GENETIC INFLUENCE ON FACTORS OF OXYGEN TRANSPORT Claudio Marconi IBFM-Sect. of Muscle Physiology and Proteome National Research Council Milano, Italy
100 90 80 % s.l. VO 2 max. 70 60 50 40 30 20 10 0 2 4 6 8 10 ALTITUDE (km)
O 2 transport system
. 5 VO 2 max (l min -1 ) 4 3 2 1 * * * 5050m 2850m 0 0-20 0 20 40 60 80 Time (days)? 6 3 Altitude (km)
ADAPTATION A change which allows an organism to live and reproduce successully in a given environment At high altitude the main stressor is the reduction of O 2 availability. Adaptations involve the O 2 transport system
. VO 2 max 60 (ml kg -1 min-1 ) 50 HANS Tibetans Genetic adaptation 40 Acclimatization 30 Developmental adaptation (Niu et al., 1995) Lhasa (3.680 m) 20-5 0 5 10 15 20 25 30 months
High altitude populations (>3,500 m) Sherpas Tibetans Aymaras Quechuas
BACKGROUND Anecdotally, high altitude natives, particularly Tibetans including Sherpas and Amerindians, have been considered more apt to carry out aerobic exercise in chronic hypoxia than acclimatized lowlanders.
60 55 50 45 40 35. VO 2 max (ml kg -1 min -1 ) Caucasians (Cerretelli, 1976) Sherpas (Cerretelli, 1976) Andeans (Frisancho et al., 1973) Accl. Peruvians (Frisancho et al., 1973) Caucasians (Frisancho et al., 1973) Aymara (Greska et al., 1985) Caucasians (Greska et al., 1985) Tibetans (Sun et al., 1990) Han (Sun et al., 1990) Accl. Peruvians (Frisancho et al., 1973) 30 3 4 5 6 ALTITUDE (km) (Cerretelli e Hoppeler, 1996)
WORKING HYPOTHESIS The maximal aerobic power of high-altitude natives is in the range of normal for sea-level values.. Can this feature be explained by a genetic and/or acquired adaptation of some determinants of VO 2 max, affecting O 2 transport and utilization at the tissue level?
AIMS 1) To show that factors determining oxygen transport at peak exercise carried out at high altitude differ among groups of individuals with different history of exposition to chronic hypoxia. 2) To provide evidence to support the hypothesis that genetic factors are responsible for the better adaptation of Tibetans compare to other high-altitude populations.
Fick s equation...(ca-cv)o2max VO2max = Qmax Oxygen delivery
O 2 DELIVERY TO TISSUES CaO 2 x Q. [Hb] x K x SaO 2 % HR x SV O 2 diffusion VA/Q mismatch
HAEMOGLOBIN CONCENTRATION
Hb (g%) 22.5 20.0 Acclimatized lowlanders 8 7 RBC (10 6 ml -1 ) 4540 m RBC Hb HCT 60 HCT (%) 55 17.5 6 50 15.0 5 45 12.5 4 0 2 4 6 8 10 12 14 TIME (weeks) 40
(22.5) Caucasians Sherpas Tib lowlanders (Redrawn by Beall, 2001)
Hb (g dl -1 ) 22 20 18 Lowlanders Skyrunners Tibetans Climbers 16 14 12 10 Hb concentration of acclimatized Tibetan lowlanders is < than that of Caucasians 0 1 2 3 4 5 6 7 8 ALTITUDE (km)
Benefits deriving from low [Hb] Lower cardiac after load (due to a concurrent drop i hematocrit and blood viscosity). Higher leg blood flow and vascular conductance
MOLECULAR BASIS OF THE INCREASE IN HB CONCENTRATION ACUTE HYPOXIA ERYTHROPOIETIN Blood Erythropoietin concentration increases sharply within few hours upon arrival at altitude Thereafter it decreases attaining a value slightly higher than that at sea level
In Andean and Tibetan highlanders erythropoietin concentration is in the range of the sea-level values
mu/ml 30 20 10 Erythropoietin Quechua Indians Sherpas Andean highlanders respond as if they are anemic 0 45 50 55 60 65 70 (Winslow et al., JAP 1989) Hct (%)
ARTERIAL OXYGEN SATURATION (SaO 2 %) is an index of the efficiency of lung gas exchange, depending on: -O 2 diffusion - alveolar ventilation-pulmonary blood flow ratio
REST
SEA LEVEL PO 2 (mmhg) 140 inspired 120 alveolar 100 80 60 40 mixed venous 20 PB = 760 Torr VO 2 = 300 ml / min end-capillary 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Time along pulmonary capillary (s) (West & Wagner, 1980)
PO 2 (mmhg) 50 40 30 20 MT. EVEREST SUMMIT PB = 253 Torr VO 2 = 350 ml / min inspired alveolar end-capillary mixed venous 10 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Time along pulmonary capillary (s) (West, 1983)
SaO 2 AT PEAK EXERCISE (after 1 mo at 5,050 m) 100 (%) 90 80 70 60 Tib 2 Sh altit C C runn untr tr
IN THE ABSENCE OF GENETIC ADAPTATIONS SaO 2 peak OF ACCLIMATIZED LOWLANDERS MAY TAKE YEARS TO APPROACH THE VALUES FOUND IN ALTITUDE NATIVES.
