Claudio Marconi

New aspects of altitude adaptation in Tibetans: a proteomic approach

A prolonged sojourn above 5500 m induces muscle deterioration and accumulation of lipofuscin in Caucasians, probably because of overproduction of reactive oxygen species (ROS). Because Sherpas, who live at high altitude, have very limited muscle damage, it was hypothesized that Himalayan natives possess intrinsic mechanisms protecting them from oxidative damage. This possibility was investigated by comparing the muscle proteomes of native Tibetans permanently residing at high altitude, second‐generation Tibetans born and living at low altitude, and Nepali control subjects permanently residing at low altitude, using 2D gel electrophoresis and mass spectrometry. Seven differentially regulated proteins were identified: glutathione‐S‐transferase P1‐1, which was 380% and 50% overexpressed in Tibetans born and living at high and low altitude, respectively; Δ2‐enoyl‐CoA‐hydratase, which was up‐regulated in both Tibetan groups; glyceraldehyde‐3‐phosphate dehydrogenase and lactate dehydrogenase, which were both slightly down‐regulated in Tibetans born and living at high altitude; phosphoglycerate mutase, which was 50% up‐regulated in the native Tibetans; NADH‐ubiquinone oxidoreductase, slightly overexpressed in Tibetans born and living at high altitude; and myoglobin, which was overexpressed in both Tibetan groups. We concluded that Tibetans at high altitude, and to some extent, those born and living at low altitude, are protected from ROS‐induced tissue damage and possess specific metabolic adaptations.

Impaired oxygen extraction in metabolic myopathies: Detection and quantification by near-infrared spectroscopy

Patients with mitochondrial myopathies (MM) or myophosphorylase deficiency (McArdles disease, McA) show impaired capacity for O2 extraction, low maximal aerobic power, and reduced exercise tolerance. Non‐invasive tools are needed to quantify the metabolic impairment. Six patients with MM, 6 with McA, 25 with symptoms of metabolic myopathy but negative biopsy (patient‐controls, P‐CTRL) and 20 controls (CTRL) underwent an incremental cycloergometric test. Pulmonary O2 uptake (V̇O2) and vastus lateralis oxygenation indices (by near‐infrared spectroscopy, NIRS) were determined. Concentration changes of deoxygenated hemoglobin and myoglobin (Δ[deoxy(Hb + Mb)]) were considered an index of O2 extraction. Δ[deoxy(Hb + Mb)] peak (percent limb ischemia) was lower in MM (25.3 ± 12.0%) and McA (18.7 ± 7.3) than in P‐CTRL (62.4 ± 3.9) and CTRL (71.3 ± 3.9) subjects. V̇O2 peak and Δ[deoxy(Hb + Mb)] peak were linearly related (r2 = 0.83). In these patients, NIRS is a tool to detect and quantify non‐invasively the metabolic impairment, which may be useful in the follow‐up of patients and in the assessment of therapies and interventions. Muscle Nerve, 2006

Exercise after heart transplantation

Exercise intolerance in heart transplant recipients (HTR) has a multifactorial origin, involving complex interactions among cardiac, neurohormonal, vascular, skeletal muscle and pulmonary abnormalities. However, the role of these abnormalities may differ as a function of time after transplantation and of many other variables. The present review is aimed at evaluating the role of cardiac, pulmonary and muscular factors in limiting maximal aerobic performance of HTR, and the benefits of chronic exercise. Whereas pulmonary function does not seem to affect gas exchange until a critical value of diffusing lung capacity is attained, cardiac and skeletal muscle function deterioration may represent relevant factors limiting maximal and submaximal aerobic performance. Cardiac function is mainly limited by chronotropic incompetence and diastolic dysfunction, whereas muscle activity seems to be limited by impaired oxygen supply as a consequence of the reduced capillary network. The latter may be due to either immunosuppressive regimen or deconditioning. Endurance and strength training may greatly improve muscle function and maximal aerobic performance of HTR, and may also reduce side effects of immunosuppressive therapy and control risk factors for cardiac allograft vasculopathy. For the above reasons exercise should be considered an important therapeutic tool in the long-term treatment of heart transplant recipients.

