Dan M. Cooper

Abnormal dynamic cardiorespiratory responses to exercise in pediatric patients after Fontan procedure

OBJECTIVES Novel protocols were used to focus on dynamic cardiorespiratory function during submaximal exercise and on the recovery from 1-min pulses of exercise in children who had undergone Fontan corrections for single-ventricle lesions. BACKGROUND Particularly in children, maximal oxygen uptake (VO2max), which is commonly used to assess the functional capability of patients after the Fontan procedure, is highly effort dependent and not physiologic and leads to uncomfortable metabolic and cardiorespiratory stress. Alternative approaches include the measurement of dynamic responses during progressive exercise and recovery after short bursts of exercise. These strategies yield mechanistic insight into cardiorespiratory impairment and can be used to gauge limitations in daily life activity. METHODS Sixteen patients (mean [+/-SD] age 12.2 +/- 2.4 years; 9 boys) and 10 age-matched control subjects (mean age 12.2 +/- 2.4 years; 6 boys) performed two separate cycle ergometer tests in which gas exchange was measured on a breath by breath basis: 1) Progressive exercise was used to determine the dynamic relation among VO2, carbon dioxide production (VCO2), ventilation (VE), heart rate (HR) and work rate (WR). 2) A 1-min constant WR test was used to determine the recovery time for gas exchange and HR. RESULTS Peak VO2 and anaerobic threshold were reduced in patients who underwent the Fontan procedure compared with control subjects by 57% and 52%, respectively (p < 0.001). Dynamic relations during progressive exercise--deltaVO2/deltaHR and deltaVO2/deltaWR--were decreased (p < 0.001) and deltaVE/deltaVCO2 was increased (p < 0.005) in the Fontan group patients. Recovery times for HR and VO2 were prolonged in the Fontan group patients by 154% and 69%, respectively (p < 0.01). CONCLUSIONS The results demonstrate that submaximal gas exchange responses to progressive exercise and recovery times after brief high intensity exercise are abnormal in patients after the Fontan procedure. These observations complement the findings of reduced VO2max observed here and by others. We speculate that the mechanisms for these responses are related to 1) a pervasive reduction in stroke volume for both low and high intensity exercise, 2) an abnormal linkage of ventilation to tissue carbon dioxide production, and 3) increased dependence on anaerobic metabolism in skeletal muscles. The prolonged recovery of HR and VO2 provides a possible mechanism for reduced physical activity.

Evidence that maturation of the peripheral chemoreceptors is not complete in childhood.

We examined the hypothesis that the peripheral chemoreceptors contribute a different degree of tone to respiration during exercise in normal young children as compared to adults. To improve resolution of the peripheral chemoreceptor contribution, the studies were conducted during controlled levels of exercise. Peripheral chemoreceptor function was assessed by the hyperoxic (FIO2 = 0.80) switch technique during steady-state, sub-anaerobic threshold exercise during air (FIO2 = 0.21) and midly hypoxic gas (FIO2 = 0.15) breathing in 9 healthy children (mean +/- 1 SD age (years) = 8.2 +/- 1.4) and 10 healthy adults (28.2 +/- 6.5). Ventilation during exercise was significantly greater under hypoxic conditions in both children and adults. During air breathing exercise the mean ventilatory decrease in response to the hyperoxic switch was similar in the two groups (27.9 +/- 10.7% in children and 23.3 +/- 6.3% in adults). In contrast, during hypoxic gas breathing exercise the children demonstrated a much greater decrease in ventilation following the hyperoxic switch (57.9 +/- 3.6%) compared to adults (38.9 +/- 5.5%) (P less than 0.0001). Thus, the peripheral chemoreceptors have a greater role in the exercise hyperpnea during hypoxic exercise in young children as compared to adults, suggesting attenuation of peripheral chemoreceptor function during maturation.

