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Am J Physiol Heart Circ Physiol 275: H1503-H1512, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 5, H1503-H1512, November 1998

Increased myocardial lactate oxidation in lambs with aortopulmonary shunts at rest and during exercise

Gertie C. M. Beaufort-Krol, Janny Takens, Marieke C. Molenkamp, Gioia B. Smid, Koos J. Meuzelaar, Willem G. Zijlstra, and Jaap R. G. Kuipers

Division of Pediatric Cardiology and Thoracic Surgery, Beatrix Children's Hospital, University of Groningen, 9700 RB Groningen; and Groningen Utrecht Institute for Drug Exploration, 9713 BZ Groningen, The Netherlands

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Free fatty acids are the major fuels for the myocardium, but during a higher load carbohydrates are preferred. Previously, we demonstrated that myocardial net lactate uptake was higher in lambs with aortopulmonary shunts than in control lambs. To determine whether this was caused by an increased lactate uptake and oxidation or by a decreased lactate release, we studied myocardial lactate and glucose metabolism with 13C-labeled substrates in 36 lambs in a fasting, conscious state. The lambs were assigned to two groups: a resting group consisting of 8 shunt and 9 control lambs, and an exercise group (50% of peak O2 consumption) consisting of 9 shunt and 10 control lambs. Myocardial lactate oxidation was higher in shunt than in control lambs (mean ± SE, rest: 10.33 ± 2.61 vs. 0.17 ± 0.82, exercise: 38.05 ± 8.87 vs. 16.89 ± 4.78 µmol · min-1 · 100 g-1; P < 0.05). There was no difference in myocardial lactate release between shunt and control lambs. Oxidation of exogenous glucose, which was approximately zero at rest, increased during exercise in shunt and control lambs. The contribution of glucose and lactate to myocardial oxidative metabolism increased during exercise compared with at rest in both shunt and control lambs. We conclude that myocardial lactate oxidation is higher in shunt than in control lambs, both at rest and during exercise, and that the contribution of carbohydrates in myocardial oxidative metabolism in shunt lambs is higher than in control lambs. Thus it appears that this higher contribution of carbohydrates occurs not only in the case of pressure-overloaded hearts but also in myocardial hypertrophy due to volume overloading.

carbon-13-labeled substrates; congenital heart disease; left-to-right shunt; glucose; metabolism

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

UNDER NORMAL CONDITIONS free fatty acids (FFA) are the major source of energy for the myocardium. Other substrates such as carbohydrates and ketone bodies, however, can also serve as fuel for the myocardium, especially under conditions of an increased supply of these substrates. For example, during a bout of exercise, in which the arterial concentration of lactate increases, the myocardium prefers lactate to FFA (13, 26). A shift in myocardial net substrate uptake from FFA to carbohydrates may be of benefit during exercise because carbohydrates are the fuels that consume O2 most efficiently (13, 26, 31). In addition, during a chronic load the myocardium seems to prefer lactate to FFA, even when the arterial lactate concentration is not increased (19, 25, 31). Gratama et al. (19), in lambs with a chronic volume load due to an aortopulmonary shunt, found a higher myocardial net lactate uptake than in control lambs. The volume loading of these hearts by the aortopulmonary shunt results in myocardial hypertrophy (44), which may lead to a shift in myocardial substrate uptake from FFA to carbohydrates, as in pressure-overloaded hearts (29, 40).

Studies with stable as well as radioactive isotopes have demonstrated that the myocardial net lactate uptake is the result of lactate uptake and lactate release. Even in the normal myocardium, lactate has been shown to be taken up and released simultaneously (17, 42, 45). The higher myocardial net lactate uptake found by Gratama et al. (19) in lambs with an aortopulmonary shunt thus may have been the result of a higher myocardial lactate uptake and oxidation and/or a decreased myocardial lactate release. We hypothesized that, to meet the higher O2 demand, myocardial lactate and glucose uptake and oxidation will be increased in shunt lambs compared with control lambs. Furthermore, we expected a more pronounced increase in carbohydrate oxidation in shunt than in control lambs during exercise. Therefore, we investigated, using 13C-labeled substrates, myocardial lactate and glucose uptake and oxidation and myocardial lactate release in conscious fasting lambs with an aortopulmonary shunt and in control lambs, both at rest and during moderate exercise on a treadmill.

    MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

We studied 36 7-wk-old lambs of mixed breed with documented dates of birth. They were assigned to two groups: a resting group consisting of 8 lambs with an aortopulmonary shunt and 9 control lambs without a shunt, and an exercise group consisting of 9 shunt and 10 control lambs. Surgical preparation, catheter care, and antibiotic administration were performed as described previously (44). In the shunt lambs a Goretex conduit (ID 6 mm; W. L. Gore, Flagstaff, AZ) was sutured between the descending aorta and the main pulmonary artery. Catheters were inserted into the aorta, the coronary sinus, the pulmonary artery, the right ventricle (only in the shunt lambs), and the right and left atria. Precalibrated electromagnetic flow transducers (ID 10-15 mm; Skalar Medical, Delft, The Netherlands) were placed around the ascending aorta just above the coronary arteries and around the pulmonary artery proximal to the conduit in the shunt lambs but only around the pulmonary artery in the control lambs. Until the day of study, each lamb remained with its mother.

Experimental Protocols

In random order each lamb underwent two similar studies with different 13C-labeled substrates ([1-13C]lactate or [U-13C]glucose) at two different days with at least 3 days in between.

Resting group. Between the 10th and 14th days after surgery, the lambs were, after an overnight fast of 18 h, brought to the experimental room, weighed, and put in a sling. After 2 h of habituation, the first measurements were made and blood samples were withdrawn. Systemic and pulmonary blood flows and aortic, pulmonary arterial, and left atrial pressures were measured every 15 min for 1 h. Every 15 min, blood samples were withdrawn with a heparinized syringe from the aortic, the coronary sinus, and the mixed venous catheters, i.e., from the right ventricular catheter in the shunt lambs and from the pulmonary arterial catheter in the control lambs. Hemoglobin concentration, blood gases, and O2 saturation were determined in all samples. Before the start of the infusion with the 13C-labeled substrate, blood samples were simultaneously withdrawn from the aorta and coronary sinus for determination of substrates (glucose, pyruvate, lactate, beta -hydroxybutyrate, acetoacetate, FFA, and triglycerides), CO2, and isotope ratio (13C/12C) to determine the natural abundance of 13C in lactate or glucose and in CO2. Next, in one experiment, a priming dose of 15.6 mg/kg [1-13C]lactate (99 atom % 13C1, Tracer Technologies, Somerville, MA) was administered in 10 min into the right atrium, followed by a constant-rate infusion (Harvard pump 2620, Millis, MA) of 0.156 mg · min-1 · kg-1 [1-13C]lactate (43, 47). In the other experiment a priming dose of 7.3 mg/kg [U-13C]glucose (99.3 atom % 13C, Isotec, Miamisburg, OH) was administered in 10 min into the right atrium, followed by a constant-rate infusion of 0.073 mg · min-1 · kg-1 [U-13C]glucose. During a steady state, three blood samples (30, 45, and 60 min after the start of the infusion of the priming dose) were obtained simultaneously from the aorta and coronary sinus. Immediately after the last blood sample had been taken, radioactive microspheres labeled with 141Ce, 113Sn, 103Ru, or 95Nb (NEN-Trac, Du Pont, Biotechnology Systems, Wilmington, DE) were injected into the left atrium, while a reference sample was withdrawn for 1.25 min at a rate of 6 ml/min with a Harvard pump from the aortic catheter into a preweighed, heparinized syringe (24).

Exercise group. In the week before surgery and from 2 days after surgery, the lambs were familiarized with running on a motor-driven treadmill (Laufergotest Junior, Erich-Jaeger, Hoechberg, Germany) during one short daily run. No training effect was pursued. The lambs could be made to run freely on the treadmill without coercive measures. For the experiments, a work load corresponding to 50% of the peak O2 consumption (VO2 peak) was to be used. VO2 peak of each lamb was determined during a graded treadmill test 1 wk after surgery as described previously (21). The graded treadmill test in the shunt lambs was modified by starting at a running speed of 2.5 km/h instead of 3.5 km/h; otherwise, speed and inclination corresponding to 50% of VO2 peak could not be determined. Between the 10th and 14th days after surgery, the lambs were, after an overnight fast of 18 h, brought to the experimental room, weighed, and put on the treadmill. After 2 h of habituation, the first measurements were made and, every 10 min, blood samples were withdrawn for the same determinations as described for the resting group. Ten minutes after the injection of the microspheres, speed and inclination of the treadmill were set to values that would impose a work load corresponding to ~50% of VO2 peak. The lamb had to run at this load for 30 min. After 20 min and before 30 min of exercise, microspheres labeled with an isotope different from that used during the resting period were injected. After the last blood sample had been withdrawn, the treadmill was stopped and the lamb was allowed to recover.

