Gioia B. Smid

Perinatal changes in myocardial supply and flux of fatty acids, carbohydrates, and ketone bodies in lambs

No information is available on perinatal changes in myocardial metabolism in vivo. We measured myocardial supply and flux of fatty acids, carbohydrates, and ketone bodies in chronically instrumented fetal, newborn (1-4 days), and juvenile (7 wk) lambs, by measuring aorta-coronary sinus concentration differences and blood flow. In the fetal lambs, myocardial supply and flux of fatty acids were zero. In the newborn lambs, the supply of fatty acids increased tenfold, but there was no flux of fatty acids. Carbohydrates were the major energy source in fetal and newborn lambs, accounting for 89 and 69% of myocardial oxygen consumption, respectively. In the juvenile lambs, the flux of fatty acids was increased threefold. The supply and flux of carbohydrates were decreased (by 31 and 82%, respectively). The supply and flux of ketone bodies gradually increased with age. We show that the myocardium of the lamb in vivo does not switch immediately after birth from carbohydrates to fatty acids. The mechanisms involved in the development of myocardial fatty acid oxidation remain to be elucidated.

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

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 micromol. 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.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 with13C-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 O2consumption) 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.

Determination of organ substrate oxidation in vivo by measurement of 13CO2 concentration in blood

Substrate oxidation by various organs in animals as well as in humans is usually studied by experiments in which radioactively labeled substrates are used and the production of 14CO2 is measured. In vivo, substrate oxidation by an organ has, up to now, not been determined by means of stable isotopes. Problems in the determination of the concentration of 13CO2 in blood may have impeded the use of 13C-labeled substrates. For the determination of 13CO2 concentration in blood a direct method for the determination of total CO2 concentration in blood was combined with the determination of the isotope ratio (13C/12C) of CO2 by isotope ratio mass spectrometry. The intra-assay relative standard deviation of the CO2 concentration (mean: 19.26 mmol l-1; n = 7) was 0.8%. The inter-assay relative standard deviation of the CO2 concentration in solutions of a weighed amount of Na2CO3 determined over a 5 year period was 0.64% (mean: 21.99 mmol l-1; n = 22). The intra-assay relative standard deviation of 13C in CO2 was 0.03% (mean 13C/12C: 0.0111557; n = 5). From the 13CO2 concentration in arterial and venous blood, substrate oxidation by various organs can be calculated. As an illustration, the determination of myocardial glucose oxidation in lambs, both at rest and during exercise, is described.

Lower arterial glucose concentrations in lambs with aortopulmonary shunts after an 18-hour fast

Spontaneously occurring hypoglycemia has been described in children with severe acute congestive heart failure. Hypoglycemia may be the result of an increase in glucose utilization in tissues, a decrease in glucose production, or a decrease in the dietary intake of nutrients. To determine whether hypoglycemia may also occur in congenital heart disease with volume overloading, we investigated glucose metabolism during and after an 18-hour fast in nine lambs with an aortopulmonary left-to-right shunt and nine control lambs. Plasma levels of hormones involved in the endocrine control of glucose metabolism were determined. The glucose production rate (rate of appearance [Ra]) was studied using [U-13C]glucose. Gluconeogenesis through the Cori cycle was estimated by measuring glucose 13C recycling. The arterial glucose concentration (3,409 +/- 104 v 4,338 +/- 172 micromol/L, P < .001) and Ra of glucose (16.97 +/- 0.89 v 25.49 +/- 4.28 micromol x min(-1) x kg(-1), P < .05) were lower in shunt versus control lambs. There were no differences in hormone levels between control and shunt lambs. Fractional glucose 13C recycling via the Cori cycle (6.9% +/- 2.8% v 7.1% +/- 2.5%) and gluconeogenesis from pyruvate and lactate (1.24 +/- 0.58 v 1.95 +/- 0.67 micromol x min(-1) x kg(-1)) were similar in both groups of lambs. The sum of glycogenolysis and gluconeogenesis from precursors other than pyruvate and lactate was lower in shunt versus control lambs (15.73 +/- 1.07 v 23.54 +/- 4.27 micromol x min(-1) x kg(-1), P < .05). In conclusion, after an 18-hour fast, the arterial glucose concentration is lower in lambs with aortopulmonary shunts. This lower glucose concentration is associated with a decreased glucose production rate. In shunt lambs, glycogenolysis is decreased, while there is no difference in gluconeogenesis or hormonal control.

Increased myocardial lactate oxidation in lambs with an aortopulmonary left-to-right shunt.

INCREASED MYOCARDIAL LACTATE OXIDATION IN LAMBS WITH AN AORTOPULMONARY LEFT-TO-RIGHT SHUNT. † 118

METABOLIC RESPONSE TO MODERATE EXERCISE IN LAMBS WITH AN AORTOPULMONARY SHUNT

The normal metabolic response to moderate exercise consists of a slight increase in glucose (glue) and a considerable increase in free fatty acids (FFA) in blood. In earlier studies we have demonstrated that at rest, after an overnight fast, lambs with an aortopulmonary shunt (SH) had lower concentrations of glue and FFA than control (C) lambs. We wondered, whether SH lambs with low glue and FFA were able to increase their arterial concentrations during exercise just like C lambs. Therefore, we studied 6 7-week-old SH lambs and 6 C lambs of the same age after an overnight fast at rest and during moderate exercise (tredmill; 50 % of Vo2-max; 30 rain). At rest as well as during exercise, 3 blood samples were taken at intervals of 10 min. At rest, mean arterial concentrations (mmol/l) of glue (SH: 3.37 ± 0.21 vs. C; 4.48 ± 0.53, mean ± SD, p < 0.05) and FFA (SH: 0.57 ± 0.17 vs. C: 0.80 ± 0.20, p < 0.05) were lower in SH than in C lambs. During exercise, glue (SH: 3.59 ± 0.19 vs. C: 5.15 ± 0.80, p < 0.05) and FFA (SH: 0.79 ± 0.32 vs. C: 1.23 ± 0.43, p < 0.05) increased significantly in SH and C lambs (p < 0.05). However, the relative increment of glue during exercise was lower in SH than in C lambs (7 ± 5 % vs. 15 ± 7 %, p < 0.05). The relative increment of FFA was not different (SH: 38 ± 37 % vs. C: 56 ± 47 %, p = 0.48). We conclude that, despite lower gluc and FFA at rest, SH lambs demonstrate a metabolic response of increment of gluc and FFA during moderate exercise like C lambs, However, the relative increment for gluc was lower in SH lambs. We speculate that this is due to an earlier glycogen depleted state in SH lambs.