Effect of increased metabolic rate on oxygen isotopic fractionation

16O16O is preferentially used over 18O16O (a stable isotope of oxygen comprising about 0.2% of atmospheric O2) as oxygen is consumed during respiration in humans (Epstein and Zeiri, 1988, Proc. Natl. Acad. Sci. USA 85: 1727-1731). To test the hypothesis that oxygen isotopic fractionation is related to the metabolic rate, 8 healthy adults performed 5 min of constant work rate cycle ergometer exercise below and above their anaerobic threshold. Moreover, 3 subjects performed an incremental exercise to the limit of tolerance. Oxygen uptake (VO2) was measured breath by breath. Samples of the exhaled breath for oxygen isotope measurement were obtained at rest and at various times during exercise and recovery. Oxygen isotopic fractionation was determined by isotope ratio mass spectrometry and calculated as the ratio of the degree of fractionation to the oxygen consumed in the breath sample (Z value). For the constant work rate protocol, both low and high intensity exercise resulted in a significant decrease in Z compared to the rest values (P less than 0.01). However, for the high intensity exercise the reduction in fractionation was greater compared to the low intensity protocol (P less than 0.05). For the incremental test, there was a significant negative correlation between oxygen isotopic fractionation and VO2 expressed as percent of the maximal oxygen uptake (r = -0.91, P less than 0.0001). These data suggest that during exercise low-fractionating processes become more important as limiting steps for O2 transport.

Erythrocyte insulin-like growth factor-I binding in younger and older males

Insulin‐like growth factor‐I (IGF‐I) levels are lower in older compared with younger subjects. We tested the hypothesis that the reduction in circulating IGF‐I would be accompanied by upregulation in tissue IGF‐I binding in at least some tissues. We tested erythrocyte IGF‐I binding since blood is an accessible tissue in humans, and there is growing evidence to suggest that erythrocyte IGF‐I binding is influenced by circulating IGF‐I.

Glucocorticoid receptor expression on circulating leukocytes differs between healthy male and female adults.

Introduction The glucocorticoid receptor (GR) is a key receptor involved in inflammatory responses and is influenced by sex steroids. This study measured GR expression on circulating leukocyte subtypes in males and females. Methods A total of 23 healthy adults (12 female) participated in this study. GR expression was measured in leukocyte subtypes using flow cytometry. Peripheral blood mononuclear cell (PBMC) gene expression of GR (NR3C1), GR β, TGF-β1 and 2, and glucocorticoid-induced leucine zipper (GILZ) were determined by real-time polymerase chain reaction. Results Leukocyte GR was lower in females, particularly in granulocytes, natural killer cells, and peripheral blood mononuclear cells (p≤0.01). GR protein expression was different across leukocyte subtypes, with higher expression in eosinophils compared with granulocytes, T lymphocytes, and natural killer cells (p<0.05). There was higher gene expression of GR β in males (p=0.03). Conclusions This is the first study to identify sexual dimorphism in GR expression in healthy adults using flow cytometry. These results may begin to explain the sexual dimorphism seen in many diseases and sex differences in glucocorticoid responsiveness.

Exercise and the Growth Hormone—Insulin-Like Growth Factor-1 Axis

Naturally occurring physical activity in humans plays a profound role in tissue anabolism, growth, and development, yet little is known about the mechanisms that link patterns of exercise with tissue anabolism. Anabolic effects of exercise are not limited to individuals engaged in competitive sports who are particularly focused on improvements in strength or cardiovascular functions. For example, limb immobilization, neural injury, and prolonged bed rest cause reduction of muscle mass and bone density even in individuals who live a sedentary lifestyle (1). These observations imply that a sizeble anabolic stimulus arises from a relatively modest physical activity of daily living. Conversely, excessive exercise may have adverse effects. For example, Theintz et al. (2) recently reported a reduction in the growth potential of female adolescent gymnasts engaging in intense training.

13 – Exercise and Lung Function in Child Health and Disease

Abstract Exercise in children is not merely play; rather, it is a critical environmental and physiological perturbation that has a profound effect on growth and development in health and disease. In this chapter, we review fundamental knowledge focused on how the growing child adapts to the physiological stress of exercise with a particular focus on respiratory disease. Cardiopulmonary exercise testing (CPET) remains the most widely used approach for precise measurement of respiratory and cardiovascular fitness in children and adults. Essential diagnostic uses of CPET in asthma, cystic fibrosis, and lung disease of prematurity are reviewed. Children at high altitude, particularly those with chronic lung disease, are at risk for exercise impairment, and the mechanisms responsible for these challenges are identified. We present new information regarding an increasingly diagnosed syndrome that limits exercise performance in adolescents, exercise-induced laryngeal obstruction. Finally, we set the stage for the next phase of discovery in exercise research in children, namely linking exercise to genomic, epigenetic, proteomic, and metabolomic technologies that will, hopefully, advance our understanding of exercise as a biomarker and therapeutic adjunct in child health.