Economy of locomotion in high-altitude Tibetan migrants exposed to normoxia

High‐altitude Tibetans undergo a pattern of adaptations to chronic hypoxia characterized, among others, by a more efficient aerobic performance compared with acclimatized lowlanders. To test whether such changes may persist upon descent to moderate altitude, oxygen uptake of 17 male Tibetan natives lifelong residents at 3500–4500 m was assessed within 1 month upon migration to 1300 m. Exercise protocols were: 5 min treadmill walking at 6 km h−1 on increasing inclines from +5 to +15% and 5 min running at 10 km h−1 on a +5% grade. The data (mean ±s.e.m.) were compared with those obtained on Nepali lowlanders. When walking on +10, +12.5 and +15% inclines, net of Tibetans was 25.2 ± 0.7, 29.1 ± 1.1 and 31.3 ± 0.9 ml kg−1 min−1, respectively, i.e. 8, 10 and 13% less (P < 0.05) than that of Nepali. At the end of the heaviest load, blood lactate concentration was lower in Tibetans than in Nepali (6.0 ± 0.9 versus 8.9 ± 0.6 mm; P < 0.05). During running, of Tibetans was 35.1 ± 0.8 versus 39.3 ± 0.7 ml kg−1 min−1 (i.e. 11% less; P < 0.01). In conclusion, during submaximal walking and running at 1300 m, Tibetans are still characterized by lower aerobic energy expenditure than control subjects that is not accounted for by differences in mechanical power output and/or compensated for by anaerobic glycolysis. These findings indicate that chronic hypoxia induces metabolic adaptations whose underlying mechanisms still need to be elucidated, that persist for at least 1 month upon descent to moderate altitude.

Blood flow distribution and its temporal variability in stimulated dog gastrocnemius muscle

The distribution of blood flow in skeletal muscle stimulated to rhythmic isotonic contractions was studied by injections of radioactive microspheres into the arterial supply in 8 gastrocnemius muscles (mean weight 84 g) of 6 anesthetized dogs (20-25 kg body weight). The distribution of 10 micron microspheres in regions of about 0.5 g was very similar to that of the standard 15 micron microspheres, whereas that of 25 micron microspheres was more uneven. The coefficient of variation (CV = SD/mean) of the ratio of simultaneously injected 10 micron and 15 micron microspheres, 0.12, was taken as the inherent scatter of the method. The average spatial distribution inequality of 10-15 micron microspheres corresponded to a CV of 0.45 and the specific local blood flow inhomogeneity to a CV = 0.43 ( = square root 0.45(2) - 0.12(2], but there were marked differences between muscles. At equal blood flow levels, the inhomogeneity during reactive hyperemia was similar to that observed during stimulation. The temporal variability of blood flow in individual muscle pieces was obtained from the comparison of fractional trapping of 4 to 5 differently labeled microspheres injected at intervals of 2 min into steadily stimulated muscles. The mean CV for the variations in time was 0.23 and that corrected for methodological scatter, 0.19, but the differences in the extent of temporal blood flow changes among muscle pieces within a muscle and between different muscles were large. The presence of considerable spatial and temporal variations of blood flow in exercising muscle during apparent steady state may be important in limiting and/or modulating tissue O2 supply.

Second generation Tibetan lowlanders acclimatize to high altitude more quickly than Caucasians

Tibetan highlanders develop at altitude peak aerobic power levels close to those of Caucasians at sea level. In order to establish whether this feature is genetic and, as a consequence, retained by Tibetan lowlanders, altitude‐induced changes of peak aerobic performance were assessed in four groups of volunteers with different ethnic, altitude exposure and fitness characteristics, i.e. eight untrained second‐generation Tibetans (Tib 2) born and living at 1300 m; seven altitude Sherpas living at ∼2800–3500 m; and 10 untrained and five trained Caucasians. Measurements were carried out at sea level or at Kathmandu (1300 m, Nepal) (PRE), and after 2–4 (ALT1), 14–16 (ALT2), and 26–28 (ALT3) days at 5050 m. At ALT3, of untrained and trained Caucasians was –31% and –46%, respectively. By contrast, of Tib 2 and Sherpas was –8% and –15%, respectively. At ALT3, peak heart rate (HRpeak) of untrained and trained Caucasians was 148 ± 11 and 149 ± 7 beats min−1, respectively; blood oxygen saturation at peak exercise was 76 ± 6% and 73 ± 6%, and haemoglobin concentration ([Hb]) was 19.4 ± 1.0 and 18.6 ± 1.2 g dl−1, respectively. Compared to Caucasians, Tib 2 and Sherpas exhibited at ALT3 higher HRpeak (179 ± 9 and 171 ± 4 beats min−1, P < 0.001), lower [Hb] (16.6 ± 0.6 and 17.4 ± 0.9 g dl−1, respectively, P < 0.001), and slightly but non‐significantly greater average values (82 ± 6 and 80 ± 7%). The above findings and the time course of adjustment of the investigated variables suggest that Tibetan lowlanders acclimatize to chronic hypoxia more quickly than Caucasians, independent of the degree of fitness of the latter.

