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Fetal programming of metabolic disease

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Presentation on theme: "Fetal programming of metabolic disease"— Presentation transcript:

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:

2 Sheffield Ward

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

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

5 With thanks to Chris Martyn
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:

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

9 Normal SUA

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

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

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

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

19 PWV differences Heavier - Lighter [ms-1] identical TTTS No TTTS 2 1 -1
-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:

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

25 Animal weights * * Control Low Protein

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

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

28 Aortic elastin & collagen
* Control Low Protein

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 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 0.4 0.5 0.6 0.7 0.8 0.9 1 Max stretch (mm)

33 Why do large arteries get stiffer with age?
Fatigue failure of irreplaceable elastin (and atherosclerosis) What are the consequences? Increased pulse pressure Increased peak load on the heart and conduit arteries (and premature failure?)

34 Fingerprints and hypertension

35 Palmar angle a c b Palmar angle: abc

36 3 basic types of fingerprint pattern
From: Holt S. Quantitative genetics of fingerprint patterns. Br. Med. Bull. 1961; 17:247

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

38 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, (1993)

39 Death By Old Age Case Sex Age Occupation Findings 1 F 101 Laundress
Cardiac hypertrophy and degeneration. Severe generalized arteriosclerosis 2 University professor Bronchopneumonia, influenza, cardiac hypertrophy, coronary sclerosis 3 M 102 Rabbi Cardiac hypertrophy, fibrosis, generalized arteriosclerosis 4 Restaurant owner Cardiac hypertrophy, fibrosis, coronary–valvular sclerosis 5 106 Shepherd Bronchopneumonia, cardiac hypertrophy, fibrosis, fibrinous pericarditis, coronary sclerosis 2 F 101 University professor Bronchopneumonia, influenza, cardiac hypertrophy, coronary sclerosis 3 M 102 Rabbi Cardiac hypertrophy, fibrosis, generalized arteriosclerosis 4 Restaurant owner Cardiac hypertrophy, fibrosis, coronary–valvular sclerosis Robert L. Exp Gerontol 1999, 34:

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