Fetal programming of metabolic disease

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
Relationship between fetal growth retardation and
blood pressure in middle age
Systolic (p 0.0005)
Diastolic (p 0.0001)
Blood PressuremmHg
Birth Weight kg
4
Relationship between fetal growth retardation and
arterial stiffness in middle age
PWV ms-1
Aorta (p 0.01)
-2.5
-3
-3.4
gt3.4
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?
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Hypothesis

• With age, progressive fragmentation and loss of
  elastin (which cannot be resynthesised) and
  replacement by collagen --gt increased arterial
  stiffness --gt 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
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
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.
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Twin to Twin Transfusion Syndrome (TTTS)

• A natural model of the effects of volume loading
  on fetal vascular development.

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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.

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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

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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?

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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

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4 groups
TTTS Symptomatically treated (n 14)
No TTTS (n 12)
TTTS laser treated (n 13)
No TTTS Non identical (n 11)
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Variables measured

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

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PWV donor recipient pairs
PWV ms-1
Symp
Laser
Non TTTS
Non I
TTTS
No TTTS
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PWV differences
Heavier - Lighter ms-1
2
1
0
-1
-2
Symp
Laser
No TTTS
Non I
identical
TTTS
No TTTS
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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

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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

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Hypothesis

• With age, progressive fragmentation and loss of
  elastin (which cannot be resynthesised) and
  replacement by collagen --gt increased arterial
  stiffness --gt 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
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Left ventricle

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Animal weights
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Aortic Dimensions

Wall cross sectional area mm2

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Aortic stiffness

Einc at ?? 1.3 kPa

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Aortic elastin collagen
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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.

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Limitations

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

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Problem

• Is the reduction in aortic elastin content a
  cause or a consequence of hypertension?

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Skin stretch for 500 mbar. 60 children aged 10
-11y
Aortic stiffness (arbitrary units)
5.0
4.5
4.0
Plt0.01
3.5
3.0
2.5
Max stretch (mm)
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• 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?)

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Fingerprints and hypertension
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Palmar angle
a
c
b
Palmar angle abc
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3 basic types of fingerprint pattern
From Holt S. Quantitative genetics of
fingerprint patterns. Br. Med. Bull. 1961 17247
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Fingerprint results
ATD angle ()
gt43
Systolic BP
No. of whorls on right hand
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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)
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Death By Old Age
Case Sex Age Occupation Findings
1 F 101 Laundress Cardiac hypertrophy and degeneration. Severe generalized arteriosclerosis
2 F 101 University professor Bronchopneumonia, influenza, cardiac hypertrophy, coronary sclerosis
3 M 102 Rabbi Cardiac hypertrophy, fibrosis, generalized arteriosclerosis
4 M 102 Restaurant owner Cardiac hypertrophy, fibrosis, coronaryvalvular sclerosis
5 M 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 M 102 Restaurant owner Cardiac hypertrophy, fibrosis, coronaryvalvular sclerosis
Robert L. Exp Gerontol 1999, 34491-501.
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