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Fetal programming of metabolic disease

Fetal programming of metabolic disease. A stimulus or insult at a critical period of early life, often when rates of growth are maximal, leads to irreversible changes in structure and function of target organs. Pancreas  Late onset diabetes Kidney?  Hypertension

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Fetal programming of metabolic disease

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  1. Fetal programming of metabolic disease A stimulus or insult at a critical period of early life, often when rates of growth are maximal, leads to irreversible changes in structure and function of target organs. • Pancreas  Late onset diabetes • Kidney?  Hypertension • Heart  Coronary artery disease • Blood vessels  Hypertension, atherosclerosis, stroke • Barker, DJ & Clark, PM. (1997) Reviews of Reproduction, 2: 105-112.

  2. Sheffield Ward

  3. 180 160 140 120 100 80 -2.5 -3 -3.4 -3.9 >3.9 Relationship between fetal growth retardation and blood pressure in middle age Systolic (p = 0.0005) Diastolic (p = 0.0001) Blood Pressure[mmHg] Birth Weight [kg]

  4. 14 Leg (p = 0.03) 13 12 11 10 9 8 7 Relationship between fetal growth retardation and arterial stiffness in middle age PWV [ms-1] Aorta (p = 0.01) -2.5 -3 -3.4 >3.4 Birth Weight [kg] Martyn CN et al. British Heart Journal, (1995). 73: 116-121.

  5. Babies With thanks to Chris Martyn

  6. What is the mechanism linking reduced birth weight and increased blood pressure in adult life?

  7. Hypothesis • With age, progressive fragmentation and loss of elastin (which cannot be resynthesised) and replacement by collagen --> increased arterial stiffness --> increased pulse pressure. • In growth retarded infants elastin synthesis is reduced in utero, arteries are stiffer than normal from an early age and never fully recover. Martyn CN and Greenwald SE. Lancet. 1997; 350: 953-955.

  8. 0 20 40 2 4 6 8 10 12 Human aortic elastin & collagen in early life Protein (% dry weight) 50 40 30 Elastin 20 Collagen 10 Birth 0 Gestational age (weeks) Months after birth Berry CL, et al. (1972) Journal of Pathology. 108: 265-274.

  9. Normal SUA

  10. 8 6 4 2 0 Compliance Histology UI present Compliance [%/10 mmHg] UI absent NORMAL SUA (+) SUA (-) Meyer WW and Lind J. (1974) Archives of Disease in Childhood,. 49: 671-679. Berry CL et al. (1976) British Heart Journal, 38: 310-315.

  11. Twin to Twin Transfusion Syndrome (TTTS) A natural model of the effects of volume loading on fetal vascular development.

  12. TTTS occurs in identical twins • Most identical twins share a common placenta (monochorionic). • Of these, 10-15% develop TTTS wherein blood is unevenly distributed between them. • Thought to be due to the presence of deep arteriovenous anastomoses within the placenta. • Recipient: • Hypervolaemia, polyuria, polyhydramnios, LV hypertrophy, systemic hypertension(?), cardiac malformations. • Donor: • Hypovolaemia, poor renal perfusion, oliguria, oligohydramnios.

  13. Prognosis & treatment • Perinatal mortality in 80 to 100% of untreated cases • Amnioreduction (symptomatic) • to reduce amniotic fluid volume and pressure • 60 to 70% survival • Laser ablation of anastomoses • to prevent inter-twin transfusion and establish separate circulations • Better than 70% survival

  14. Hypothesis • Previously shown that donor twin has 2x increase in brachial artery PWV in infancy • Is this due to chronic hypovolaemia and or abnormal pressure during uterine life? • If so, laser treatment, by restoring normal pressure and flow, should prevent vascular remodelling and reduce inter-twin PWV differences?

