John C. Werner

Lactate metabolism of isolated, perfused fetal, and newborn pig hearts.

ABSTRACT. The role of lactate as an energy substrate in fetal (0.9 gestation) and newborn (2 day old) hearts was investigated in isolated, perfused hearts. Perfusions were performed with Krebs-Henseleit buffer supplemented with glucose (5 mM) in combination with varying concentrations of lactate. Isolated working heart perfusions, in which the heart ejects the buffer at controlled pressure, were carried out with glucose (5 mM) alone and with glucose (5 mM) and lactate (5 mM) combined. With glucose as sole substrate, lactate was produced by the heart and glucose uptake accounted for approximately two-thirds of oxygen consumption. When both glucose and lactate were provided, lactate accounted for more than 80% of oxygen consumption and profoundly suppressed glucose uptake. Further investigations using retrograde perfusion through the aorta demonstrated that lactate uptake was consistently observed when exogenous lactate concentrations exceeded 1.25 mM. Glucose uptake was suppressed with lactate concentrations as low as 0.5 mM and progressive suppression occurred with increasing lactate concentrations. Fetal and newborn pig hearts utilize lactate as a primary substrate for energy production when lactate concentrations are in the physiological range.

Dexamethasone induces a transient relative cardiomegaly in neonatal rats

ABSTRACT: Effects of s.c. administration of dexamathasone (1–25 μg/rat pup/d) during the first 5 d postpartum on survival rates, body weight, heart weight, heart-to-body weight ratios, and heart dimensions were determined. Dexamethasone decreased survival, body weight, and heart weight, but increased heart-to-body weight ratios and myocardial percentage of dry weight (0.44 to 0.52–1.06 and 20 to 23%, respectively; p < 0.05) by 7 d postpartum. By 21 d postpartum, differences in absolute body weight and heart weight between control and experimental animals were reduced; however, myocardial percentage of dry weight and heart-to-body weight ratios were indistinguishable. Microscopic analysis of 7-d-old hearts disclosed that interventricular septum, left ventricular free wall thicknesses, and left ventricle chamber diameter were reduced (0.93 to 0.76–0.85 mm, 1.19–1.34 to 0.92–1.07 mm, and 1.35–1.40 to 0.89–1.23 mm, respectively; p < 0.05), whereas right ventricular free wall thickness was unaffected and right ventricle chamber diameter was increased (0.29–0.31 to 0.42–0.46 mm) by dexamethasone. Thus, dexamethasone reduced survival and retarded growth of neonatal rats. Retardation of heart growth was less severe, producing a transient relative cardiomegaly characterized by 1) increased myocardial percentage of dry weight, 2) increased left ventricular free wall-to-chamber ratio, and 3) retention of absolute right ventricular free wall thickness. This relative cardiomegaly appeared to be resolved by 21 d postpartum, as reflected in myocardial percentage of dry weight and heart-to-body weight ratios. These data suggest that this system might be a useful model for elucidating cellular and molecular mechanisms through which ventricular hypertrophy might arise in infants receiving dexamethasone therapy for bronchopulmonary dysplasia.

Mitral valve prolapse in persons with down syndrome

This study was designed to determine the prevalence of mitral valve prolapse and aortic insufficiency in home-reared, young persons with Down syndrome. Of the 36 individuals (ages 20-32 years) enrolled in this study, 20 had abnormal echocardiographic findings. Thirteen patients had mitral valve prolapse, 3 had both mitral valve prolapse and aortic insufficiency, 2 had only aortic insufficiency, and 2 had other mitral valve disorders. In 14 of the 16 patients with mitral valve prolapse, a midsystolic click was heard. Theories of the pathogenesis and possible complications of mitral valve prolapse and its relationship to exercise and sport activities are discussed.

Insulin Reduces Basal Release of Atrial Natriuretic Factor by Isolated, Perfused Neonatal Pig Hearts

Plasma atrial natriuretic factor (ANF) levels are markedly altered in diabetic rodents suggesting that insulin might be a modulator of ANF release. Effects of insulin (25 mU/ml) on basal (nonstimulated) immunoreactive (ir)-ANF release by isolated neonatal pig hearts paced at 150 beats/min and perfused with no change in atrial stretch were examined. Release of ir-ANF decreased with age from 1-3 days postpartum (146.0 +/- 38.4 to 62.2 +/- 20.5 fmol/g/min). Insulin stimulated myocardial glucose utilization and lactate production approximately 2-fold, but uniformly decreased ir-ANF release by approximately 25%, regardless of age. Correlations between ir-ANF release and myocardial metabolism suggest independent influences of insulin on these two events. In addition, it appears that this model might be reasonably exploited to investigate episodic ANF release and its regulation during ontogeny and in a variety of physiological states.

