Alan Lucas

Early origins of cardiovascular disease: is there a unifying hypothesis?

That early nutrition and growth could affect cardiovascular disease (CVD) later in life has intrigued the public and scientific community. However, most published data are observational and retrospective, making interpretation difficult and providing an insecure basis for practice. Prompted by animal studies on long-term effects of early nutrition, we initiated intervention studies with strict experimental design to test the importance of early nutrition in humans. Long-term findings are now emerging. We showed that early postnatal nutrition permanently affects the major components of the metabolic syndrome—hypertension, dyslipidaemia, obesity, and insulin resistance—that affect propensity to CVD. Here we discuss our new findings together with existing studies in man and animals, and propose a synthesis with major implications for public-health practice and future research. Historical perspective More than 100 years ago, critical windows in development were first described in relation to imprinting in chicks. That nutrition can act during such windows to affect later biology was shown in the 1960s by McCance, 1 who found that rats raised in small litters, and therefore overfed postnatally, were larger in adulthood. Subsequently, early overfeeding in rats was shown to raise later concentrations of plasma insulin and cholesterol, 2

Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials

BACKGROUND Despite data relating body size in early life to later cardiovascular outcomes, the hypothesis that nutrition affects such outcomes has not been established. Breastfeeding has been associated with lower blood pressure in later life, but previous studies have not controlled for possible confounding factors by using a randomised design with prospective follow-up. We undertook such a study to test the hypothesis that early diet programmes blood pressure in later life in children randomly assigned different diets at birth. METHODS Blood pressure was measured at age 13-16 years in 216 (23%) of a cohort of 926 children who were born prematurely and had participated at birth in two parallel randomised trials in five neonatal units in the UK. Dietary interventions were: donated banked breastmilk versus preterm formula and standard term formula versus preterm formula. FINDINGS Children followed up at age 13-16 years were similar to those not followed up in terms of social class and anthropometry at birth. Mean arterial blood pressure at age 13-16 years was lower in the 66 children assigned banked breastmilk (alone or in addition to mothers milk) than in the 64 assigned preterm formula (mean 81.9 [SD 7.8] vs 86.1 [6.5] mm Hg; 95% CI for difference -6.6 to -1.6; p=0.001). In non-randomised analyses, the proportion of enteral intake as human milk in the neonatal period was inversely related to later mean arterial pressure (beta=-0.3 mm Hg per 10% increase [95% CI -0.5 to -0.1]; p=0.006). No differences were found in the term formula (n=44) versus preterm formula (n=42) comparison. INTERPRETATION Breastmilk consumption was associated with lower later blood pressure in children born prematurely. Our data provide experimental evidence of programming of a cardiovascular risk factor by early diet and further support the long-term beneficial effects of breastmilk.

Low nutrient intake and early growth for later insulin resistance in adolescents born preterm.

BACKGROUND In animals, acceleration of neonatal growth is thought to increase the later propensity to insulin resistance and non-insulin-dependent diabetes, whereas slow growth as a consequence of undernutrition is thought to have a beneficial effect. To test this hypothesis in people, we measured fasting concentrations of 32-33 split proinsulin, a marker of insulin resistance, in adolescents born preterm who had participated in randomised intervention trials of neonatal nutrition, and in adolescents born at term. METHODS We determined fasting 32-33 split proinsulin concentration in participants aged 13-16 years born preterm and randomised to receive a nutrient-enriched or lower-nutrient diet (n=216) or in a reference group born at term (n=61). FINDINGS Fasting 32-33 split proinsulin concentration was greater in children given a nutrient-enriched diet (geometric mean 7.2 pmol/L, 95% CI 6.4-8.1) than in those given the lower-nutrient diet (5.9 pmol/L [5.2-6.4]; mean difference 20.6% [5.0-36.3]; p=0.01). Healthy babies born at term had similar fasting 32-33 split proinsulin concentrations (6.9 pmol/L; 6.0-8.2) to the nutrient-enriched group. In non-randomised analyses, fasting 32-33 split proinsulin concentration was associated with greater weight gain the first 2 weeks of life (13.2% [5.4-20.9] change per 100 g weight increase; p=0.001) independent of birthweight, gestation, neonatal morbidity, and demographic, anthropometric, and socioeconomic factors. INTERPRETATION Our results suggest that relative undernutrition early in life in children born preterm may have beneficial effects on insulin resistance.

