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.
Sheffield Ward
Relationship between fetal growth
retardation and blood pressure in middle age
Blood Pressure[mmHg]
180
Systolic (p = 0.0005)
Diastolic (p = 0.0001)
160
140
120
100
80
-2.5
-3
-3.4
-3.9
Birth Weight [kg]
>3.9
Relationship between fetal growth retardation
and arterial stiffness in middle age
PWV [ms-1]
14
Aorta (p = 0.01)
Leg (p = 0.03)
13
12
11
10
9
8
7
-2.5
-3
-3.4
Birth Weight [kg]
Martyn CN et al. British Heart Journal, (1995). 73: 116-121.
>3.4
Babies
With thanks to Chris Martyn
What is the mechanism
linking reduced birth weight
and increased blood
pressure in adult life?
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.
Human aortic elastin & collagen in early life
Protein (% dry weight)
50
40
30
Elastin
Collagen
20
10
Birth
0
0
20
40
2
Gestational age (weeks)
4
6
8
10
12
Months after birth
Berry CL, et al. (1972) Journal of Pathology. 108: 265-274.
Normal
aorta
umbilical arteries
common iliac
external iliac
internal iliac
SUA
Compliance [%/10 mmHg]
Compliance
Histology
8
UI present
6
4
2
UI absent
0
NORMAL
SUA (+)
SUA (-)
Berry CL et al. (1976) British Heart
Journal, 38: 310-315.
Meyer WW and Lind J. (1974) Archives of
Disease in Childhood,. 49: 671-679.
Twin to Twin Transfusion
Syndrome (TTTS)
A natural model of the effects of
volume loading on fetal vascular
development.
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.
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
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?
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
4 groups
TTTS
Symptomatically
treated (n = 14)
No TTTS
TTTS
laser treated
No TTTS
Non identical
(n = 13)
(n= 11)
(n = 12)
Identical
(monochorionic)
Non-identical
dichorionic
Variables measured
•
•
•
•
•
•
Brachial artery PWV
Birthweight
Gestational age
BP differences between twins
Age at diagnosis
Mean age at PWV measurement
PWV donor recipient pairs
PWV [ms-1]
11
9
7
5
3
1
D
R
D
Symp
Laser
TTTS
R
L
L
H
Non TTTS
Non I
No TTTS
identical
H
PWV differences
Heavier - Lighter [ms-1]
2
1
0
-1
-2
Symp
Laser
No TTTS
Non I
identical
TTTS
No TTTS
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
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
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.
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
Left ventricle
Control
Low Protein
LV thickness/ext rad.
0.7
Caudal artery systolic BP [mmHg]
150
*
0.6
*
100
0.5
50
0
4
8
Age [weeks]
0.4
4
8
Age [weeks]
12
16
Animal weights
Birthweight [g]
Weight at death [kg]
8
1
6
0.75
*
4
*
*
0.5
*
2
0.25
0
0
4
8
12
16
Age [weeks]
4
8
12
Age [weeks]
Control
Low Protein
16
Wall cross sectional area [mm2]
Aortic Dimensions
2.0
1.5
*
Control
1.0
Low Protein
0.5
*
0.0
4
8
Age [weeks]
12
16
Aortic stiffness
Einc at  = 1.3 [kPa]
1000
Control
*
750
Low Protein
500
*
250
0
4
8
Age [weeks]
12
16
Aortic elastin & collagen
Collagen [%DW]
Elastin [% DW]
80
80
60
60
*
*
40
40
20
20
0
0
4
8
12
16
4
8
Age [weeks]
Age [weeks]
Control
Low Protein
12
16
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.
Limitations
• Preliminary study, limited age range
• Lack of in vivo central pressure
measurements.
• Applicability of rat model to human in utero
growth retardation?
Problem
Is the reduction in aortic elastin
content a cause or a consequence
of hypertension?
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
Max stretch (mm)
1
Fingerprints and hypertension
Palmar angle
a
c
b
Palmar angle: abc
3 basic types of fingerprint pattern
From: Holt S. Quantitative genetics of fingerprint patterns. Br. Med. Bull. 1961; 17:247
Fingerprint results
150
ATD angle (°)
Systolic BP
≤ 39
40-42
145
>43
140
135
0
1-2
3-5
No. of whorls on right hand
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)
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,
coronary–valvular sclerosis
5
M
106
Shepherd
Bronchopneumonia, cardiac
hypertrophy, fibrosis, fibrinous
pericarditis, coronary sclerosis
Robert L. Exp Gerontol 1999, 34:491-501.