EFFECTS OF LOW DOSE PROPHYLACTIC INDOMETHACIN (plndo) ON HEMODYNAMICS IN VERY LOW BIRTH WEIGHT (VLBW) INFANTS. † 1512

EFFECTS OF LOW DOSE PROPHYLACTIC INDOMETHACIN (plndo) ON HEMODYNAMICS IN VERY LOW BIRTH WEIGHT (VLBW) INFANTS. † 1512

Atrial natriuretic peptide in newborn piglets with a patent ductus arteriosus.

Atrial natriuretic peptide (ANP) is a hormone involved in fluid and blood pressure homeostasis. We studied the effects of left-to-right shunting through a patent ductus arteriosus on blood pressure changes and plasma ANP concentrations in newborn piglets. In five experimental piglets, the ductus arteriosus was bathed with PGE1 and infiltrated with formalin to maintain its patency. In four age-matched control piglets, the ductus arteriosus was ligated. Plasma ANP concentrations and blood pressure determinations were obtained prior to (base-line) and 25 +/- 1 h (day 1), and 48 +/- 1 h (day 2) after surgery. Radionuclide-microsphere determinations of left-to-right patent ductus arteriosus shunts were performed on days 1 and 2 in the 5 piglets with a patent ductus arteriosus. Plasma ANP concentrations were significantly elevated in the left atrium on day 1 and the right atrium on day 2 in the PDA piglets. No correlation was demonstrated between plasma ANP concentrations and right or left atrial pressures. We conclude that left and right plasma atrial ANP concentrations are significantly elevated in newborn piglets with left-to-right patent ductus arteriosus shunts.

Antenatal Steroids and Hemodynamic Maturation of Very Low Birth Weight (VLBW) Infants |[dagger]| 1114

Antenatal glucocorticoids (AG) for the prevention of respiratory distress syndrome in VLBW infants reduce the incidence of patent ductus arteriosus, intraventricular hemorrhage and necrotizing enterocolitis. In preterm fetal lambs, AG increase postnatal cardiac output (CO), heart rate (HR) and blood pressure (BP). We hypothesized that AG improve hemodynamic maturation in preterm infants. Twenty infants (750-1250 g; 24-31 wk) were enrolled in a prospective observational study. We measured middle cerebral (C) and superior mesenteric (M) artery Doppler blood flow velocities (BFV) and cardiac function at 6, 30, 54 and 168 hr of life. Infants were divided into three groups: non-treated controls (n=6), one dose (n=4), and two or more doses (n=10) of AG. Mean and end-diastolic CBFV increased (ANOVA, p<0.0001) by 83 and 230%, respectively, from 6 to 168 hr of age. Cerebral relative vascular resistance(RVR) decreased (ANOVA, p<0.05) by 27%. Mean MBFV and MRVR did not change, but end-diastolic MBFV increased (ANOVA, p<0.05) by 47%. HR, BP, and CO (fig.) increased (ANOVA, p<0.001) by 7, 35, and 60%, respectively. Contractility did not change. Mean and end-diastolic CBFV, mean and end-diastolic MBFV, CRVR, MRVR, HR, BP, CO and contractility did not differ among groups. We conclude that AG do not alter Doppler ultrasound indices of postnatal hemodynamic maturation in VLBW infants. Funded by Wyeth Pediatrics.