Heart rate variability in the human transplanted heart: Nonlinear dynamics and QT vs RR-QT alterations during exercise suggest a return of neurocardiac regulation in long-term recovery

Rationale. Functional reinnervation of the transplanted human heart by the autonomic nervous system has not been demonstrated. A lack of autonomic control of the transplanted allograft is reflected by an increased resting heart rate, a sluggish heart rate response to dynamical exercise and a reduced heart rate variability. Recent evidence suggests that a measure of deterministic chaos in the heartbeat interval series (point correlation dimension, PD2i) is superior to the conventional power spectrum or other stochastic measures in detecting changes in the mechanism underlying heartbeat generation.Methods. The PD2i is based on the presumption that the variability is determined and patterned, whereas the stochastic measures all assume that the variability is around a stationary mean and is noise. The PD2i reconstructs the degrees of freedom (number of independent variables) in the system that generates the time series examined, and does this irrespective of whether the system is stochastic or deterministic and is stationary in time.Results. PD2i was determined for heartbeat intervals (RR, ECG digitized at 1200 Hz; supine posture) of 23 heart transplant recipients (HTR: 9 adults, 14 children; 0.04-7.7 years after transplantation) and 21 healthy control subjects (CTL; 13 adults, 8 children). The PD2i (+/− SD) averaged 5.4 +/− 0.7 for the CTL adults and 5.4 +/− 0.6 for the CTL children. Mean PD2i was reduced after transplantation to 1.1 +/− 0.1 in 6 HTRs recorded within 1 year after surgery; in one HTR recorded 2 weeks after surgery the mean PD2i was 3.7. Between 1 to 2 years PD2i was found increased in 2 of 3 subjects and between 2 to 8 years it was increased in 13 of 13, but not to control levels. In normal hearts the QT subinterval of each heartbeat cycle is associated with inotropy and the RR-QT remainder with chronotropy (i.e., the dyastolic interval during which RR is primarily regulated). To examine more closely the residual and returning heartbeat dynamics of the HTR subjects, these subinterval series were examined during mild exercise (40 to 90 Watts) and its recovery. In recent HTRs, resting QT and RR-QT were moderately reduced and modulated by exercise and recovery, but with an approximate 100 beat latency. In long-term (7-8 years) HTR subjects there was a rapid and larger response to exercise/recovery, but compared to normal the range was smaller and the complexity of the subinterval trajectories in time was simpler.Conclusions. Recurrence of low-dimensional deterministic dynamics after transplantation suggests recovery of neurocardiac control attributable to 1) reorganization of the viable intrinsic cardiac nervous system, 2) reinnervation by the extrinsic autonomic nervous system, or 3) both.

The metabolic and ventilatory response to exercise in Tibetans born at low altitude

The exercise response of 20 Tibetans (T) born and living in Kathmandu, Nepal (1300 m) was compared to that of 21 age- and sex-matched local lowlanders. The subjects carried out an incremental exercise protocol on a bicycle ergometer (30 watt steps every 4 min) until exhaustion. The kinetics of readjustment of VO2 measured as half time (t-on) upon a 90 watt constant load exercise was also determined. Breath-by-breath gas exchange, heart rate (HR) and blood lactate concentration ([La]) were measured at rest, at the end of each load and during recovery. The slope of the straight line relating VO2 to work load was 10.8 ml.watt-1 in both groups which corresponds to a mechanical efficiency of 0.26 (assuming a RQ of 0.89 and an energy equivalent of 20.9 kJ.L-1 O2). At submaximal loads T were characterized by higher VE (P < 0.05), VE.VO2(-1) (P < 0.01) and VCO2 levels (P < 0.001) than N. The found higher VE in T, resulting from a lower tidal volume coupled to a higher respiratory frequency, led to higher PETO2 (P < 0.001) and SaO2 (P < 0.001) at all work levels. Absolute VO2max in the two investigated groups were 1977 +/- 72 (T) and 2095 +/- 80 (N) ml.min-1 (NS). Specific (i.e. per kg body weight) VO2max were identical (37.0 +/- 1.1 [T] vs. 36.7 +/- 1.1 ml.kg-1.min-1 [N]). [La]max were 11.4 +/- 0.4 (T) vs. 12.3 +/- 0.4 (N) mM (NS). [La] accumulation in blood as a function of workload and its rate of disappearance during recovery were similar. t-on at 90 watt was 30.7 +/- 2.4 sec in T and 28.9 +/- 2.3 sec in N (NS). The corresponding average contracted O2 deficit were 971 ml for T and 994 ml for N (NS). In conclusion, Tibetans born at low altitude do not seem to differ from lowlanders with regard to their metabolic response whereas their ventilatory response to exercise is greater.

