ibfm-sect. of muscle physiology and proteome national ... · claudio marconi ibfm-sect. of muscle...
TRANSCRIPT
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Claudio Marconi
IBFM-Sect. of Muscle Physiology and Proteome National Research Council
Milano, Italy
GENETIC INFLUENCE ON FACTORS OF OXYGEN
TRANSPORT
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ALTITUDE (km)0 2 4 6 8 10
% s
.l. V
O2m
ax
10
20
30
40
50
60
70
80
90
100
.
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O2 transport system
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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)
* * *
.
?
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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
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-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
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High altitude populations (>3,500 m)
AymarasQuechuas
SherpasTibetans
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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.
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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)
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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
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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.
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Fick’s equation
VO2max = Qmax (Ca-Cv)O2max.. .
Oxygen delivery
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O2 DELIVERY TO TISSUES
CaO2 x Q.
[Hb] x K x SaO2% HR x SV
O2 diffusion – VA/Q mismatch
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HAEMOGLOBIN CONCENTRATION
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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
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Tib lowlanders
Caucasians
(22.5)
Sherpas
(Redrawn by Beall, 2001)
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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
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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
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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
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In Andean and Tibetan highlanders erythropoietin concentration is in the range of the sea-level values
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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
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ARTERIAL OXYGEN SATURATION (SaO2%)
is an index of the efficiency of lung gas exchange, depending on:- O2 diffusion- alveolar ventilation-pulmonary blood flow ratio
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REST
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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
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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
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60
70
80
90
100
Tib 2 Sh altit C Crunn untr tr
SaO2 AT PEAK EXERCISE (after 1 mo at 5,050 m)
(%)
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IN THE ABSENCE OF GENETIC ADAPTATIONS SaO2peak OF ACCLIMATIZED LOWLANDERS MAY TAKE YEARS TO APPROACH THE VALUES FOUND IN ALTITUDE NATIVES.
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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
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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
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HYPOXIC PULMONARY VASOCONSTRICTION
At sea level, this mechanism is active in the fetal life and is immediately
released upon exposure to normoxia
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O2 breathing reduces PAP only partially, due to muscle cells in the small pulmonary vessels
O2
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MOLECULAR BASIS FOR PULMONARY VASOCONSTRICTION
A DOWNREGULATION OF PULMONARY SYNTHESIS OF NITRIC OXIDE, A
POWERFUL VASODILATOR
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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.
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Tibetans ventilate as much as acclimatized lowlanders, whereas Andeans hypoventilate
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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.
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CARDIAC OUTPUT
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Qmax(l/min)
.
ALTITUDE (km)
0 2 4 6 8 1010
15
20
25
30
35
High altitude long-distance runners
Andean natives
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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
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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
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Time (days)-20 0 20 40 60 80
HRmax
120
140
160
180
200
Alti
tude
(km
)
0
3
6
2850m5050m
(b/min)
** *
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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
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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.
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-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)
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OXYGEN CONVECTIVE TRANSPORT TO TISSUES IN
ACCLIMATIZED LOWLANDERS AND ANDEANS
Qmax x [HbO2]
P50
(15-20%)
.(~30%)
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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).