RCIU Risque cardio-vasculaire

chez l’adulte

EA2193, Université de la Méditerranée INSERM UMR608

Service de néonatologie, AP-HM, Marseille

5

.5

-6.5

-7.5

-8.5

-9.5

>9.5

Birthweight (pounds)

20

40

60

80

100

120

Sta

nd

ard

ised

Mo

rtal

ity

Rat

io

Men

5

.5

-6.5

-7.5

-8.5

-9.5

>9.5

Birthweight (pounds)

20

40

60

80

100

120 Women

CORONARY HEART DISEASEStandardised mortality ratios in 10141 men & 5585 women

Barker et al, Lancet 1989

Growth of 357 boys who later developed coronary heart disease in a cohort of 4630

boys born in Helsinki

0 1 2 3 4 5 6 7 8 9 10 11 12

Age (years)

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

Standarddeviation(Z)-score

Height

Weight

BMI

Cohort

Eriksson et al, 2001Barker et al, 2005

Arterial Blood Pressure in 20-23 Year Old Adults

0

20

40

60

80

100

120

140

Controls Preterm IUGR

systolic

mean

diastolic

mmHg *

The development of hypertension

20 40 60 800

120

100

140

160

180

200

||

SystolicPressure(mmHg)

Age (years)

Lowbirthweight

Normal

Improved early nutrition

Improvedneurodevelopmental outcome

Cardio-vascular disease & type 2 diabetes in adulthood

Programmation précoce des maladies cardio-vasculaires et métaboliques

Hypertension artérielle:– Mécanismes artériels

– Mécanismes rénaux

– Mécanismes endocrines

Résistance à l’insuline

Pulse wave velocity in adults

6,36

6,97 *

5,5

6

6,5

7

7,5

8

1

m/s

Born preterm Controls

Systemic Arterial Compliance (Cart) in premature infants

1,6

1,4

1,2

1,0

0,8

0,6

0,4

0,2

Group A(1)

Group A(2)

Group B

*

* p<0,05 compared to group B

*

mm3/mmHg/m2

Preterm <30wks Term

Umbilical Artery: Elastin Content

Term newborn Preterm 30 wks

(catechin)

TEC PEC 32-36 W PEC 26-31 W

Ela

stin

(m

g/10

0 m

g d

ry t

issu

e)

0

1

2

3

4

Umbilical artery elastin content

4

5

6

7

8

9

<-116 -116 -56 -55 +13 13Quarters of weight change (g)

Flo

w m

edia

ted

dila

tion

(%)

Singhal et al, Circulation, 2004

Flow-mediated endothelium-dependent dilation (FMD) and early VLBW infant growth

Programmation précoce des maladies cardio-vasculaires et métaboliques

Hypertension artérielle:– Mécanismes artériels

– Mécanismes rénaux

– Mécanismes endocrines

Résistance à l’insuline

Birth weight and glomerular number

Birth weight(moy +/- SEM)

01234567

*

0

3000

6000

9000

12000

Glomerular number(moy +/- SEM)

*

g n

Control IUGR OF IUGR+OF Control IUGR

*

Systolic blood pressure (SBP)

5 0

7 5

1 0 0

1 2 5

1 5 0

1 7 5

1 M 2 M 4 M

SB

P (

mm

Hg

)

C o n t r o l I U G R O F I U G R + O F

**

* * * * *

0

10

20

30

40

50

60

70

Up

rV (

ml/

min

/kg

bo

by

we

igh

t)

controls IUGR OF IUGR+OF0

2

4

6

C r e a t C l ( m l / m i n / k g )Control IUGR OF IUGR+OFControl IUGR OF IUGR+OF

Proteinuria(mean+/-SD)

CreatCl (mean+/-SD)

mg/kg/d

Renal function at 4 months

mL/min/kgBW*

IUGR(nephron number

reduction)

Glomerular filtration surface aera

Glomerular Pressure

Brenner et al. Am J Hypertens 1988

Postnatal overfeeding

Arterial blood pressure

RAS

Vascular remodelling

Endocrine factors

Glomerulosclerosis

Single nephron glomerular filtration rate

(SNGFR)

Proteinuria

0

10000

20000

30000

40000

50000 Control

IUGR

OF

IUGR+OF

Glomerular number (12 months)

(mean+/- SE)

