PULMONARY CIRCULATION AT HIGH ALTITUDE

Jean COUDERT

Laboratoire de Physiologie – Biologie du SportFaculté de Médecine – Université d’AuvergneCLERMONT-FERRAND, FRANCE

The most striking changes at High Altitude (HA)

! Pulmonary Arterial Hypertension (PAH)

! In Acclimatized Lowlanders at HA

! In HA natives (Highlanders)

PLAN1) Values of pulmonary Arterial Pressures (PAP) at HA2) Factors acting upon these values

! Exercise! Ambient temperature (cold, heat)! Individual reactivity! Age! Others

3) Mechanisms involved

3-1 Pulmonary Arteriolar Vasoconstriction (PAV)! Effects of hypoxia! Cellular responses

3-2 Structural changes

4) Effects of Hypoxic PAV and Structural Changes induced by Hypoxia

5) Summary

Values of PAP at HA

1) Values in LA PAZ (3700m)

2) Values at different altitudes

Values in LA PAZ (3700m)

67 normal male Highlanders

(Arch. Inst. Biol. Andina, 1971)

Data compared with values obtained in Lima (n = 22)

(Banchero et al, Circulation, 1966)

Ageyear

Ht%

Hbg%

PaO2mmHg

SaO2%

PaCO2mmHg

CaO2vol.%

CvO2vol.%

LA PAZ(3700m)

m

SD

23.6

4.8

48.8

4.1

16.5

2.6

58.5

9.2

28.0

4.6

90.1

4.38

19.3

2.12

15.0

2.09

LIMA(150m)

m

SD

20.7

1.28

44.1

2.59

14.8

0.88

95.7

2.06

19.04

0.998

15.04

1.26

LA PAZ(3700m)

m

SD

5

1.9

29

6.6

21

4.2

9

2.7

6.43

1.69

3.91

1.09

265

80

148

43

13

3.8

s d m

PaP (mmHg)

RAP(mmHg)

WPP(mmHg)

COl.min-1

CIl.min-1.m-2

PRdynes.sec-1.cm-5

T a

LIMA(150m)

m

SD

2.6

1.3

22

3.5

12

2.2

3.97

0.97

160

46.7

73

24.4

6

2.1

6.5

1.68

Values at different altitudes

From GROVES et al, J. Appl. Physiol., 1987

Factors interfering with PAP at HA

1) Muscular exercise (Lockhart et al, J. Appl. Physiol., 1976)

6 normal male Highlanders in LA PAZ

At rest and during exercise (75W) breathing air (PIO2 = 100mmHg)

and 30% oxygen (PIO2 = 150mmHg)

2) Ambient temperature (Coudert J., Séminaire CNRS/NSF., 1980)

21 normal male Highlanders in LA PAZ

2–1 Heat exposure (13 subjects)

2–2 Cold exposure (8 subjects)

2-3 Responses to local cold exposure in pathological chronic hypoxia (COPD)

(Bedu et al, Am. J. Respir. Crit. Care Med., 1996)

From BIGH J, in « Hypoxia and Cold », Eds. SUTTON JR, HOUSTON CS, COATES G, 1987

Individual reactivity

Case of Highlander, studied in LA PAZ, one month after HAPO

oo

O

AGE

! Foetus, at sea level (SL) and at HA :

! PAP and PVR very high

! Newborn :

! ↓ Adult level

" after 10 days, at SL

" after 1 – 5 months, at HA (Morococha, 4540m)

GAMBOA R. and MARTICORENA E., Arch. Inst. Biol. Andina,1971

SEX

Possible protection against pulmonary hypertension,in female by sexual hormones

(↓ expression of endotheline-1 by estradiol)

Earley S. et al, Am. J Physiol. Lung Cell Mol Physiol., 2002

MECHANISMS

1) Pulmonary Arterial Vasoconstriction (PAV)

! Acute hypoxia

! Cellular responses

2) Structural changes

! Chronic hypoxia

" histological changes of the pulmonary arterioles

" cellular and molecular responses

EFFECTS OF ACUTE HYPOXIA

Pulmonary Arteriolar Vasoconstriction

very short delay of the responses

N2 and O2 TESTS

Effects of hypoxia and hyperoxia of short duration on the

pulmonary circulation of Highlanders and Lowlanders

living at 3750m

COUDERT J. et al, Prog Resp Res, 1975

CELLULAR RESPONSES INDUCED BY ACUTE HYPOXIA

Hypoxia inhibits K+ current in an oxygen sensitive potassium channel

! Cellular membrane depolarisation

! Opening of Ca2+ channels

! ↑ Intracellular Ca2+

! Contraction of pulmonary arteriolar smooth muscle cell

From BRIJ S.O. and PEACOCK A.J., Thorax, 1998

CONTRACTIONe.g. smooth muscle cell

HYPOXIAmay directly activate theHIF-1 binding sequence

Cellular responses to hypoxia in the pulmonary circulation

?

