatography–mass spectrometry, as described previously.14 The coefficient of variation was 3.7% (n=5).
The blood samples for determination of CO2 were withdrawn in heparinized vacuum tubes (Becton Dickinson) and stored at -20°C until further analysis. For the determination of total CO2 concentration, the titrimetric method described by Dijkhuizen et al15 is used. The titration was carried out as described previously.16 The coefficient of variation was 0.8% (n=7). For the determination of the isotope ratio of CO2, the same extraction procedure in the same blood sample was used.16 For measurement of the isotope ratio, the sample vial was connected to an isotope ratio mass spectrometer (VG Sira 9 Isotope Ratio Mass Spectrometer, VG). Two masses (m/z 44, mass of 12CO2, and m/z 45, mass of 13CO2) were measured. The molar fraction of 13CO2 (FCO2) was calculated from the isotope ratio (RCO2) as follows: FCO2=RCO2/(1+RCO2).
The molar fraction was used to calculate the concentration of 13CO2: [13CO2]=FCO2x[CO2], where [CO2] is the total CO2 concentration.
Calculations
Blood O2 concentration was calculated as
the product of oxygen saturation, hemoglobin concentration, and a
hemoglobin binding capacity of 1.36 mL/g. Left ventricular
oxygen supply was calculated as the product of arterial
oxygen concentration and blood flow to the left ventricular
free wall. Because coronary sinus blood of lambs consists
predominantly of venous blood from the left ventricle, we calculated
oxygen consumption of the left ventricular free wall (LV
O2) as follows (expressed
in µmol · min-1 · 100
g-1): LV
O2=([O2]AO-[O2]CS)xQ,
where Q is left ventricular free wall blood flow obtained
with the radionuclide-labeled microspheres and
[O2]AO and
[O2]CS are the oxygen
concentrations in the aorta and coronary sinus,
respectively.
The left ventricular flux, uptake, release, and oxidation of lactate were calculated as follows (expressed in µmol · min-1 · 100 g-1): Flux=([L]AO-[L]CS)xQ, where [L] is the concentration of lactate determined enzymatically.
Uptake={(FAOx[L]AO)-(FCSx[L]CS)}x(1/FAO)xQ, where FAO and FCS are the molar fractions of [1-13C]lactate in the aorta and coronary sinus, respectively.
Release=uptake-flux.
Oxidation=([13CO2]CS-[13CO2]AO)x(1/FAO)xQ, where [13CO2]CS and [13CO2]AO are the concentrations of [13CO2] in the coronary sinus and aorta, respectively, which are both corrected for the natural abundance of 13CO2.16 The contribution of lactate oxidation to left ventricular oxygen consumption was calculated by multiplying the oxidation rate of lactate by 3, the amount of oxygen that is used for the oxidation of 1 mole of lactate, and dividing it by left ventricular oxygen consumption.
Statistical Analysis
Data are presented as mean±SEM. We tested for
differences between the fetal and newborn lambs with the unpaired
t test and for differences within the groups with the paired
t test. A value of P<0.05 was considered
significant.
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Results |
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On the day of the study, all lambs had normal heart rates, blood pressures, oxygen saturations, and pH values (Table 1
). There were several differences
between fetal and newborn lambs in baseline variables (Table 1). That is, arterial pressure, oxygen saturation,
and pH were higher in newborn lambs than in fetal lambs. Left
ventricular free wall blood flow in newborn lambs was not
significantly different from that in fetal lambs (P=0.08),
but left ventricular oxygen supply and left
ventricular oxygen consumption were both higher in newborn
than in fetal lambs. There were marked differences in substrate
concentrations that were similar to those described in a previous study
(Table 2 and Reference 33 ).
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There was no significant difference in lactate oxidation between
newborn and fetal lambs (Figure 1). In
fetal as well as in newborn lambs, 74% of the lactate taken up was
immediately oxidized. The contribution of lactate oxidation to
myocardial oxygen consumption was 28±6% in newborn lambs and 36±11%
in fetal lambs (P=0.11). There was no relation between
lactate uptake and oxidation or between lactate flux and oxidation.
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The arterial lactate concentration (Table 2
) and left ventricular
supply of lactate were not different between the fetal and newborn
lambs (238±31 versus 349±54 µmol ·
min-1 · 100 g-1,
respectively). The net arteriovenous concentration difference of
lactate was lower in the newborn (225±41 µmol/L) than in the
fetal lambs (376±58 µmol/L, P<0.05). There were no
significant differences between the fetal and newborn lambs in left
ventricular lactate flux or uptake (Figure 1).
Lactate flux was related to lactate uptake (y=-50+1.67
x-0.003 x2,
r2=0.833, P<0.0001). The
left ventricular uptake of lactate was significantly higher
than the flux in the fetal as well as in the newborn lambs (Figure 1).
These results imply release of lactate by the left ventricle
simultaneously with uptake.