Tibetan natives of and Han 8 year residents at 100 Lhasa (3658 m) SaO 2 peak (%) 90 80 70 60 (Sun et al., 1990) Tibetans Hans
SaO 2 peak of altitude Tibetans is greater than that of acclimatized lowlanders, likely due to : Less extravascular accumulation of fluids in the lungs More limited ventilation-perfusion inequalities
HYPOXIC PULMONARY VASOCONSTRICTION At sea level, this mechanism is active in the fetal life and is immediately released upon exposure to normoxia
O 2 O 2 breathing reduces PAP only partially, due to muscle cells in the small pulmonary vessels
MOLECULAR BASIS FOR PULMONARY VASOCONSTRICTION A DOWNREGULATION OF PULMONARY SYNTHESIS OF NITRIC OXIDE, A POWERFUL VASODILATOR
HYPOXIC VENTILATORY RESPONSE (HVR) HVR can be defined as an Increase in ventilation induced by acute hypoxia During acclimatization HVR progressively decreases until resting pulmonary ventilation resumes sea-level values: acquired blunting of HVR.
Tibetans ventilate as much as acclimatized lowlanders, whereas Andeans hypoventilate
HVR 1. In acclimatized lowlanders, HVR progressively declines. 2. In high-altitude native Andeans HVR is blunted. 3. In Tibetans, HVR is in the normal for sea-level range.
CARDIAC OUTPUT
. Qmax (l/min) 35 30 25 High altitude long-distance runners 20 15 10 Andean natives 0 2 4 6 8 10 ALTITUDE (km)
. Q (l/min) 30 25 20 15 s.l. 5.800 m (Cerretelli, 1980) 10 5 0 0 1. 2 3 4 VO 2 (l/min)
ACCLIMATIZATION-INDUCED INDUCED REDUCTION IN Qmax Expanded blood volume Reduced plasma volume Lower cardiac filling pressures Increased blood viscosity. lower Qmax Increased [Hb] Reduced myocardial Isovolemic hemodilution contractility -Water shifting out of the vascular space -Sweating -Respiration -Urine production. Muscle deterioration.. lower wmaxw max and VO 2 max Lower HRmax Adaptations in ANS
200 HRmax (b/min) 180 160 140 * 5050m 2850m * * 6 3 120 0-20 0 20 40 60 80 Time (days) Altitude (km)
% s.l. HRmax 100 95 90 85 80 75 Astrand 1958 Christensen and Forbes 1937 Cerretelli 1976 Balke 1956 Niu 1995 Grassi et al., 1996 Saltin et al., 1968 Vogel et al., 1967 Hartley et al., 1974 Buskirk et al., 1967 Pugh et al., 1964 West et al., 1983 EAST-1994 EAST-1997 70 65 simulated hypoxia 60 0 1 2 3 4 5 6 7 8 9 ALTITUDE (km)
beats min -1 210 200 190 180 170 160 150 140 130 120 110 MAXIMAL HEART RATE 0 1 2 3 4 5 6 7 8 ALTITUDE (km) Untrained lowlanders Trained lowlanders Skyrunners Tibetans Climbers A. D. P. B. C.
HR max (beats min -1 ) 200 190 HANS Tibetans 180 170 (Niu et al., 1995) Lhasa (3.680 m) 160-5 0 5 10 15 20 25 30 months
OXYGEN CONVECTIVE TRANSPORT TO TISSUES IN ACCLIMATIZED LOWLANDERS AND ANDEANS. (15-20%) Qmax x [HbO 2 ] P50 (~30%)
CONCLUSIONS Acclimatized lowlanders and high-altitude natives maintain adequate maximal O 2 delivery to tissues, by different means: -increasing [Hb] (acclimatized lowlanders and Andeans) -keeping high values of HRpeak and SaO 2 % (Tibetans).