Measurements

Systemic and pulmonary blood flows, heart rate, aortic, pulmonary arterial, and left and right atrial pressures were measured as previously described (44). The precalibrated electromagnetic flow transducers were connected to Skalar MDL 400 flowmeters. Systemic and pulmonary blood flows in shunt lambs were obtained from the pulmonary and the aortic flow transducers, respectively; systemic blood flow of the control lambs was obtained from the pulmonary flow transducer. The position of the aortic flow transducer was distal to the origin of the coronary arteries. To obtain total left ventricular output, coronary blood flow as obtained with the microspheres was added to the aortic flow measured with the flow transducer (33). Heart rate was obtained from the blood flow signal. Aortic, pulmonary arterial, and left and right atrial pressures were measured with Gould P23 ID pressure transducers (Spectramed, Oxnard, CA) referenced to atmospheric pressure with zero obtained with the pressure transducer at right atrial level. All variables were recorded on an Elema Mingograf 800 ink-jet recorder (Siemens-Elema, Solna, Sweden). Hemoglobin concentration was determined with the Haemocue method (B Hemoglobin Photometer, Haemocue, Helsingborg, Sweden). pH, PCO2, PO2, and plasma HCO-3 concentrations were determined with an ABL-2 blood gas analyzer (Radiometer, Copenhagen, Denmark). O2 saturation was determined with an OSM2 hemoximeter (Radiometer). Blood flow to the myocardium was determined with one of the four radionuclide-labeled microspheres (15-µm diameter) as previously described (24, 44).

Concentrations of glucose, pyruvate, lactate, beta -hydroxybutyrate, acetoacetate, FFA, total glycerol, and free glycerol were determined using enzymatic methods (5, 11). To obtain the triglyceride concentration, we subtracted free glycerol from total glycerol concentration. The coefficients of variation in our laboratory were 0.4% for glucose (n = 27), 1.4% for lactate (n = 20), 12.8% for pyruvate (n = 5), 2.9% for beta -hydroxybutyrate (n = 10), 2.8% for acetoacetate (n = 5), 0.5% for FFA (n = 15), 0.6% for total glycerol (n = 18), and 0.7% for free glycerol (n = 15).

For the determination of the isotope ratio of lactate, fatty acids were removed from the plasma by extraction with chloroform. The lactate was then extracted with diethyl ether-ethyl acetate and dried under N2. [1-13C]lactate was determined as an n-heptafluorobutyric anhydride-n-butylamine derivative (3) using gas chromatography-mass spectrometry (GC-MS). We used a Hewlett-Packard 5890 gas chromatograph (Hewlett-Packard, Palo Alto, CA) interfaced to a VG Trio-2 quadrupole mass spectrometer (Fisons Instruments, Manchester, UK). The mass spectrometer was used in the chemical ionization (CI) mode. Single ion monitoring (SIM) was carried out at mass-to-charge ratio (m/e) 359 (m + 0) and m/e 360 (m + 1), corresponding to [m + NH4]+ of the unlabeled and labeled lactate, respectively. Standards containing 0.0, 2.5, 5.0, and 7.5% [1-13C]lactate were prepared by diluting natural lactate with [1-13C]lactate. A calibration graph was obtained by plotting isotope ratio versus molar fraction (Fs; r = 0.998). Fs of [1-13C]lactate of the blood samples was calculated from this calibration graph. The coefficient of variation for Fs of [1-13C]lactate was 3.7% (n = 10).

For the determination of the isotope ratio of glucose, blood samples were centrifuged, and the plasma was deproteinized with ethanol for 30 min at 4 °C and centrifuged again. The supernatant was removed and dried under N2. Pyridine and acetic anhydride (1:2 vol/vol) were added. This mixture was allowed to react for at least 24 h at room temperature to form a penta-acetate derivative (47). Isotope ratios were determined by GC-MS as described above. The mass spectrometer was used in the CI mode. SIM was carried out at m/e 408 (m + 0) and m/e 414 (m + 6), corresponding to [m + NH4]+ of the unlabeled and labeled glucose, respectively. Standards containing 0.0, 1.5, 3.0, and 4.5% [U-13C]glucose were prepared by diluting natural D-glucose with [U-13C]glucose. A calibration graph was obtained by plotting isotope ratio versus Fs (r = 0.997). Fs of [U-13C]glucose was calculated from this calibration graph. The coefficient of variation for Fs of [U-13C]glucose was 3.1% (n = 9).

The blood samples for determination of CO2 were withdrawn in heparinized vacutainer tubes (Becton-Dickinson, Rutherford, NJ) and stored at -20 °C until further analysis. Total CO2 concentration was determined with a titration method (4, 12). In this method, CO2 was set free from the blood by lactic acid and carried by a stream of CO2-free air to the titration vessel. The coefficient of variation for CO2 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. After extraction, the CO2 was carried by a stream of CO2-free air through a trap immersed in liquid air in which the CO2 was frozen. The CO2 was separated from water vapor and other gases (mainly O2 and N2) by leading it through a trap immersed in a mixture of acetone and dry ice and subsequently freezing it in a liquid air trap. For measurement of the isotope ratio, the sample vial was connected to an isotope ratio mass spectrometer (VG Sira 9 IRMS, VG, Manchester, UK) for measurement of the isotope ratio. Two masses (m/e 44 = mass of 12CO2, m/e 45 = mass of 13CO2) were measured.