Although there were no differences between the fetal and newborn lambs
in myocardial lactate metabolism, there were differences
within the group of newborn lambs. Lactate flux and lactate uptake
declined with age in the newborn lambs (Figure 2). Lactate oxidation and lactate release
were not related to age in the newborn lambs. Parallel to the decrease
in uptake, the arterial concentration of lactate slowly
decreased with age in the newborn lambs (Figure 3). There was no relation between lactate
uptake and the arterial concentration of lactate.
Conversely, lactate uptake was closely related to lactate supply
(Figure 4);
r2 was 0.87.
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The supply of alternative substrates did not interfere with
lactate uptake. Lactate uptake was related to glucose supply
(y=50.9+0.046 x,
r2=0.453, P<0.01), but the
slope of this regression curve was positive. Lactate uptake was also
positively related to the supply of free fatty acids (Figure 5). Lactate oxidation was also positively
related to the supply of glucose or ketone bodies. In the newborn
lambs, lactate oxidation was not significantly related to the supply of
free fatty acids, but lactate oxidation was inversely related to the
flux of free fatty acids (Figure 6).
Conversely, there was no relation between the supply of lactate and the
flux of glucose, free fatty acids, or ketone bodies.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we show that lactate is an important energy source for the myocardium of the developing lamb not only before birth but also in the first 2 weeks after birth. We also show that in both fetal and newborn lambs, there is release of lactate by the myocardium simultaneously with uptake of lactate. Furthermore, we show that lactate oxidation may be attenuated by fatty acids but not by glucose.
The finding that lactate uptake and oxidation were the same in the newborn lambs and fetal lambs shows that lactate is an important energy substrate for the myocardium before birth as well as in the first weeks after birth. These results are in accordance with the suggestion from our previous study,3 in which we measured only lactate flux. In the present study, we measured lactate uptake and oxidation with the use of 13C-labeled lactate. Lactate uptake was closely related to the flux of lactate, but lactate oxidation was not. These findings show that flux of lactate cannot be used to estimate actual lactate metabolism. Moreover, it shows that under physiological conditions, the oxidation of lactate is controlled at the intracellular level rather than at the level of the cellular membrane.17
The finding that lactate uptake and oxidation were the same in
the newborn lambs as in the fetal lambs is surprising, considering the
increase in arterial concentration of fatty acids and
glucose. Previous studies in human adults showed that the arteriovenous
concentration difference of lactate can be attenuated by an increase in
the arterial concentration of free fatty
acids.10 In our lambs, the arterial
concentration of free fatty acids also is inversely related to the
arteriovenous concentration difference of lactate across the
myocardium (data not shown). However, the actual supply to
the myocardium is the product of the
arterial concentration and myocardial blood flow. In the
study in human adults, no myocardial blood flow was measured. In our
lambs, an increase in the actual supply of glucose or fatty acids to
the myocardium did not attenuate lactate uptake. Instead,
myocardial lactate uptake was closely related to lactate supply (Figure 5). This lack of interference of the supply of alternative
substrates with lactate uptake leads to the suggestion that the heart
prefers lactate as a substrate, as has been suggested by studies in
adult anesthetized dogs.18 However, although
lactate uptake was not attenuated by the supply of alternative
substrates, lactate oxidation was inversely related to the flux of free
fatty acids. With the assumption that the flux of free fatty acids
represents the uptake of free fatty acids, these data show that
free fatty acids can attenuate lactate metabolism.
Lactate metabolism can be attenuated at several steps. Because lactate oxidation was inversely related to the supply or flux of free fatty acids but not to that of glucose, it is suggested that free fatty acids interfere with lactate metabolism at the level of acetyl coenzyme A produced by the pyruvate dehydrogenase complex. The site of interference is the same, as previously suggested by studies in adult hearts.10 However, this is in contrast with results from previous studies19 suggesting that fatty acid oxidation is limited in the newborn heart by limitations in mitochondrial uptake of long-chain fatty acids. But it should be noted that in this study, we measured the flux of free fatty acids rather than actual oxidation. Further studies in which fatty acid oxidation in vivo is measured are necessary to verify these suggestions.
The importance of lactate for myocardial metabolism around birth is determined not only by lactate oxidation itself but also by oxidation of other substrates. Although lactate oxidation did not yet decrease in the newborn lambs, myocardial oxygen consumption increased. Therefore, other substrates have to be used as well, indicating that a transition in the use of substrates by the myocardium after birth has already started, although it is not yet complete. It is unlikely that the heart can work with lactate as the sole substrate. If that were true, newborns who become hypoglycemic should be able to sustain myocardial performance, because these infants have normal arterial lactate concentrations.20 Nevertheless, newborns who become hypoglycemic sometimes develop cardiomegaly and heart failure.21 22 The finding that these symptoms disappear rapidly after glucose administration21 22 shows that the heart of the newborn cannot sustain function on lactate alone but seems to be dependent on other substrates as well. Therefore, we conclude that lactate is an important but not the preferred substrate for the myocardium shortly after birth.