HEMODYNAMIC MATURATION IN VERY LOW BIRTH WEIGHT (VLBW) INFANTS.|[dagger]| 1511

We investigated regional hemodynamic maturation over the first two weeks of life in 17 VLBW infants (775 to 1245 g, 24 to 31 weeks gestation). Infants did not have symptomatic PDA but were given indomethacin (Indo) for IVH prophylaxis. Middle cerebral (C) and superior mesenteric artery (M) Doppler blood flow velocities (BFV) and cardiac function were recorded before Indo at 6, 30 and 54 hours of age and before and after feeding on days 7 and 14 of life (Fig., M ± SE). Cardiac output (CO) increased (ANOVA, p < 0.05) over the first 14 days of life as a result of combined increases in stroke volume and heart rate (p < 0.05). Contractility did not change. Mean and end-distolic CBFV increased by 71 and 374%, respectively (ANOVA, p < 0.05), from 6 to 54 hours of life with no further change from 3 to 14 days. In contrast, baseline MBFV did not change over the first 54 hours of life, but coincident with the initiation of feedings increased by 54% (ANOVA, p < 0.05) from 3 to 14 days. In response to feeding, mean MBFV increased 35% (p < 0.05) on day #7 and 17% (p = ns) on day #14. The post-prandial MBFV did not differ significantly on days 7 and 14. Maturational increases in cardiac function and regional BFVs were not related statistically to changes in ductus arteriosus patency, BP, SaO2, pH or PaCO2. We conclude that in VLBW infants, cerebral and mesenteric regional BFVs and CO increase significantly over the first 2 weeks of life. Region specific patterns of hemodynamic maturation are observed, with cerebral BFV increasing in the first 54 hours of life and preprandial mesenteric BFV increasing from 3 to 14 days, after enteral nutrition has been established. (Supported by Wyeth Pediatrics.)

226 HEMODYNAMIC EFFECTS OF PROLONGED SEIZURES IN NEONATAL PIGS

The cardiovascular effects of seizures in the neonate are not well defined. To determine the changes in systemic and pulmonary artery pressure, cardiac output, and left ventricular contractility during seizures, one week old pigs were intubated, paralyzed, mechanically ventilated, and catheterized with a swan-ganz catheter. Seizures were induced with bicuculline (5 mg/kg/hr continuously i.v.) in 5 animals (6 controls received saline). Early changes consisted of significant systemic and pulmonary arterial hypertension. After 2 hours of seizures, the animals developed progressive systemic hypotension (saline, 93 ± 4 mmHg; bicuculline, 66 ± 8; Mean ± SE; p<0.01; student t test) and decreased cardiac function (cardiac output: saline, 174 ± 27 ml/kg/min; bicuculline, 91 ± 15 ml/kg/min; p<0.01). M-mode echocardiography disclosed a decrease in left ventricular contractility (Ejection Fraction: Saline, 0.70 ± 0.03; bicuculline, 0.49 ± 0.08; p<0.001). Cardiac tissue frozen in situ showed significant increase in lactate (Saline, 13.3 ± 0.7 mmol/g/dry wt.; bicuculline, 102.8 ± 4.9: p<0.01), and reductions in glucose, triglyceride, and ATP (Saline, 17.1 ± 0.1 mmol/g/dry wt.; bicuculline, 11.5 ± 0.3; p<0.01). Prolonged seizures result in severe cardiac dysfunction which may be due to tissue acidosis or catecholamine release.

155 THE ROLE OF LACTATE IN MEETING THE ENERGY REQUIREMENTS OF THE LATE FETAL HEART

An isolated perfused working heart preparation was used to investigate the role of lactate in the energy metabolism of the fetal heart. Hearts were perfused under working conditions with Krebs-Henseleit buffer containing either glucose 5mM or glucose 5mM and lactate 5mM combined. Insulin 100 μU/ml was present in all perfusions. Pressure development in both great vessels was maintained at 55 mmHg and mean atrial pressure was adjusted to 6 mmHg. Glucose uptake was measured by production of 3H2O from 23H glucose and lactate uptake by measuring changes in buffer concentration. With glucose as the sole exogenous substrate its utilization(3.48 ± .29 μmol/min/g dry), corrected for lactate production by the heart(3.06 ± μmol/min/g dry)could account for only 56 ± 9% of the total oxygen consumption of the heart(20.7 ± μmol/min/g dry). When both glucose and lactate were present in the buffer, glucose uptake was inhibited(0.71 μmol/min/g dry)and lactate- uptake(6.55 μmol/min/g dry)accounted for approximately 91 ± 12% of the total oxygen consumption(22.3 ± 1.8 μmol/min/g dry). These findings suggest that lactate oxidation is the primary source of metabolic energy for the fetal heart in late gestation, since glucose alone does not satisfy the oxidative needs of the fetal heart and since the presence of lactate profoundly suppresses glucose uptake. Lactate is the primary metabolic substrate for the fetal heart when present in concentrations similar to those observed in vivo, much as lipids are the primary metabolic substrate in more mature hearts.