13C as the fraction of total carbon present in CO2 (FCO2) is calculated from the isotope ratio (RCO2)
F<SUB>CO<SUB>2</SUB></SUB> = <FR><NU>R<SUB>CO<SUB>2</SUB></SUB></NU><DE>1 + R<SUB>CO2</SUB></DE></FR> (1)
The coefficient of variation for RCO2 was 0.03% (n = 5).

The 13CO2 concentration ([13CO2]) follows from the total CO2 concentration ([CO2]) in the sample and the corresponding 13CO2 fraction
[<SUP>13</SUP>CO<SUB>2</SUB>] = F<SUB>CO<SUB>2</SUB></SUB> ⋅ [CO<SUB>2</SUB>] (2)
  [13CO2] measured during the infusion with 13C-labeled substrates was corrected for the natural abundance of 13CO2, which was determined in blood samples taken before the infusion of a 13C-labeled substrate.

Calculations

Left-to-right shunt flow was obtained by subtracting systemic from pulmonary blood flow. Left-to-right shunt fraction was calculated by dividing left-to-right shunt flow by pulmonary blood flow. Effective left ventricular stroke volume was calculated by dividing systemic blood flow by heart rate. Blood O2 concentration was calculated as the product of O2 saturation, hemoglobin concentration, and a hemoglobin binding capacity of 1.36 ml/g (37). Systemic O2 supply was calculated as the product of the arterial O2 concentration and the systemic blood flow. Whole body O2 consumption (VO2) was calculated by multiplying the arteriovenous O2 concentration difference by systemic blood flow. Myocardial VO2 was calculated by multiplying the aortocoronary sinus O2 concentration difference by the blood flow to the left ventricular free wall obtained with the radioactive microspheres (16). Myocardial substrate supply was calculated by multiplying the arterial substrate concentration by the blood flow to the left ventricular free wall.

The oxidation of a 13C-enriched substrate (Sox; in µmol · min-1 · 100 g-1) relates to the 13CO2 release by the myocardium (4)
S<SUB>ox</SUB> = <FR><NU>1</NU><DE>F<SUB>s<SUB>ao</SUB></SUB></DE></FR> ⋅ <A><AC>Q</AC><AC>˙</AC></A> ⋅ <FR><NU>1</NU><DE><IT>k</IT></DE></FR> ⋅ ([<SUP>13</SUP>CO<SUB>2</SUB>]<SUB>cs</SUB> − [<SUP>13</SUP>CO<SUB>2</SUB>]<SUB>ao</SUB>) (3)
where Fs is the molar fraction of 13C in the substrate, Q is the myocardial blood flow (in ml · min-1 · 100 g-1), k is the number of 13C atoms in a molecule of substrate (k = 1 for [1-13C]lactate and k = 6 for [U-13C]glucose), and [13CO2]cs and [13CO2]ao are the 13CO2 concentrations (in µmol/ml) in the coronary sinus and aorta, respectively.

For lactate, there is release as well as uptake of the substrate by the myocardium. Therefore, the substrate uptake (Sup; in µmol · min-1 · 100 g-1) is calculated from the difference in 13C-enriched substrate concentration (in µmol/ml) between the aorta and coronary sinus
S<SUB>up</SUB> = <FR><NU>1</NU><DE>F<SUB>s<SUB>ao</SUB></SUB></DE></FR> ⋅ <A><AC>Q</AC><AC>˙</AC></A> ⋅ (F<SUB>S<SUB>ao</SUB></SUB> ⋅ [S]<SUB>ao</SUB> − F<SUB>s<SUB>cs</SUB></SUB> ⋅ [S]<SUB>cs</SUB>) (4)
where [S] is substrate concentration.

The substrate release (Sre; in µmol · min-1 · 100 g-1) follows from
S<SUB>re</SUB> = <A><AC>Q</AC><AC>˙</AC></A> ⋅ ([S]<SUB>cs</SUB> − [S]<SUB>ao</SUB>) + S<SUB>up</SUB> (5)
To assess the relative participation of lactate and glucose in myocardial oxidative metabolism, we multiplied the amounts of these substrates calculated in Eq. 3 by the amount of O2 required for the complete oxidation of 1 mol of substrate (N). For the other substrates we resorted to calculating the O2 extraction ratio (OER)
OER = <FR><NU>([S]<SUB>ao</SUB> − [S]<SUB>cs</SUB>) ⋅ N</NU><DE>[oxygen]<SUB>ao</SUB> − [oxygen]<SUB>cs</SUB></DE></FR> (6)
where [S]ao - [S]cs is the aortocoronary sinus concentration difference for substrate and [O2]ao - [O2]cs is the aortocoronary sinus concentration difference for O2. Nglucose = 6, Nlactate = 3, Nbeta -hydroxybutyrate = 4.5, Nacetoacetate = 4, and NFFA = 25 mol/mol (31).