Unexpectedly, lactate supply tended to be higher in the newborn lambs than in the fetal lambs. We expected a decrease in lactate supply because of removal of the placenta, which produces lactate.23 However, despite the abrupt removal of the placenta at birth, the arterial concentration and the supply of lactate to the left ventricular free wall were not different between newborn and fetal lambs. The arterial lactate concentration measured in our lambs was equal to that measured previously in newborn lambs5 and even somewhat lower than that measured in healthy newborn infants.24 Therefore, the unexpectedly high lactate concentration found in newborns seems to be a physiological phenomenon. This phenomenon can be due to either increased production or diminished removal of lactate. Lactate production is probably not increased, because our lambs were resting in a sling and did not show signs of hypoxia or infection. We suggest that this phenomenon is caused by impaired lactate removal, because of immaturity of gluconeogenesis25 26 and a low renal glomerular filtration rate in newborns.
The oxidation rates measured in the fetal and newborn lambs are in contrast with results from studies in isolated working hearts from newborn rabbits.8 In these studies, it was found that lactate oxidation was increased in hearts from 7-day-old rabbits compared with those of 1-day-old rabbits.8 We converted their oxidation rates expressed per gram dry weight to oxidation rates expressed per 100 g wet weight assuming a dry/wet ratio of 0.2. The converted oxidation rates in isolated hearts of 1-day-old rabbits (85±3 µmol · min-1 · 100 g-1) are similar to the oxidation rates measured in our fetal and neonatal lambs, but those in hearts of 7-day-old rabbits (228±58 µmol · min-1 · 100 g-1) are much higher than those in the 1-week-old lambs. These differences might be due to species differences or to differences in experimental setup. In the isolated heart preparations, a substantially greater amount of carbohydrates was supplied. Moreover, these preparations lack hormonal influences other than insulin. Finally, in these studies, the amount of insulin was fixed, whereas insulin levels are reported to change in the first weeks after birth.26 Hence, it is difficult to compare our data with previously reported data from isolated heart preparations.
The myocardial blood flow measured in our fetal lambs was approximately the same as measured previously2 (175±15 mL · min-1 · 100 g-1), but that in the newborn lambs was higher than measured previously5 (201±21 mL · min-1 · 100 g-1). The difference in myocardial blood flow in the newborn lambs may be due to the difference in age range between the 2 studies. Myocardial blood flow normalized for weight seems to decrease with age, because in a previous study in 7-week-old lambs, we measured a myocardial blood flow of 127±11 mL · min-1 · 100 g-1.27 Fisher et al5 studied lambs ranging in age from 4 to 25 days, whereas we studied lambs ranging in age from 1 to 14 days.
Whether the simultaneous occurrence of uptake and release
of lactate by the myocardium actually means uptake and
production or just exchange between intracellular and
extracellular lactate is a matter of debate.28 Release of
lactate by the myocardium is shown by the fact that in the
fetal as well as in the neonatal lambs, the uptake of lactate was
significantly higher than the flux of lactate (Figure 1). The
lactate released was considered to be unlabeled lactate produced by
anaerobic glycolysis. It has been suggested, however, that
lactate apparently produced in this way is actually a result of label
exchange with an intracellular pyruvate pool via the reversible
conversion of lactate to pyruvate catalyzed by the enzyme lactate
dehydrogenase.28 Although this phenomenon may occur, it
does not seem to contribute substantially to lactate release in our
lambs, because we measure a considerable amount of lactate oxidation;
74% of the lactate taken up is immediately oxidized. Thus, although
exchange may have added to the lactate released by the
myocardium in our lambs, it is not likely to explain the
total lactate release.
Lactate production by anaerobic glycolysis was previously thought to be a sign of a mismatch between myocardial oxygen demand and supply. However, in studies in well-oxygenated isolated heart preparations, it was found that the rate of anaerobic glycolysis was even higher than that of glucose oxidation.8 29 Release of lactate by the myocardium, simultaneously with uptake, has also been found in studies in healthy human adults.30 31 These authors suggested that subendocardial regions are relatively underperfused, hence producing lactate, whereas other regions are consuming lactate. However, in newborn and in 7-week-old lambs, it was found that blood flow to the endocardial layer was higher than flow to the epicardial layer.27 32 Alternatively, it can be speculated that anaerobic glycolysis and complete oxidation of glucose occur simultaneously in the heart but that the balance between these 2 pathways differs under different conditions.8 29
In conclusion, we show that lactate is an important energy source for the myocardium of the developing lamb not only before birth but also in the first 2 weeks after birth. We also show that both in fetal and in newborn lambs, there is release of lactate by the myocardium simultaneously with uptake of lactate. Furthermore, we show that lactate oxidation can be attenuated by the supply of free fatty acids but not by that of glucose.
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Acknowledgments |
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This study was supported by the Netherlands Heart Foundation (NHS 94.149). The authors thank Berthe M.A.A. Verstappen-DuMoulin and G. Henk Visser for the analysis of the isotope ratios of CO2 in blood and Gijs T. Nagel for the analysis of the isotope ratios of lactate.
Received August 5, 1998; revision received November 23, 1998; accepted December 7, 1998.
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