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RCIU Risque cardio-vasculaire chez l’adulte

RCIU Risque cardio-vasculaire chez l’adulte. EA2193, Université de la Méditerranée INSERM UMR608 Service de néonatologie, AP-HM, Marseille. Barker et al, Lancet 1989. Growth of 357 boys who later developed coronary heart disease in a cohort of 4630 boys born in Helsinki. 0.05. Cohort.

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RCIU Risque cardio-vasculaire chez l’adulte

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  1. RCIU Risque cardio-vasculaire chez l’adulte EA2193, Université de la Méditerranée INSERM UMR608 Service de néonatologie, AP-HM, Marseille

  2. Barker et al, Lancet 1989

  3. Growth of 357 boys who later developed coronary heart disease in a cohort of 4630 boys born in Helsinki 0.05 Cohort 0 BMI -0.05 Standard -0.1 Weight deviation (Z)-score Height -0.15 -0.2 -0.25 0 1 2 3 4 5 6 7 8 9 10 11 12 Eriksson et al, 2001 Barker et al, 2005 Age (years)

  4. Arterial Blood Pressure in 20-23 Year Old Adults * mmHg

  5. The development of hypertension Low birthweight 200 Normal 180 160 Systolic Pressure (mmHg) 140 120 100 || 0 20 40 60 80 Age (years)

  6. Improved early nutrition Cardio-vascular disease & type 2 diabetes in adulthood Improved neurodevelopmental outcome

  7. Programmation précoce des maladies cardio-vasculaires et métaboliques Hypertension artérielle: • Mécanismes artériels • Mécanismes rénaux • Mécanismes endocrines Résistance à l’insuline

  8. Pulse wave velocity in adults

  9. Systemic Arterial Compliance (Cart) in premature infants Term Preterm <30wks

  10. Umbilical Artery: Elastin Content Term newborn Preterm 30 wks (catechin)

  11. Umbilical artery elastin content

  12. Flow-mediated endothelium-dependent dilation (FMD) and early VLBW infant growth Flow mediated dilation (%) Quarters of weight change (g) Singhal et al, Circulation, 2004

  13. Programmation précoce des maladies cardio-vasculaires et métaboliques Hypertension artérielle: • Mécanismes artériels • Mécanismes rénaux • Mécanismes endocrines Résistance à l’insuline

  14. Birth weight and glomerular number g n * * * Control IUGR OF IUGR+OF Control IUGR Birth weight (moy +/- SEM) Glomerular number (moy +/- SEM)

  15. Systolic blood pressure (SBP) * * * * * * *

  16. Renal function at 4 months mg/kg/d mL/min/kgBW * Control IUGR OF IUGR+OF Control IUGR OF IUGR+OF Proteinuria (mean+/-SD) CreatCl (mean+/-SD)

  17. Proteinuria IUGR (nephron number reduction) Postnatal overfeeding • Glomerular filtration surface aera RAS  Single nephron glomerular filtration rate (SNGFR) Vascular remodelling  Arterial blood pressure Endocrine factors Glomerular Pressure Glomerulosclerosis Brenner et al. Am J Hypertens 1988

  18. Glomerular number (12 months) * * * (mean+/- SE)

  19. Glomerular volume * * (mean+/- SE)

  20. C Control IUGR Control OF HNPN IUGR+OF

  21. Environment: - Environment: + Fetal life and early infancy Later development

  22. Epithelial cells (nephrons) Mesenchymal cells (metanephros) C-ret Wnt 11 WT1 Midkine Retinol Ureteric bud

  23. Several genes harbour a dramatic variation of expression between the Substracted Libraries 25 20 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 SSH TPI1 is considerably induced in IUGR-Normal kidney SSH CUL4B is considerably reduced in Normal-IUGR kidney SSH GPOX is considerably induced in IUGR-Normal SSH, but not the last exon 15 10 Kidney R-N Difference in cycles on the rat SSH products 5 Placenta R-N 0 TPI1 FTH1 CUL4B GlutPerox -5 exon 1+2 GPOXexon1 GPOXexon2 GPOXexon3 -10 -15 Genes

  24. Alimentation Environnement Santé Durée de vie Style de vie Génétique Epigénétique

  25. 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

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

  27. Igf2 Differentially Methylated Region 2 DMR2-IGF2 DMR2bis-IGF2 • Placenta • 8-14 wks • 37-42 wks.éclampsie • IUGR • Maternal lymphocytes DNA • 37-42 wks • Preeclampsia • IUGR

  28. ORGAN SYSTEM 0rgan size/ Cellular phenotype Heart Vascular Brain Liver Adrenals Pancreas Kidney Lung Fat Bone Vasculogenis/ Angiogenis PERTURBATION Nutrition Caloric restriction Environment Experimental/therapeutic drugs Utero-placental circulation Pre-implantation Environment / conditions PATHOLOGY Cardiorenal disease Hypertension Diabetes Dyslipidemia Obesity Hypercortisolism GH/GF programming Tumors Respiratory Disease Psychiatric disorders Epigenetic Mechanism ? Mother Placenta Foetus ? Epigenetic Mechanism McMillen and Robinson, 2005

  29. 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

  30. 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

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