Statistical Analysis

Data are presented as means ± SE. The mean values of the hemodynamic parameters and substrate concentrations of both studies taken together are presented when two similar studies with the different 13C-labeled substrates were performed in the same lamb. Student's two-tailed t-test for unpaired samples was used to compare the differences in hemodynamic variables between shunt and control lambs. Wilcoxon's signed-rank test was used to compare the arterial concentrations and arteriovenous differences of substrates, CO2, and isotope ratios of lactate, glucose, and CO2, the myocardial net substrate uptake, the myocardial glucose and lactate oxidation, and the myocardial lactate release between shunt and control lambs. Student's two-tailed t-test or Wilcoxon's signed-rank test for matched pairs was used to compare the variables before and during exercise in the exercise group. Linear regression analysis was performed with the use of a statistical computer program (NCSS, Kaysville, UT). A P value <0.05 was considered as statistically significant.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Resting Group

At the day of the study there were no differences in age (45 ± 1 vs. 47 ± 1 days) between control and shunt lambs. Weight tended to be lower in shunt lambs (11.3 ± 0.8 vs. 13.5 ± 0.7 kg; P = 0.06). The left-to-right shunt led to significant hemodynamic and O2-related differences between shunt and control lambs that were similar to those previously reported from our laboratory (19, 44) (Table 1). Myocardial blood flow was significantly higher in shunt than in control lambs. The mass of the left ventricular free wall was higher in shunt than in control lambs (34 ± 2 vs. 27 ± 1 g; P < 0.001).

                              
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  		Table 1.   Hemodynamic data and oxygen-related variables for resting group

Arterial O2 and substrate concentrations and myocardial net uptake are shown in Fig. 1. Arterial O2 concentration was lower in shunt than in control lambs. Mean arterial glucose and lactate concentrations were similar in shunt and control lambs. Mean myocardial glucose supply was higher in shunt than in control lambs (726.6 ± 88.2 vs. 502.9 ± 45.6 µmol · min-1 · 100 g-1; P < 0.05). The myocardial glucose uptake was also higher in the shunt lambs, but the difference did not reach statistical significance. This was also true for mean myocardial lactate supply, which tended to be higher in shunt than in control lambs (201.1 ± 36.1 vs. 141.9 ± 15.2 µmol · min-1 · 100 g-1). In both shunt and control lambs there was a negative myocardial net lactate uptake consistent with net myocardial lactate release (Fig. 1). There was no significant difference between shunt and control lambs in mean myocardial net uptake of any substrate, except for acetoacetate, which was significantly higher in shunt than in control lambs (Fig. 1). Myocardial uptake of FFA tended to be lower in shunt than in control lambs (Fig. 1).


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  		Fig. 1.   Arterial O2 and substrate concentrations and myocardial net uptake in control (open bars; n = 9) and shunt lambs (filled bars; n = 8) of resting group. Data are means ± SE. * P < 0.05, shunt vs. control. BOB, beta -hydroxybutyrate; FFA, free fatty acid. When 2 similar studies with different 13C-labeled substrates were performed within 1 lamb, we used mean values of both studies taken together.

Table 2 shows that the mean myocardial lactate oxidation was higher in shunt than in control lambs and that the mean myocardial lactate release tended to be lower in the shunt lambs. In both shunt and control lambs myocardial uptake and release, as determined with 13C-labeled substrates, were balanced, which resulted for both groups of lambs in a net lactate uptake that was not statistically different from zero. The myocardial glucose oxidation was not different between shunt and control lambs and was not statistically different from zero (Table 2).

                              
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  		Table 2.   Mean myocardial uptake, release, and oxidation of [1-13C]lactate and myocardial uptake and oxidation of [U-13C]glucose in resting group

The contributions of FFA, beta -hydroxybutyrate, acetoacetate, and lactate to the OER were 56.4, 40.0, 1.9, and 0% in control lambs and 22.8, 36.2, 5.3, and 5.1% in shunt lambs, respectively.

There was a statistically significant correlation between myocardial lactate supply and myocardial lactate uptake for control lambs but not for shunt lambs (Fig. 2). There was neither a correlation between arterial concentration of glucose or lactate and myocardial uptake or oxidation of these substrates nor a correlation between myocardial supply of glucose or lactate and oxidation of the substrates.