  15. Subjects • 50 twin pairs (London & Hamburg) • PWV measured in brachioradial artery • Median corrected postnatal age 11.1 months • Range 1 week to 64 months • Ethical approval in both centres

  16. Identical (monochorionic) Non-identical dichorionic 4 groups TTTS Symptomatically treated (n = 14) No TTTS (n = 12) TTTS laser treated (n = 13) No TTTS Non identical (n= 11)

  17. Variables measured • Brachial artery PWV • Birthweight • Gestational age • BP differences between twins • Age at diagnosis • Mean age at PWV measurement

  18. 11 9 7 5 3 1 L D L D H R R H identical PWV donor recipient pairs PWV [ms-1] Symp Laser Non TTTS Non I TTTS No TTTS

  19. PWV differences Heavier - Lighter [ms-1] 2 1 0 -1 -2 Symp Laser No TTTS Non I identical TTTS No TTTS

  20. Limitations • Milder manifestation of TTTS in conservatively treated group • Variable onset and duration of TTTS before treatment • Radial artery compliance may not reflect that of central arteries and LV load • Cross sectional measurements at different (young) ages, no idea yet of long term effects

  21. Conclusions • Vascular programming seen in identical twins with TTTS • PWV discordancy altered but not abolished by intrauterine laser treatment, to resemble that seen in fraternal twins with separate uterine circulations

  22. Hypothesis • With age, progressive fragmentation and loss of elastin (which cannot be resynthesised) and replacement by collagen --> increased arterial stiffness --> increased pulse pressure. • In growth retarded infants elastin synthesis is reduced in utero, arteries are stiffer than normal from an early age and never fully recover. Martyn CN and Greenwald SE. Lancet. 1997; 350: 953-955.

  23. Animal model of fetal growth retardation • Pregnant rats divided into two groups • Low protein (LP) group given 9% protein diet • Control group (C) given 18% protein diet, isocaloric • Offspring weaned at 4 weeks onto normal diet • Animals killed at 4, 8 and12 weeks • Measure • BP or Left ventricular dimensions • Aortic elasticity & chemical composition Unpublished data

  24. Control Low Protein Caudal artery systolic BP [mmHg] 150 * 100 50 0 4 8 Age [weeks] Left ventricle *

  25. Control Low Protein * * * * Animal weights

  26. Control Low Protein Aortic Dimensions * Wall cross sectional area [mm2] *

  27. Control Low Protein Aortic stiffness * Einc at  = 1.3 [kPa] *

  28. Control Low Protein * * Aortic elastin & collagen

  29. Conclusions • Reduced body weight, aortic dimensions, elastin content and increased BP or LV hypertrophy in 4 & 12 week LP animals is consistent with the hypothesis that protein deprivation in utero leads changes in vessel structure and composition. • The elasticity differences in 4 and 12 week animals were consistent with the hypothesis. However the results from the 8 week animals are not.

  30. Limitations • Preliminary study, limited age range • Lack of in vivo central pressure measurements. • Applicability of rat model to human in utero growth retardation?

  31. Problem Is the reduction in aortic elastin content a cause or a consequence of hypertension?

  32. 0.4 0.5 0.6 0.7 0.8 0.9 1 Skin stretch for 500 mbar. 60 children aged 10 -11y Aortic stiffness (arbitrary units) 5.0 4.5 4.0 P<0.01 3.5 3.0 2.5 Max stretch (mm)

  33. Fingerprints and hypertension

  34. Palmar angle a c b Palmar angle: abc

  35. 3 basic types of fingerprint pattern From: Holt S. Quantitative genetics of fingerprint patterns. Br. Med. Bull. 1961; 17:247

  36. 150 ≤ 39 145 40-42 140 135 0 1-2 3-5 Fingerprint results ATD angle (°) >43 Systolic BP No. of whorls on right hand

  37. Fingerprint Summary • Blood pressure in middle age is strongly correlated with number of finger whorls • Inversely correlated with palmar angle Godfrey et al. BMJ 307, 405-409 (1993)

  38. Death By Old Age Robert L. Exp Gerontol 1999, 34:491-501.

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