Effects of beta-blockade on exercise performance at high altitude: a randomized, placebo-controlled trial comparing the efficacy of nebivolol versus carvedilol in healthy subjects.

AIMS: Exposure to high altitude (HA) hypoxia decreases exercise performance in healthy subjects. Although ß-blockers are known to affect exercise capacity in normoxia, no data are available comparing selective and nonselective ß-adrenergic blockade on exercise performance in healthy subjects acutely exposed to HA hypoxia. We compared the impact of nebivolol and carvedilol on exercise capacity in healthy subjects acutely exposed to HA hypobaric hypoxia. METHODS: In this double-blind, placebo-controlled trial, 27 healthy untrained sea-level (SL) residents (15 males, age 38.3 ± 12.8 years) were randomized to placebo (n = 9), carvedilol 25 mg b.i.d. (n = 9), or nebivolol 5 mg o.d. (n = 9). Primary endpoints were measures of exercise performance evaluated by cardiopulmonary exercise testing at sea level without treatment, and after at least 3 weeks of treatment, both at SL and shortly after arrival at HA (4559 m). RESULTS: HA hypoxia significantly decreased resting and peak oxygen saturation, peak workload, VO(2) , and heart rate (HR) (P < 0.01). Changes from SL (no treatment) differed among treatments: (1) peak VO(2) was better preserved with nebivolol (-22.5%) than with carvedilol (-37.6%) (P < 0.01); (2) peak HR decreased with carvedilol (-43.9 ± 11.9 beats/min) more than with nebivolol (-24.8 ± 13.6 beats/min) (P < 0.05); (3) peak minute ventilation (VE) decreased with carvedilol (-9.3%) and increased with nebivolol (+15.2%) (P= 0.053). Only peak VE changes independently predicted changes in peak VO(2) at multivariate analysis (R= 0.62, P < 0.01). CONCLUSIONS: Exercise performance is better preserved with nebivolol than with carvedilol under acute exposure to HA hypoxia in healthy subjects.

Continuous positive airway pressure increases haemoglobin O2 saturation after acute but not prolonged altitude exposure.

AIMS: It is unknown whether subclinical high-altitude pulmonary oedema reduces spontaneously after prolonged altitude exposure. Continuous positive airway pressure (CPAP) removes extravascular lung fluids and improves haemoglobin oxygen saturation in acute cardiogenic oedema. We evaluated the presence of pulmonary extravascular fluid increase by assessing CPAP effects on haemoglobin oxygen saturation under acute and prolonged altitude exposure. METHODS AND RESULTS: We applied 7 cm H(2)O CPAP for 30 min to healthy individuals after acute (Capanna Margherita, CM, 4559 m, 2 days permanence, and <36 h hike) and prolonged altitude exposure (Mount Everest South Base Camp, MEBC, 5350 m, 10 days permanence, and 9 days hike). At CM, CPAP reduced heart rate and systolic pulmonary artery pressure while haemoglobin oxygen saturation increased from 80% (median), 78-81 (first to third quartiles), to 91%, 84-97 (P < 0.001). After 10 days at MEBC, haemoglobin oxygen saturation spontaneously increased from 77% (74-82) to 86% (82-89) (P < 0.001) while heart rate (from 79, 64-92, to 70, 54-81; P < 0.001) and respiratory rate (from 15, 13-17, to 13, 13-15; P < 0.001) decreased. Under such conditions, these parameters were not influenced by CPAP. CONCLUSION: After ascent excessive lung fluids accumulate affecting haemoglobin oxygen saturation and, in these circumstances, CPAP is effective. Acclimatization implies spontaneous haemoglobin oxygen saturation increase and, after prolonged altitude exposure, CPAP is not associated with HbO(2)-sat increase suggesting a reduction in alveolar fluids.

Functional involvement of central nervous system at high altitude.

Acute mountain sickness is a common discomfort experienced by unacclimatized persons on ascent to high altitude. We tested the hypothesis that exposure to high altitude affects cortical excitability using transcranial magnetic stimulation. We specifically analyzed the motor cortex excitability in normal subjects at high altitude and in a control condition near sea level. Mean resting motor threshold (RMT) was significantly higher at high altitude than at sea level (69.3 +/- 10.4 versus 56.3 +/- 10.9%; P = 0.042). Mean short intracortical inhibition (SICI) was significantly lower at high altitude than at sea level (percentage of test motor-evoked potential = 79.3 +/- 19.8 versus 28.7 +/- 17.5%; P = 0.0004). Symptoms of acute mountain sickness correlated with resting motor threshold changes induced by high altitude (R 2 = 0.53, P = 0.037). SaO2 correlated with SICI changes induced by high altitude (R 2 = 0.45, P = 0.036). We suggest that high altitude deeply changes cortical excitability by affecting both inhibitory and excitatory circuits and that this is reflected in acute mountain sickness symptoms.

