Claudio Marconi

IBFM-Sect. of Muscle Physiology and Proteome National Research Council

Milano, Italy

GENETIC INFLUENCE ON FACTORS OF OXYGEN

TRANSPORT

ALTITUDE (km)0 2 4 6 8 10

% s

.l. V

O2m

ax

10

20

30

40

50

60

70

80

90

100

.

O2 transport system

Time (days)-20 0 20 40 60 80

VO2max

0

1

2

3

4

5

Alti

tude

(km

)

0

3

6

2850m5050m

(l·min-1)

* * *

.

?

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 O2 availability.

Adaptations involve the O2 transport system

-5 0 5 10 15 20 25 3020

30

40

50

60

Lhasa (3.680 m)

months

HANS Tibetans

VO2 max(ml·kg-1·min-1)

.

(Niu et al., 1995)

Developmental adaptation

Genetic adaptation

Acclimatization

High altitude populations (>3,500 m)

AymarasQuechuas

SherpasTibetans

BACKGROUND

Anecdotally, high altitude natives, particularly Tibetans including Sherpas and Amerindians,have been considered more apt to carry outaerobic exercise in chronic hypoxia than acclimatized lowlanders.

3 4 5 630

35

40

45

50

55

60

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)

VO2max (ml·kg-1· min-1).

(Cerretelli e Hoppeler, 1996)

The maximal aerobic power of high-altitude natives is in the range of normal for sea-level

values.Can this feature be explained by agenetic and/or acquired adaptation

of some determinants of VO2max, affecting O2transport and utilization at the tissue level?

.

WORKING HYPOTHESIS

AIMS1) 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

VO2max = Qmax (Ca-Cv)O2max.. .

Oxygen delivery

O2 DELIVERY TO TISSUES

CaO2 x Q.

[Hb] x K x SaO2% HR x SV

O2 diffusion – VA/Q mismatch

HAEMOGLOBIN CONCENTRATION

0 2 4 6 8 10 12 144

5

6

7

8

12.5

15.0

17.5

20.0

22.5

40

45

50

55

60RBCHbHCT

TIME (weeks)

4540 mHCT(%)

RBC(106 ml-1)

Hb(g%)

Acclimatized lowlanders

Tib lowlanders

Caucasians

(22.5)

Sherpas

(Redrawn by Beall, 2001)

ALTITUDE (km)

Hb(g·dl-1)

Hb concentration of acclimatized Tibetan lowlanders is < than that of Caucasians

0 1 2 3 4 5 6 7 810

12

14

16

18

20

22Lowlanders Skyrunners Tibetans Climbers

ALTITUDE (km)

Hb(g·dl-1)

Hb concentration of acclimatized Tibetan lowlanders is < than that of Caucasians

0 1 2 3 4 5 6 7 810

12

14

16

18

20

22Lowlanders Skyrunners Tibetans Climbers

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

ERYTHROPOIETIN

Blood Erythropoietin concentration increases sharply within few hours upon arrival at altitude

Thereafter it decreases attaininga value slightly higher than thatat sea level

ACUTE HYPOXIA

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

Erythropoietin

45 50 55 60 65 700

10

20

30

Quechua IndiansSherpas

(Winslow et al., JAP 1989) Hct (%)

mU/

ml

Andean highlanders respond as if they are anemic

ARTERIAL OXYGEN SATURATION (SaO2%)

is an index of the efficiency of lung gas exchange, depending on:- O2 diffusion- alveolar ventilation-pulmonary blood flow ratio

REST

SEA LEVEL

Time along pulmonary capillary (s)0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

PO2

(mm

Hg)

0

20

40

60

80

100

120

140 inspired

alveolar

mixed venous

end-capillary

VO2 = 300 ml / min

(West & Wagner, 1980)

PB = 760 Torr

MT. EVEREST SUMMIT

Time along pulmonary capillary (s)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

PO2

(mm

Hg)

10

20

30

40

50

inspired

alveolar

mixed venous

end-capillary

VO2 = 350 ml / min

(West, 1983)

PB = 253 Torr

60

70

80

90

100

Tib 2 Sh altit C Crunn untr tr

SaO2 AT PEAK EXERCISE (after 1 mo at 5,050 m)

(%)

IN THE ABSENCE OF GENETIC ADAPTATIONS SaO2peak OF ACCLIMATIZED LOWLANDERS MAY TAKE YEARS TO APPROACH THE VALUES FOUND IN ALTITUDE NATIVES.

