GENETIC INFLUENCE ON FACTORS OF OXYGEN TRANSPORT

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1 GENETIC INFLUENCE ON FACTORS OF OXYGEN TRANSPORT Claudio Marconi IBFM-Sect. of Muscle Physiology and Proteome National Research Council Milano, Italy

2 % s.l. VO 2 max ALTITUDE (km)

3 O 2 transport system

4 . 5 VO 2 max (l min -1 ) * * * 5050m 2850m Time (days)? 6 3 Altitude (km)

5 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

7 . 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) months

8 High altitude populations (>3,500 m) Sherpas Tibetans Aymaras Quechuas

9 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.

10 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) ALTITUDE (km) (Cerretelli e Hoppeler, 1996)

11 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?

12 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.

13 Fick s equation...(ca-cv)o2max VO2max = Qmax Oxygen delivery

14 O 2 DELIVERY TO TISSUES CaO 2 x Q. [Hb] x K x SaO 2 % HR x SV O 2 diffusion VA/Q mismatch

15 HAEMOGLOBIN CONCENTRATION

16 Hb (g%) Acclimatized lowlanders 8 7 RBC (10 6 ml -1 ) 4540 m RBC Hb HCT 60 HCT (%) TIME (weeks) 40

17 (22.5) Caucasians Sherpas Tib lowlanders (Redrawn by Beall, 2001)

18 Hb (g dl -1 ) Lowlanders Skyrunners Tibetans Climbers Hb concentration of acclimatized Tibetan lowlanders is < than that of Caucasians ALTITUDE (km)

19 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

20 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

21 In Andean and Tibetan highlanders erythropoietin concentration is in the range of the sea-level values

22 mu/ml Erythropoietin Quechua Indians Sherpas Andean highlanders respond as if they are anemic (Winslow et al., JAP 1989) Hct (%)

23 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

24 REST

25 SEA LEVEL PO 2 (mmhg) 140 inspired 120 alveolar mixed venous 20 PB = 760 Torr VO 2 = 300 ml / min end-capillary Time along pulmonary capillary (s) (West & Wagner, 1980)

26 PO 2 (mmhg) MT. EVEREST SUMMIT PB = 253 Torr VO 2 = 350 ml / min inspired alveolar end-capillary mixed venous Time along pulmonary capillary (s) (West, 1983)

27 SaO 2 AT PEAK EXERCISE (after 1 mo at 5,050 m) 100 (%) Tib 2 Sh altit C C runn untr tr

28 IN THE ABSENCE OF GENETIC ADAPTATIONS SaO 2 peak OF ACCLIMATIZED LOWLANDERS MAY TAKE YEARS TO APPROACH THE VALUES FOUND IN ALTITUDE NATIVES.

29 Tibetan natives of and Han 8 year residents at 100 Lhasa (3658 m) SaO 2 peak (%) (Sun et al., 1990) Tibetans Hans

30 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

31 HYPOXIC PULMONARY VASOCONSTRICTION At sea level, this mechanism is active in the fetal life and is immediately released upon exposure to normoxia

32 O 2 O 2 breathing reduces PAP only partially, due to muscle cells in the small pulmonary vessels

33 MOLECULAR BASIS FOR PULMONARY VASOCONSTRICTION A DOWNREGULATION OF PULMONARY SYNTHESIS OF NITRIC OXIDE, A POWERFUL VASODILATOR

34 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.

36 Tibetans ventilate as much as acclimatized lowlanders, whereas Andeans hypoventilate

38 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.

39 CARDIAC OUTPUT

40 . Qmax (l/min) High altitude long-distance runners Andean natives ALTITUDE (km)

41 . Q (l/min) s.l m (Cerretelli, 1980) VO 2 (l/min)

42 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

43 200 HRmax (b/min) * 5050m 2850m * * Time (days) Altitude (km)

44 % s.l. HRmax 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 simulated hypoxia ALTITUDE (km)

45 beats min MAXIMAL HEART RATE ALTITUDE (km) Untrained lowlanders Trained lowlanders Skyrunners Tibetans Climbers A. D. P. B. C.

46 HR max (beats min -1 ) HANS Tibetans (Niu et al., 1995) Lhasa (3.680 m) months

47 OXYGEN CONVECTIVE TRANSPORT TO TISSUES IN ACCLIMATIZED LOWLANDERS AND ANDEANS. (15-20%) Qmax x [HbO 2 ] P50 (~30%)

48 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).

CHAPTER 6. Oxygen Transport. Copyright 2008 Thomson Delmar Learning

CHAPTER 6. Oxygen Transport. Copyright 2008 Thomson Delmar Learning CHAPTER 6 Oxygen Transport Normal Blood Gas Value Ranges Table 6-1 OXYGEN TRANSPORT Oxygen Dissolved in the Blood Plasma Dissolve means that the gas maintains its precise molecular structure About.003