Disappearance of isocapnic buffering period during increasing work rate exercise at high altitude.

BACKGROUND: At sea level, ventilation kinetics are characterized during a ramp exercise by three progressively steeper slopes, the first from the beginning of exercise to anaerobic threshold, the second from anaerobic threshold to respiratory compensation point, and the third from respiratory compensation point to peak exercise. In the second ventilation phase, body CO2 stores are used to buffer acidosis owing to lactate production; it has been suggested that this extra CO2 production drives the ventilation increase. At high altitude, ventilation increases owing to hypoxia. We hypothesize that ventilation increase reduces body CO2 stores affecting ventilation kinetics during exercise. DESIGN: In eight healthy participants, we studied the ventilation kinetics during an exercise performed at sea level and at high altitude (4559 m). METHODS: We used 30 W/2 min step incremental protocol both at sea level and high altitude. Tests were done on a cyclo-ergometer with breath-by-breath ventilation and inspiratory and expiratory gas measurements. We evaluated cardiopulmonary data at anaerobic threshold, respiratory compensation point, peak exercise and the VE/VCO2 slope. RESULTS: At high altitude: (a) peak VO2 decreased from 2595+/-705 to 1745+/-545 ml/min (P<0.001); (b) efficiency of ventilation decreased (VE/VCO2 slope from 25+/-2 to 38+/-4, P<0.0001); (c) at each exercise step end-tidal pressure change for CO2 was lower; and (d) the isocapnic buffering period disappeared in seven over eight participants and was significantly shortened in the remaining participant. CONCLUSION: Exercise performed at high altitude is characterized by two, instead of three, ventilation slopes.

Evaluation of a multisensor armband in estimating energy expenditure in obese individuals.

OBJECTIVE: To examine the reliability and validity of the SenseWear Pro 2 Armband (SWA; Body Media, Pittsburgh, PA) during rest and exercise compared with indirect calorimetry (IC) in obese individuals. RESEARCH METHODS AND PROCEDURES: Energy expenditure was assessed during rest with the SWA and IC in 142 obese adults (37 men and 105 women, BMI = 42.3 +/- 7.0) and in 25 lean and overweight adults (BMI = 25.3 +/- 3.2) who were used as a comparison group. Twenty-nine of the obese adults also participated in three separate short exercise sessions including cycle ergometry, stair stepping, and treadmill walking. RESULTS: The repeatability of SWA estimates in obese subjects was high (r = 0.88, p < 0.001). The SWA generally underestimated the resting energy expenditure (REE) (1811 +/- 346 vs. 1880 +/- 382 kcal/d) and highly overestimated the energy expenditure during the exercise sessions in obese individuals. REE estimations by SWA were significantly correlated with fat-free mass (r = 0.88, p < 0.001). Bland-Altman plots based statistical analysis for the estimated REE, and measured IC showed a low agreement (Total Error > 20% but Systematic Error < 5%) between the two methods in obese subjects, although they showed a high correlation and a very good agreement in lean and overweight patients. DISCUSSION: The SWA is an easy to handle, practical, new portable device for measuring energy expenditure. The accuracy of the SWA appeared to be poor in the obese subjects we examined, especially those with high REE both in rest and exercise. We believe that it is necessary to incorporate new, obesity-specific algorithms in the relative software.

Role of endothelin-1 in exposure to high altitude: Acute Mountain Sickness and Endothelin-1 (ACME-1) study.

