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

-2.5 -3 -3.4 -3.9 >3.980

100

120

140

160

180 Systolic (p = 0.0005)Diastolic (p = 0.0001)

Birth Weight [kg]

Blo

od

Pre

ssu

re[m

mH

g]

Relationship between fetal growth retardation and blood pressure in

middle age

Aorta (p = 0.01)

7

8

9

10

11

12

13

14

PWV [ms-1]

-2.5 -3 -3.4 >3.4

Birth Weight [kg]

Relationship between fetal growth retardation and arterial stiffness in

middle age

Martyn CN et al. British Heart Journal, (1995). 73: 116-121.

Leg (p = 0.03)

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.

Berry CL, et al. (1972) Journal of Pathology. 108: 265-274.

0

10

20

30

40

50

ElastinCollagen

Gestational age (weeks) Months after birth

40200 2 864 1210

Birth

Protein (% dry weight)

Human aortic elastin & collagen in early life

aorta

common iliac

external iliac

umbilical arteries

internal iliac

Normal SUA

Histology

UI present

UI absent

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.

Compliance

0

2

4

6

8

NORMAL SUA (+) SUA (-)

Co

mp

lian

ce

[%

/10

mm

Hg

]

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

TTTSSymptomatically

treated (n = 14)

TTTSlaser treated

(n = 13)

No TTTS(n = 12)

No TTTSNon identical

(n= 11)

Identical(monochorionic)

Non-identicaldichorionic

4 groups

Variables measured

• Brachial artery PWV

• Birthweight

• Gestational age

• BP differences between twins

• Age at diagnosis

• Mean age at PWV measurement

PWV [ms-1]

1

3

5

7

9

11

L H

Symp Laser Non TTTS Non I

L HD RD R

identical

TTTS No TTTS

PWV donor recipient pairs

PWV differences

-2

-1

0

1

2

Heavier - Lighter [ms-1]

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 compositionUnpublished data

Left ventricle

0.4

0.5

0.6

0.7

LV thickness/ext rad.

4 8 12 16

Age [weeks]

*

*

0

50

100

150

Caudal artery systolic BP [mmHg]

4 8Age [weeks]

Control

Low Protein

Animal weights

0

2

4

6

8

Birthweight [g]

4 8 12 16

Age [weeks]

* * *

0

0.25

0.5

0.75

1

Weight at death [kg]

4 8 12 16

Age [weeks]

*

Control

Low Protein

Aortic Dimensions

0.0

0.5

1.0

1.5

2.0

4 8 12 16

Age [weeks]

*

*

Wall

cross

sect

ional are

a [

mm

2]

Control

Low Protein

Aortic stiffness

0

250

500

750

1000

4 8 12 16

Age [weeks]

Ein

c at

= 1

.3 [k

Pa

]

*

*

Control

Low Protein

Aortic elastin & collagen

0

20

40

60

80

Collagen [%DW]

4 8 12 16

Age [weeks]

0

20

40

60

80

Elastin [% DW]

4 8 12 16

Age [weeks]

**

Control

Low Protein

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?

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

2.5

3.0

3.5

4.0

4.5

5.0

Aortic stiffness (arbitrary units)

0.4 0.5 0.6 0.7 0.8 0.9 1

Max stretch (mm)

P<0.01

Skin stretch for 500 mbar. 60 children aged 10 -11y

Fingerprints and hypertension

Palmar angle: abc

a

c

b

Palmar angle

3 basic types of fingerprint pattern

From: Holt S. Quantitative genetics of fingerprint patterns. Br. Med. Bull. 1961; 17:247

0 1-2 3-5135

140

145

150

No. of whorls on right hand

>43

ATD angle (°)

Sy

sto

lic B

P

Fingerprint results

40-42

≤ 39

Godfrey et al. BMJ 307, 405-409 (1993)

Fingerprint Summary

• Blood pressure in middle age is strongly correlated with number of finger whorls

• Inversely correlated with palmar angle

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

Death By Old Age

Robert L. Exp Gerontol 1999, 34:491-501.

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