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 diabetesKidney? HypertensionHeart Coronary artery diseaseBlood vessels Hypertension, atherosclerosis, strokeBarker, DJ & Clark, PM. (1997) Reviews of Reproduction, 2:
3 Relationship between fetal growth retardation and blood pressure in middle age 80100120140160180Systolic (p = )Diastolic (p = )Blood Pressure[mmHg]-2.5-3-3.4-3.9>3.9Birth Weight [kg]
4 Relationship between fetal growth retardation and arterial stiffness in middle age PWV [ms-1]7891011121314Aorta (p = 0.01)Leg (p = 0.03)-2.5-3-3.4>3.4Birth Weight [kg]Martyn CN et al. British Heart Journal, (1995). 73:
5 With thanks to Chris Martyn BabiesWith thanks to Chris Martyn
6 What is the mechanism linking reduced birth weight and increased blood pressure in adult life?
7 HypothesisWith 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)504030Elastin20Collagen10Birth402028641210Gestational age (weeks)Months after birthBerry CL, et al. (1972) Journal of Pathology. 108:
10 Compliance Histology Compliance [%/10 mmHg] UI present UI absent 2 4 6 2468UI presentCompliance [%/10 mmHg]UI absentNORMALSUA (+)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 & treatmentPerinatal mortality in 80 to 100% of untreated casesAmnioreduction (symptomatic)to reduce amniotic fluid volume and pressure60 to 70% survivalLaser ablation of anastomosesto prevent inter-twin transfusion and establish separate circulationsBetter than 70% survival
14 HypothesisPreviously shown that donor twin has 2x increase in brachial artery PWV in infancyIs 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 arteryMedian corrected postnatal age 11.1 monthsRange 1 week to 64 monthsEthical approval in both centres
16 4 groups TTTS Symptomatically treated (n = 14) No TTTS TTTS laser treated(n = 13)No TTTSNon identical(n= 11)Identical(monochorionic)Non-identicaldichorionic
17 Variables measured Brachial artery PWV Birthweight Gestational age BP differences between twinsAge at diagnosisMean age at PWV measurement
20 LimitationsMilder manifestation of TTTS in conservatively treated groupVariable onset and duration of TTTS before treatmentRadial artery compliance may not reflect that of central arteries and LV loadCross 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 HypothesisWith 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 groupsLow protein (LP) group given 9% protein dietControl group (C) given 18% protein diet, isocaloricOffspring weaned at 4 weeks onto normal dietAnimals killed at 4, 8 and12 weeksMeasureBP or Left ventricular dimensionsAortic elasticity & chemical compositionUnpublished data
24 Left ventricle * * Control Low Protein 50 100 150 50100150Caudal artery systolic BP [mmHg]48Age [weeks]*
29 ConclusionsReduced 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 ProblemIs 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)5.04.54.0P<0.013.53.02.188.8.131.52.70.80.91Max stretch (mm)
33 Why do large arteries get stiffer with age? Fatigue failure of irreplaceable elastin(and atherosclerosis)What are the consequences?Increased pulse pressureIncreased peak load on the heart and conduit arteries(and premature failure?)