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  		Fig. 2.   Correlation between myocardial lactate supply and myocardial lactate uptake in control and shunt lambs of resting group. A: control lambs (r = 0.67, P < 0.01, n = 15, y = -14.4 + 0.23x). B: shunt lambs (r = 0.19, not significant, n = 19, y = 7.0 + 0.03x).

Exercise Group

At the day of the study there were no differences in age (45 ± 1 vs. 46 ± 1 days) between control and shunt lambs. Weight tended to be lower in shunt lambs (12.0 ± 0.7 vs. 13.7 ± 0.6 kg). The left-to-right shunt led to significant hemodynamic and O2-related variables between shunt and control lambs (Table 3), as was found in the resting group. The hemodynamic response to moderate exercise was similar in shunt and control lambs, and most of the differences that existed between the two groups before exercise persisted during exercise. Heart rate increased in both shunt and control lambs during exercise. Systemic blood flow, systemic O2 supply, and VO2 increased during exercise in both shunt and control lambs. Myocardial blood flow, which before exercise was significantly higher in shunt than in control lambs, increased during exercise in both groups of lambs to a similar absolute value.

                              
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  		Table 3.   Hemodynamic data and oxygen-related variables at rest and during moderate exercise (50% of VO2 peak ) in exercise group

Arterial O2 and substrate concentrations and myocardial net uptake before and during exercise are shown in Fig. 3. Arterial concentrations of glucose, pyruvate, and lactate increased in both groups of lambs during exercise, whereas the arterial concentrations of beta -hydroxybutyrate decreased. The mean myocardial net uptake of acetoacetate was during exercise higher than before exercise in both shunt and control lambs despite the absence of a change in arterial concentration (Fig. 3).


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  		Fig. 3.   Arterial O2 and substrate concentrations and myocardial net uptake in control (open bars; n = 9) and shunt lambs (filled bars; n = 8) of exercise group. Data are means ± SE. * P < 0.05, shunt vs. control. § P < 0.05, rest vs. exercise. When 2 similar studies with different 13C-labeled substrates were performed within 1 lamb, we used mean values of both studies taken together.

Table 4 shows that the mean myocardial lactate oxidation before exercise tended to be higher in shunt than in control lambs. In both shunt and control lambs we found an increase in myocardial glucose and lactate oxidation during exercise compared with the values before exercise.

                              
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  		Table 4.   Mean myocardial uptake, release, and oxidation of [1-13C]lactate and myocardial uptake and oxidation of [U-13C]glucose before and during moderate exercise (50% of VO2 peak ) in exercise group

The contributions of FFA, beta -hydroxybutyrate, acetoacetate, and lactate to the OER were 64.0, 38.7, 3.4, and 0% before exercise and 53.3, 25.6, 5.1, and 5.1% during exercise in control lambs, respectively. In shunt lambs, the contributions were 51.5, 34.0, 4.4, and 2.1% before exercise and 47.0, 21.5, 4.5, and 11.2% during exercise, respectively. The contribution of lactate in myocardial oxidative metabolism during exercise was higher in shunt than in control lambs (11.2 vs. 5.1%). The total contribution of carbohydrates (glucose and lactate) in myocardial metabolism during exercise was higher in shunt than in control lambs (36.1 vs. 19.4%).

There was a statistically significant correlation between the arterial lactate concentration and myocardial lactate oxidation (Fig. 4).


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  		Fig. 4.   Correlation between arterial lactate concentration and myocardial lactate oxidation in both control (open circle ) and shunt lambs (bullet ) of exercise group. Line represents best fit between data points [y = 48(e0.0002x - 1)].

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

We found that, in the resting group, myocardial lactate oxidation in shunt lambs was higher than in control lambs despite similar arterial lactate concentrations. Myocardial glucose oxidation was not statistically different from zero in the two groups of lambs. For a proper interpretation of these results we should consider the overall picture of myocardial metabolism. We found that, in shunt lambs, myocardial metabolism was shifted from FFA to carbohydrates and acetoacetate. This shift is in agreement with other studies in which a preferential use of carbohydrates and acetoacetate by the myocardium was shown during a higher load (14, 15, 19, 25, 29, 31, 40). In the control lambs FFA and beta -hydroxybutyrate accounted for almost all the myocardial VO2 (96.4%), whereas in the shunt lambs these substrates accounted for only 59.0% of the myocardial VO2. Lactate and acetoacetate accounted for another 10.4%. The myocardial uptake of glucose was 21.3 ± 10.3 µmol · min-1 · 100 g-1, which could have accounted for 20.9% of the myocardial VO2 if this exogenous glucose had been oxidized. However, the oxidation of exogenous glucose by the myocardium was zero. Therefore, the sum of the OER does not add up to 100% in shunt lambs, which suggests that endogenous substrates are utilized for oxidation. The exogenous glucose taken up by the myocardium may have been utilized for lactate release or formation of glycogen, whereas endogenous glycogen was broken down for oxidation. Wisneski et al. (45) also found that only 20.1 ± 19.4% of the glucose uptake underwent oxidation and concluded that the remainder of the glucose uptake is probably stored as glycogen. The latter is consistent with the concept of Henning et al. (23), who showed that exogenous glucose is converted to glycogen and that the degradation of glycogen takes place in a random order. Although at first sight one would not expect that exogenous glucose disappears into glycogen stores during fasting, Schneider and Taegtmeyer (41) have shown in rat hearts that, especially during fasting, the myocardial glycogen content was raised. The presence of glycogen in biopsies of the left ventricle in our shunt lambs, but not in the control lambs (unpublished data), favors the possibility that glycogen is available for oxidation in the myocardium of the shunt lambs.