STABILITY OF HEARTBEAT INTERVAL DISTRIBUTIONS IN CHRONIC HIGH ALTITUDE HYPOXIA

Recent studies of nonlinear dynamics of the long-term variability of heart rate have identified nontrivial long-range correlations and scale-invariant power-law characteristics (1/f noise) that were remarkably consistent between individuals and were unrelated to external or environmental stimuli (Meyer et al., 1998a). The present analysis of complex nonstationary heartbeat patterns is based on the sequential application of the wavelet transform for elimination of local polynomial nonstationary behavior and an analytic signal approach by use of the Hilbert transform (Cumulative Variation Amplitude Analysis). The effects of chronic high altitude hypoxia on the distributions and scaling functions of cardiac intervals over 24 hr epochs and 4 hr day/nighttime subepochs were determined from serial heartbeat interval time series of digitized 24 hr ambulatory ECGs recorded in 9 healthy subjects (mean age 34 yrs) at sea level and during a sojourn at high altitude (5,050 m) for 34 days (Ev-K2-CNR Pyramid Laboratory, Sagarmatha National Park, Nepal). The results suggest that there exists a hidden, potentially universal, common structure in the heterogeneous time series. A common scaling function with a stable Gamma distribution defines the probability density of the amplitudes of the fluctuations in the heartbeat interval time series of individual subjects. The appropriately rescaled distributions of normal subjects at sea level demonstrated stable Gamma scaling consistent with a single scaled plot (data collapse). Longitudinal assessment of the rescaled distributions of the 24 hr recordings of individual subjects showed that the stability of the distributions was unaffected by the subject’s exposure to a hypobaric (hypoxic) environment. The rescaled distributions of 4 hr subepochs showed similar scaling behavior with a stable Gamma distribution indicating that the common structure was unequivocally applicable to both day and night phases and, furthermore, did not undergo systematic changes in response to high altitude. In contrast, a single function stable over a wide range of time scales was not observed in patients with congestive heart failure or patients after cardiac transplantation. The functional form of the scaling in normal subjects would seem to be attributable to the underlying nonlinear dynamics of cardiac control. The results suggest that the observed Gamma scaling of the distributions in healthy subjects constitutes an intrinsic dynamical property of normal heart function that would not undergo early readjustment or late acclimatization to extrinsic environmental physiological stress, e.g., chronic hypoxia.

Energetics of locomotion in African pygmies

SummaryThe energy cost of walking (Cw). and running (Cr), and the maximal O2 consumption (VO2max) were determined in a field study on 17 Pygmies (age 24 years, SD 6; height 160 cm, SD 5; body mass 57.2 kg, SD 4.8) living in the region of Bipindi, Cameroon. TheCw varied from 112 ml·kg−1·km−1, SD 25 [velocity (ν), 4 km·h−1] to 143 ml·kg−1·km−1, SD 16 (ν, 7 km·h−1). Optimal walking ν was 5 km·h−1. TheCr was 156 ml·kg−1·km−1, SD 14 (ν, 10 km·h−1) and was constant in the 8–11 km·h−1 speed range. TheVO2max was 33.7 ml·kg−1· min−1, i.e. lower than in other African populations of the same age. TheCr andCw were lower than in taller Caucasian endurance runners. These findings, which challenge the theory of physical similarity as applied to animal locomotion, may depend either on the mechanics of locomotion which in Pygmies may be different from that observed in Caucasians, or on a greater mechanical efficiency in Pygmies than in Caucasians. The lowCr values observed enable Pygmies to reach higher running speeds than would be expected on the basis of theirVO2max.