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Vascular Programming The fetal origins hypothesis proposes that adaptation of the fetus to its intrauterine environment and postnatal stressors may have life-long consequences and that the fetal response to an environmental challenge may result in programming of different organs, depending on the timing of the insult The original concept of fetal programming has been expanded and now encompasses both prenatal and postnatal adaptation under the umbrella of the developmental origins of adult disease Environmental factors contribute to permanent effects resulting from altered epigenetic and genetic regulation that can be demonstrated in population studies.218 Vascular Programming in the Setting of Restricted Growth The fetal cardiovascular system differs from that of the neonate in that the interdependence between cardiac and pulmonary physiology is less important than that of the placental vasculature Normal placental development includes appropriate trophoblastic invasion to remodel placental spiral arteries and create a low impedance circulation This is important in the development of normal fetal cardiovascular responses.29 This vascular change does not occur in cases of placental dysfunction The reduction in placental flow may then result in a growth-restricted fetus.54,55 The fetus alters its adaptive responses to enable survival in these adverse conditions, sometimes to the detriment of later functional and adaptive responses.57 These have been termed “predictive adaptive responses.”219 This model proposes that the risk of disease depends on the degree of mismatch between the predicted postnatal environment and that which exists The prediction usually anticipates a worse outcome than exists, which further increases the mismatch Adverse early influences are thought to result in the so-called thrifty phenotype This describes an individual that can match supply and demand successfully to permit survival, even though some of the adaptive mechanisms this involves may lead to later disease through disturbances of normal cardiovascular and neurohormonal control mechanisms Postnatal nutrition often results in catch-up growth in growth-restricted infants, and this may further disturb the “thrifty phenotype,” permitting an individual to live within his or her predicted environment Many Doppler ultrasound studies of the growth-restricted fetus have been published, and, more recently, reports propose that cardiac development itself is affected, the growth-restricted fetus having an increased sphericity index compared with those that are normally grown.39,40 These findings have been described in infancy, and long-term studies are required to assess their future impact on cardiac function Fetal studies have described the effects of increased systemic impedance, due to placental dysfunction, on the circulatory system This results in an impairment of venous flow toward the heart during diastole, with a consequent reduction of peak velocity of inward flow61,62 and a reduction in the pulsations of the wall of the inferior caval vein The increased central venous pressure may contribute to impairment of systemic venous return and a reduction in normal forward flow during late diastole in the pulmonary trunk This suggests that there is abnormal veno-ventricular-vascular coupling.220 Increased shunting through the venous duct in growth-restricted fetuses reduces umbilical blood supply to the fetal liver, which may be detrimental in those surviving with restricted growth.221 Occlusion of the venous duct leads to a significant increase in cell proliferation in fetal skeletal muscle, heart, kidneys, and liver and possibly to an increase in expression of IgF1 and 2 and mRNA These alterations may have a significant long-term influence on metabolism in the growth-restricted individual, lending support to the concept of altered metabolism seen in adults with reduced birth weight.222 Some studies have reported a reduction in systolic velocities through the arterial valves in growth-restricted fetuses However, this is not a universal finding and does not necessarily reflect poor ventricular function Other authors have reported increased peak systolic velocities of flow but found that the flow commenced later in systole than normal, thus resulting in an increased preejection period and a shorter ejection time because of the increased systemic impedance, resulting in a reduced stroke volume.223 Cardiac output corrected for weight is normal in growth-restricted fetuses, but the mean velocity of flow in the descending aorta is significantly less, and the volume of blood flowing showed a similar, but nonsignificant trend, suggesting more is directed cephalad.220 The effects of vascular programming associated with altered intrauterine nutrition may not be obvious in individuals studied early in life Although component parts of the fetal arterial pulse waveform are significantly different in the growth-restricted fetus, no differences have been found in pulse wave velocity.220 The relationship between pulse wave velocity and intrauterine growth restriction is not yet clear, but in babies delivered at normal term, there appears to be an inverse association between the velocity of the neonatal arterial pulse wave and maternal systolic blood pressure, with a positive relationship for neonatal gestational age, birth weight, length, and neonatal blood pressure.224 Prematurity alone does not appear to influence the velocity of the pulse wave Children born prior to term with a z-score for birthweight below minus two standard deviations had significantly higher mean blood pressure and higher pulse wave velocity at school age than those born prior to term but of normal weight.225 Longitudinal studies have shown that young adults studied in fetal life because of restricted growth have smaller aortas than controls and higher resting heart rates, suggesting altered cardiovascular modulation.226 It may be that maturation of the aortic wall is required Alternatively, a process of amplification227 may need to occur during infancy before any differences can be appreciated in the properties of the aortic wall The finding of increased arterial wall thickness is widely reported in growth restricted fetuses and babies.228–230 In addition to isolated growth restriction the response of the fetal endothelium to maternal hypertension is important as growth restriction and preeclampsia are closely correlated and appear to be associated with elevated blood pressure in childhood.231,232 However, a more recent study using very-high-frequency linear probes of 35 to 55 MHz reports that arterial wall layer, lumen diameter, and carotid artery wall stress were attributable to somatic growth, implying the use of lower frequency transducers may have overestimated wall layer measurements of thickness.233 Cardiovascular Programming in Twin-Twin Transfusion Syndrome TTTS is an extreme model of circulatory imbalance occurring in monochorionic pregnancies where there are two genetically identical individuals Within-pair responses in the cardiovascular response to differences in volume load and the effect of increased placental resistance can be measured Studies have confirmed that fetal vascular programming occurs and reduced arterial distensibility is detectable in the growth-restricted donor twin during infancy.234 Furthermore, the intertwin differences are altered by intrauterine laser ablation of placental