In the exercise group we found a higher myocardial lactate oxidation in shunt than in control lambs, both before and during exercise, although the results before exercise were not statistically significant different between shunt and control lambs. Myocardial lactate oxidation increased during exercise in both shunt and control lambs as was expected (Table 4). This is in agreement with the relationship found between the myocardial lactate oxidation and the arterial lactate concentration, which increased during exercise (Fig. 4). A similar relationship has been described by Gertz et al. (18) in humans. Furthermore, our results demonstrate that, in addition to carbohydrates, acetoacetate is a preferred fuel when the myocardium needs to work at a higher load, as in the shunt lamb at rest and during exercise in both the shunt and control lambs.

The reason for this study was to analyze the higher myocardial net lactate uptake in shunt lambs compared with that in control lambs, as previously found in our laboratory (19). In the present experiments, however, the net lactate uptake was negative (Fig. 1). This difference in net uptake from the former experiments probably results from the difference in feeding status of the lambs. In the present experiments 18-h fasted lambs were used to minimize the differences in feeding status between the groups of lambs, whereas during the former experiments the lambs were in a fed state. Because of fasting, a situation in which FFA and ketone bodies become more important as substrates for the myocardium, the myocardial net lactate uptake decreases to approximately zero in our study, as also has been shown by others (2, 18).

We found that lactate uptake and release occurs simultaneously in the myocardium of both shunt and control lambs, as was described by others in humans with normal and ischemic hearts (17, 42). The evidence that lactate and pyruvate metabolism in the myocardium is compartmentalized in different layers of the myocardium (27, 35, 38) is in accordance with the simultaneously occurring uptake and release of lactate. The results of Leunissen and Piatnek-Leunissen (35) in dogs suggested that there may be a transmural gradient in myocardial metabolism with glycolysis in the endocardium and oxidation in the epicardium. This transmural gradient is in agreement with the results of Jedeikin (27), who found that cells in the endocardial layers contain more glycogen than cells in the epicardial layers. These findings are further supported by Lundsgaard-Hansen et al. (38), who found a transmural gradient of glycolytic enzyme activity. In addition, the nonhomogenous flow across the myocardial wall fits in with the compartmentalization model of myocardial lactate metabolism (32). Gratama et al. (20) found that both subepicardial and subendocardial blood flows were higher in shunt lambs than in control lambs. However, the subendocardial-to-subepicardial blood flow ratio of the left ventricular free wall was significantly lower in shunt lambs than in control lambs. There probably was a relatively higher subepicardial blood flow in shunt lambs, which may favor the increased lactate oxidation that probably takes place in the epicardium.

It has generally been assumed that the fate of lactate taken up by the myocardium is oxidation (6, 22). However, we found that, in the shunt lambs of the resting group, 76% of the lactate taken up by the myocardium was immediately oxidized, whereas, in control lambs, the lactate taken up by the myocardium did not seem to be oxidized at all. In the exercise group, these percentages during exercise were 66 and 37%, respectively. A similar finding was obtained by Brooks et al. (7) in human leg muscles. They found that, at rest, only 4.5 ± 3.1% of the lactate uptake was oxidized. During exercise, however, this percentage increased to 93.1 ± 26.5% (7). Jorfeldt (28) found that only 52% of the skeletal muscle lactate uptake in an exercising forearm was oxidized. In humans with symptomatic but stable ischemic heart disease at rest, Gertz et al. (17) found a mean myocardial lactate oxidation of 85% (range: 59-110%) of the myocardial lactate uptake, whereas Stanley (42) found that, during exercise, the percentage of myocardial lactate oxidation increased to 100%.

The difference between myocardial lactate uptake and oxidation raises the question of the fate of lactate that was taken up by the myocardium but not oxidized. In the cell, lactate is interchangeable with pyruvate produced from exogenous glucose or from breakdown of endogenous glycogen (17). Lactate, via pyruvate, is in equilibrium with alanine (34, 36). Therefore, lactate taken up by the myocardium may disappear into alanine or pyruvate.