Nuclearsynthesis

K+ current inhibition leadsto membrane depolarisation

HIF-1

Gene products e.g.erythropoietin

From Brij S.O. and Peacock A.J., Thorax, 1998

K+

K+

Hypoxia inhibits K+

current in a delayedrectifier K channel

↑CALCIUM Ca2+ Ca2+ influx throughvoltage gated channels

HIF-1 α + β

Hémoprotéine oxygène Sensor O2

Hémoprotéine oxygène Sensor O2 O2

Phosphorylation des protéines

Factor X

VOIES DE REPONSES A L’HYPOXIE, INDUITES PAR HIF-1

Métabolismeanaérobie

Induction des gènes desenzymes de la glycolyse

Induction du géne dela tyrosine hydroxylase

Induction dugène EPO

Induction dugène vEGF

Angiogénèse Vasodilatation Erythropoïèse Respirationaugmentée

Induction des gènesI-NOS et HO-1

From Coudert J., Urgence pratique, 66, 2004

STRUCTURAL RESPONSES INDUCED BY CHRONIC HYPOXIA

! Bands of smooth muscle develop in the small pulmonary arteries (arterioles)

! Smooth muscles bonded by internal and external elastic laminae

! Narrowing of the lumen of the pulmonary arterioles and increase of PVR

From Heath and Williams, 1977

STRUCTURAL CHANGES : CELLULAR AND MOLECULAR

! Hypoxic proliferation and intracellular signaling (PKC and MAP kinases)

! Hypoxia and the upregulation of growth mitogens

! Nuclear synthesis

! Proliferation and remodelling of all three cell types of the pulmonary arterioles

(Possible regulation by HIF1)

Cellular responses to hypoxia in the pulmonary circulation

PKC

Nuclearsynthesis

PROLIFERATION and REMODELLINGof all three cell types

?

Phosphorylationevents e.g.MAP kinases

Hypoxia upregulatesthe stress activatedMAP kinases

From Brij S.O. and Peacock A.J., Thorax, 1998

CONTRACTIONe.g. smooth muscle cell

HYPOXIAmay directly activate the HIF-1 binding sequence

?

K+ current inhibition leads to membrane depolarisation

HIF-1

Gene products e.g.erythropoietin

K+

K+

Hypoxia inhibits K+

current in a delayedrectifier K channel

↑CALCIUM Ca2+ Ca2+ influx throughvoltage gated channels

Activationof secondmessengersignal e.g.DAG, IP3

Cell surface receptorvasoconstrictor growth factors e. g. ET-1, PDGF

EFFECTS OF HYPOXIC PVC AND STRUCTURAL CHANGESINDUCED BY CHRONIC HYPOXIA

Structural changes PAH Right ventricular hypertrophy

PVC Improvement in ventilation perfusion relationships ?

Regional distribution of pulmonary blood flow, at HA

COUDERT J. et al Respiration, 1975

SUMMARY

1) At rest : PAP and Pulmonary Resistances (PR)are higher at HA than at SL

! in LL, importance of PVC

! in HL, importance of structural changes

2) ↑ + + + of PAP and PR

during exercise and cold exposure

↑ + + + in hyperreactive subjects

(triggering factor of HAPE ? and predictive factor of HAPE ?)

Δ PAPmax=Ex hypoxia-rest normoxia

3) PAH : useful factor ?

! No improvement of the perfusion of the apex in standing position

! Risk of « chronic pulmonary heart » with right cardiac insufficiency

Co authors of the studies performed in LA PAZ,in the laboratories of IBBA

ANTEZANA G.BARRAGAN L.BRIANCON L.CUDKOWICZ JDURAND J.LOCKHART A.MENSH-DECHENE J.PAZ-ZAMORA M.SPIELVOGEL H.VARGAS E.ZELTER M.