Tibetan natives of and Han 8 year residents at Lhasa (3658 m)

(Sun et al., 1990) Tibetans Hans

SaO2peak (%)

60

70

80

90

100

Tibetan natives of and Han 8 year residents at Lhasa (3658 m)

(Sun et al., 1990) Tibetans Hans

SaO2peak (%)

60

70

80

90

100

SaO2peak 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

O2 breathing reduces PAP only partially, due to muscle cells in the small pulmonary vessels

O2

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)

.

ALTITUDE (km)

0 2 4 6 8 1010

15

20

25

30

35

High altitude long-distance runners

Andean natives

Q(l/min)

.

VO2 (l/min).

(Cerretelli, 1980)0 1 2 3 4

0

5

10

15

20

25

30

s.l. 5.800 m

Q(l/min)

.Q

(l/min)

.

VO2 (l/min).

VO2 (l/min).

(Cerretelli, 1980)0 1 2 3 4

0

5

10

15

20

25

30

s.l. 5.800 m

ACCLIMATIZATIONACCLIMATIZATION--INDUCED REDUCTION IN INDUCED REDUCTION IN QmaxQmax..

--Water Water shifting shifting out of the out of the vascularvascular spacespace

--SweatingSweating--RespirationRespiration--Urine productionUrine production

Reduced Reduced plasma volumeplasma volume

Lower cardiac filling pressures Lower cardiac filling pressures

lower Qmaxlower Qmax..

Increased blood viscosityIncreased blood viscosity

Increased Increased [[HbHb]] Reduced myocardial Reduced myocardial contractilitycontractility

Adaptations Adaptations in in ANSANS

Lower HRLower HRmaxmax

Muscle deteriorationMuscle deterioration

lower wlower wmaxmax and VOand VO22maxmax....

Expanded blood volume

Isovolemic hemodilution

Time (days)-20 0 20 40 60 80

HRmax

120

140

160

180

200

Alti

tude

(km

)

0

3

6

2850m5050m

(b/min)

** *

ALTITUDE (km)0 1 2 3 4 5 6 7 8 9

% s

.l. H

Rm

ax

60

65

70

75

80

85

90

95

100

Astrand 1958 Christensen and Forbes 1937Cerretelli 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

simulated hypoxia

MAXIMAL HEART RATE

ALTITUDE (km)

beats·min-1

0 1 2 3 4 5 6 7 8110120130140150160170180190200210

Untrained lowlandersTrained lowlandersSkyrunners Tibetans Climbers A. D. P. B. C.

MAXIMAL HEART RATE

ALTITUDE (km)

beats·min-1

MAXIMAL HEART RATE

ALTITUDE (km)

beats·min-1

0 1 2 3 4 5 6 7 8110120130140150160170180190200210

Untrained lowlandersTrained lowlandersSkyrunners Tibetans Climbers A. D. P. B. C.

-5 0 5 10 15 20 25 30160

170

180

190

200HR max

(beats ·min-1)

months

Lhasa (3.680 m)

TibetansHANS

(Niu et al., 1995)

-5 0 5 10 15 20 25 30160

170

180

190

200HR max

(beats ·min-1)

months

Lhasa (3.680 m)

TibetansHANS

HR max(beats ·min-1)

months

Lhasa (3.680 m)Lhasa (3.680 m)

TibetansTibetansHANS

(Niu et al., 1995)

OXYGEN CONVECTIVE TRANSPORT TO TISSUES IN

ACCLIMATIZED LOWLANDERS AND ANDEANS

Qmax x [HbO2]

P50

(15-20%)

.(~30%)

CONCLUSIONS

• Acclimatized lowlanders and high-altitude natives maintain adequate maximal O2delivery to tissues, by different means:

-increasing [Hb] (acclimatized lowlanders and Andeans)

-keeping high values of HRpeak and SaO2% (Tibetans).