Whether uptake and release of lactate actually means uptake and production or simply exchange between intra- and extracellular lactate is a matter of debate (34). The lower isotope ratio of lactate in the coronary sinus in control lambs compared with that in the aorta, in combination with a net lactate release of zero and a lactate oxidation of zero, favors the exchange of label and not of actual lactate uptake and production. On the other hand, in shunt lambs, actual uptake of lactate must have occurred because there was a considerable amount of lactate oxidation, and, because the net lactate release was zero, there actually was lactate production, not just exchange of label.

In in vitro studies with NMR, different pools of pyruvate, which are either in slow exchange or nonexchanging, were described in the cytosolic compartment of the myocardium (8, 9, 36, 39). There may not be a rapid equilibration between cytosolic and mitochondrial pyruvate. Zhao et al. (48) showed that one pool of lactate is tightly bound to macromolecules, which results in an apparently metabolically inactive pool, and that the other pool is free and in rapid exchange with tissue pyruvate. Moreover, the ratio of free to bound lactate pools may change in response to changes in cardiac work or substrate utilization or after physiological pertubations such as ischemia (9). The concept of intracellular compartmentalization of lactate and pyruvate might explain that not all exogenous lactate is oxidized because it does not immediately enter the intramitochondrial pyruvate pool. In control lambs, lactate taken up by the myocardium was not oxidized at all. This may be due to exogenous lactate not entering the intramitochondrial pyruvate pool. The correlation found between myocardial lactate supply and myocardial lactate uptake in control lambs of the resting group (Fig. 2) may favor a gradual exchange between exogenous lactate and endogenous lactate that does not enter into the intramitochondrial pyruvate pool. [1-13C]lactate present in blood exchanges slowly with [12C]lactate present in the cytosol of the myocardial cell according to the concentration gradient, although there is no oxidation and no production of 13CO2. However, in the myocardium of the shunt lambs, in which [1-13C]lactate is oxidized and converted to 13CO2, the intramitochondrial pool is active. This activity of the intramitochondrial pool in addition to a cytosolic pool appears to abolish the correlation between the myocardial lactate supply and the myocardial lactate uptake.

There are several possible explanations for the increased myocardial lactate oxidation in shunt lambs. First, in the hypertrophic myocardium, which must exert much effort, it is more efficient to oxidize substrates such as lactate or glucose, which generate more ATP per mole of O2 than other substrates (13, 26, 31). Second, the hypertrophy of the myocardium of the shunt lambs may result in a shift from oxidation of FFA to oxidation of lactate, because it has been shown that hypertrophy in rat hearts, due to a pressure or volume overload, leads to a reduced carnitine content that is associated with reduced fatty acid oxidation (1, 14, 40). The shortage of carnitine may also lead to a shift from FFA to acetoacetate, because carnitine is necessary for the transport of FFA into the mitochondria, whereas it is not indispensible for the transport of ketone bodies (15). Third, the hypertrophy may lead to a change in gene expression, resulting in the formation of fetal myocardial protein isoforms (30), which stimulate the oxidation of lactate similar to that occurring in the fetal myocardium (10, 46).

In conclusion, we have found that, after an overnight fast, myocardial lactate oxidation is higher in shunt than in control lambs despite similar arterial lactate concentrations and that, during exercise, myocardial lactate oxidation is increased in both groups of lambs. There was no difference in myocardial lactate release between shunt and control lambs. Oxidation of exogenous glucose, which was approximately zero at rest, increased during exercise in shunt and control lambs. The contribution of carbohydrates in myocardial oxidative metabolism in shunt lambs is higher in shunt than in control lambs. Thus it appears that this higher contribution of carbohydrates occurs not only in the case of pressure-overloaded hearts but also in myocardial hypertrophy due to volume overloading.

    ACKNOWLEDGEMENTS

The authors thank Berthe M. A. A. Verstappen-DuMoulin and G. Henk Visser for the analysis of the isotope ratios of CO2 in blood, Gijs T. Nagel for the analysis of the isotope ratios of lactate and glucose, Alie M. Gerding for the computation of the microspheres, Peter Nikkels for microscopic examination of glycogen in the myocardial biopsies, and Klaas R. Visser for the statistical analysis and fit of Fig. 4.

    FOOTNOTES

This study was supported by a grant from the Netherlands Heart Foundation (NHS 90.250).

Part of this study was presented at the Annual Scientific Session of the American Pediatric Society/Society for Pediatric Research, May 6-10, 1996, Washington, DC.

Address for reprint requests: G. C. M. Beaufort-Krol, Beatrix Children's Hospital, Div. of Pediatric Cardiology, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, The Netherlands.

Received 31 December 1997; accepted in final form 9 July 1998.

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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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