BACKGROUND: The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1. The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension, renal water, and sodium balance under acute and prolonged exposure to high-altitude-associated hypoxia. METHODS AND RESULTS: In a double-blind fashion, healthy volunteers were randomly assigned to receive bosentan (62.5 mg for 1 day and 125 mg for the following 2 days; n=10) or placebo (n=10) at sea level and after rapid ascent to high altitude (4559 m). At sea level, bosentan did not induce any significant changes in hemodynamic or renal parameters. At altitude, bosentan induced a significant reduction of systolic pulmonary artery pressure (21+/-7 versus 31+/-7 mm Hg, P<0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H2OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100+/-200 versus 1610+/-590 mL; -6.7+/-3.5 versus -1.8+/-4.8 mL/min, P<0.05 versus placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration. CONCLUSIONS: The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation. These findings must be considered for the prevention and treatment of acute mountain sickness.

Free and bound plasma leptin in normal weight and obese men and women: relationship with body composition, resting energy expenditure, insulin-sensitivity, lipid profile and macronutrient preference.

OBJECTIVE: The adipose-borne hormone leptin circulates in free and protein-bound forms but little information is available about their biological significance. Free leptin (FL) levels are related to changes in fat mass, whereas bound leptin (BL) appears to be associated with resting energy expenditure (REE). Our aim was to assess FL and BL levels in normal weight and obese subjects and correlate them with metabolic and nutritional variables. DESIGN AND PATIENTS: The partitioning of plasma leptin between FL and BL was evaluated in a population (n = 44) including both genders and different degrees of adiposity [body mass index (BMI) range 18.6-79.6 kg/m2]. MEASUREMENTS: Total leptin and FL and BL concentrations were measured by fast protein liquid chromatography (FPLC) followed by radioimmunoassay (RIA). Body composition, REE, insulin sensitivity, lipid parameters associated with cardiovascular risk and macronutrient preference were also assessed. RESULTS: The BL/FL ratio was significantly reduced in obese subjects due to a major increase in FL compared with BL. Consequently, the gender difference of the %BL/%FL ratio present in lean subjects (35/65 in women; 65/35 in men) was lost in obese subjects. REE was negatively correlated with total leptin (P < 0.0001) and %FL (P < 0.0001), and positively with %BL (P < 0.001). Total leptin and FL were correlated with the diet carbohydrate content in all subjects. CONCLUSIONS: FL increases with the amount of fat mass; the prevalence of FL in normal weight women in comparison to men suggests that this fraction is particularly linked to the amount of subcutaneous fat. Moreover, the correlation of BL with REE and the relationship of FL with food intake favours the view of different biological activities for the two circulating forms of leptin.

The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure.

Ghrelin is a gastric hormone that exerts a stimulatory effect on appetite and fat accumulation. Ser(3) octanoylation is regarded as a prerequisite for ghrelin biological activity, although des-octanoylated forms may retain biological functions in vitro. Circulating ghrelin levels are usually low in obesity and in states of positive energy balance. Hence, the aim of our study was to analyze plasma active and serum total ghrelin levels in 20 obese (ages, 22-42 yr; body mass index, 41.3 +/- 1.1 kg/m(2)) and 20 lean subjects (ages, 22-43 yr; body mass index, 22.4 +/- 0.6 kg/m(2)) as well as their relationship to measures of glucose homeostasis, body fat, and resting energy expenditure (REE). The measured/predicted REE percentage ratio was calculated to subdivide groups into those with positive (> or = 100% ) and negative (<100%) ratio values. In obese patients, plasma active (180 +/- 18 vs. 411 +/- 57 pg/ml; P < 0.001) and serum total ghrelin levels (3650 +/- 408 vs. 5263 +/- 643 pg/ml; P < 0.05) were significantly lower when compared with lean subjects. Hence, ghrelin activity, defined as the proportion of active over total ghrelin levels, was similarly reduced in the obese state (6.1 +/- 0.9% vs. 8.4 +/- 1%; P < 0.05). There was a significant correlation between active and total ghrelin (r = 0.62; P < 0.001), and between total ghrelin and insulin (r = -0.53; P < 0.001) or insulin resistance using the homeostatis model of assessment-insulin resistance (r = -0.49; P < 0.001) approach. Significantly higher active ghrelin levels (214 +/- 22 vs. 159 +/- 30 pg/ml; P < 0.05) and ghrelin activity (8 +/- 1.7% vs. 4.9 +/- 0.9%; P < 0.05) were observed in patients with positive compared with negative measured/predicted REE ratio values. Our study shows that obesity is associated with an impairment of the entire ghrelin system. The observation that ghrelin is further decreased in cases of abnormal energy profit adds new evidence to the relationship between ghrelin activity and energy balance in obesity.