*

**

0

0,5

1

1,5

2 control

IUGR

OF

IUGR+OF

Glomerular volume

(mean+/- SE)

*

*

HNPN

C IUGR

IUGR+OF

Control

OF

Control

Environment: - Environment: +

Fetal life and early infancy Later development

Ureteric bud

Epithelial cells(nephrons)

Mesenchymal cells(metanephros) C-retC-ret

Wnt 11Wnt 11WT1WT1MidkineMidkine

C-retC-retWnt 11Wnt 11WT1WT1MidkineMidkine

RetinolRetinolRetinolRetinol

Several genes harbour a dramatic variation of expression between the

Substracted Libraries

-15

-10

-5

0

5

10

15

20

25

FT

H1

TP

I1

CU

L4B

GlutP

eroxexon 1+

2

GP

OX

exon1

GP

OX

exon2

GP

OX

exon3

Genes

Dif

fere

nce

in c

ycle

s o

n t

he

rat

SS

H p

rod

uct

s

Kidney R-N

Placenta R-N

On the SSH products, 4 genes present very high variations between IUGR and controls, with differences between the tissues explored:

FTH1 is considerably induced in IUGR-Normal placenta SSHTPI1 is considerably induced in IUGR-Normal kidney SSHCUL4B is considerably reduced in Normal-IUGR kidney SSHGPOX is considerably induced in IUGR-Normal SSH, but not the last exon

Santé

Durée de vie

Alimentation

Environnement

Génétique

Epigénétique

Style de vie

Mécanismes épigénétiques

• Susceptible d’expliquer une empreinte métabolique• Méthylation (inactivation) ou déméthylation

(activation) de séquences CpG du DNA ou des histones (acetylation –desacetylation)

• Mise en évidence par traitement au bisulfite, D-HPLC et RT PCR

• Les méthyles proviennent de l’environnement nutritif (maternel)

• Les métabolites actifs de l’oxygène induisent une déméthylation

Methyl metabolism: major metabolic intermediates,cofactors, dietary sources (adapted from Cooney et al, J Nutr 2002;132:2393S)

Maternal lymphocytes DNA37-42 wks•Preeclampsia•IUGR

DMR2-IGF2

0

10

20

30

40

50

60

70

80

90

100

3 4 5 6 7 8 9 10 11

0

10

20

30

40

50

60

70

80

90

100

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

DMR2bis-IGF2

Placenta• 8-14 wks• 37-42 wks.éclampsie•IUGR

0

10

20

30

40

50

60

70

80

90

100

3 4 5 6 7 8 9 10 11

0

10

20

30

40

50

60

70

80

90

100

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Igf2 Differentially Methylated Region 2

PERTURBATION

Nutrition

Caloric restriction

Environment

Experimental/therapeutic drugs

Utero-placental circulation

Pre-implantationEnvironment / conditions

Mother

Placenta

ORGAN

SYSTEM

0rgan size/ Cellular phenotype

Heart Vascular

Brain Liver Adrenals Pancreas

Kidney

Lung Fat

Bone Vasculogenis/ Angiogenis

PATHOLOGY

Cardiorenal disease

Hypertension

Diabetes

Dyslipidemia

Obesity

Hypercortisolism

GH/GF programming

Tumors

Respiratory Disease

Psychiatric disorders

Foetus

Epigenetic Mechanism

?

?

Epigenetic Mechanism

McMillen and Robinson, 2005

Programmation précoce du risque cardio-vasculaire

• Suivi à long terme des enfants de faible poids de naissance: – PA– microalbuminurie

• Nutrition postnatale précoce équilibrée– Évitant un retard de croissance extra-utérin– Respectant le potentiel de croissance individuel

• Allaitement maternel, mesures éducatives concernant la prévention des autres facteurs de risque cardio-vasculaire

• Perspectives de recherche:– Caractérisation épidémiologique du risque– Optimisation de la nutrition postnatale des enfants

de faible PN– Approches préventives pharmacologiques

EA 2193 Université Méditerranée, Marseille, France F. BoubredC. BuffatL TauzinF. Risso C. OliverU. Simeoni

INSERM U709, ParisD. VaimanH. Jammes

INSERM U364, ParisM. Lelièvre-Pégorier

INSERM U608, MarseilleF. Dignat-George

L. Camoin P. Charpiot