Influence of Leptin on Arterial Distensibility. A Novel Link Between Obesity and Cardiovascular Disease

Background—The mechanisms by which obesity increases the risk of atherosclerotic cardiovascular disease (CVD) are poorly understood. In experimental models, leptin, a hormone produced by adipose tissue, has been shown adversely to affect vascular health. Therefore, we tested the hypothesis that high leptin concentrations are associated with lower arterial distensibility, an index of circulatory function relevant to the atherosclerotic process. Methods and Results—Noninvasive, high-resolution, vascular ultrasound was used to measure brachial artery distensibility in 294 healthy adolescents (aged 13 to 16 years) who had a broad range of body mass indexes. Fat mass was measured by bioelectric impedance analysis; fasting serum leptin concentration by radioimmunoassay; and lipid profile, fasting insulin, glucose, and C-reactive protein concentrations by standard laboratory techniques. Higher leptin concentrations were associated with impaired arterial distensibility (regression coefficient, −1.3% change in arterial distension per 10% increase in leptin; 95% CI, −1.9% to −0.8%;P <0.001). This association was independent of fat mass, blood pressure, and C-reactive protein, fasting insulin, or LDL cholesterol concentrations. Conclusions—Elevation in leptin was associated with impaired vascular function, independent of the metabolic and inflammatory disturbances associated with obesity. Our observations are consistent with data from experimental models and suggest that high leptin concentration is an important mechanism for the adverse influence of body fatness on CVD.

Energy Expenditure and Intake in Infants Born to Lean and Overweight Mothers

We investigated the contributions of low energy expenditure and high energy intake to excessive weight gain in infants born to overweight mothers. The subjects were infants of 6 lean and 12 overweight mothers, recruited soon after birth. Total energy expenditure and metabolizable energy intake were measured with a new doubly labeled water method over a period of seven days when the infants were 3 months of age, and the postprandial metabolic rate was measured by indirect calorimetry when the infants were 0.1 and 3 months of age. The results were related to weight gain in the first year of life. No significant difference was observed between infants who became overweight by the age of one year (50 percent of infants born to overweight mothers) and those who did not, with respect to weight, length, skinfold thicknesses, metabolic rate at 0.1 and 3 months of age, and metabolizable energy intake at 3 months. However, total energy expenditure at three months of age was 20.7 percent lower in the infants who became overweight than in the other infants (means +/- SE, 256 +/- 27 and 323 +/- 12 kJ per kilogram of body weight per day; P less than 0.05). This difference could account for the mean difference in weight gain. These data suggest that reduced energy expenditure, particularly on physical activity, was an important factor in the rapid weight gain during the first year of life in infants born to overweight mothers.

Is Slower Early Growth Beneficial for Long-Term Cardiovascular Health?

Background—Accelerated neonatal growth increases the later propensity to cardiovascular disease (CVD) in animals, whereas slower growth is thought to have a beneficial effect. To test this hypothesis in humans, we measured flow-mediated endothelium-dependent dilation (FMD) in a population subject to slower early growth and in healthy controls. Methods and Results—High-resolution vascular ultrasound was used to measure the change in brachial artery diameter in response to reactive hyperemia in adolescents age 13 to 16 years who were either part of a cohort born preterm and followed up prospectively (n=216) or controls born at term (n=61). Greater weight gain or linear growth in the first 2 weeks postnatally was associated with lower FMD at adolescence (regression coefficient, −0.026-mm change in mean arterial diameter per 100-g increase in weight; 95% CI, −0.040 to −0.012 mm; P =0.0003) independent of birthweight and potential confounding factors. Mean FMD in the half of the preterm population with the lowest rates of early growth was higher than in both the half with the greatest growth (P =0.001) and subjects born at term (P =0.03). Conclusions—FMD was 4% lower in adolescents with the highest compared with the lowest rate of weight gain in the first 2 weeks after birth, a substantial negative effect similar to that for insulin-dependent diabetes mellitus or smoking in adults. Our findings are consistent with the adverse effects of accelerated neonatal growth on long-term cardiovascular health and suggest that postnatal growth patterns could explain the previously reported association between birthweight and later CVD.

Organ-selective growth in the offspring of protein-restricted mothers

Recent epidemiological studies in people whose birth weights were recorded many years ago suggest links between impaired growth during early life and the development of diseases, including diabetes, much later in life. The long-term effects of retarded early growth are proposed to result from malnutrition at critical periods of fetal or infant development leading to reduction in the growth of organs and permanent changes in their metabolism or structure, or both. In order to investigate this, a rat model was established which involved feeding either a diet containing 200 g protein/kg or an isoenergetic diet containing 80 g protein/kg to pregnant and lactating rats. In addition, cross-fostering techniques were employed which allowed a separate evaluation of the prenatal or the postnatal periods. The offspring were studied at 21 d of age or were weaned onto a normal laboratory chow and studied at 11 months of age. The 80 g protein/kg diet during pregnancy did not affect the overall reproductive although more subtle differences were evident. Permanent growth retardation was evident in offspring subjected to maternal protein restriction during the postnatal period. At 21 d of age the offspring of protein-restricted mothers exhibited selective changes in organ growth: compared with the body weight, the lung and brain experienced a smaller decrease in weight: the heart, kidney and thymus decreased proportionately: whereas, the pancreas, spleen, muscle and liver showed a greater reduction in weight. In older animals the muscle weight was lower in the male rats and the relative weight of pancreas was increased in the female rats.

Hippocampal Volume and Everyday Memory in Children of Very Low Birth Weight

Children born preterm and of very low birth weight have an increased incidence of learning difficulties, but little is known about the specific nature of their cognitive deficits and the underlying neuropathology. We hypothesized that their vulnerability to hypoxic, metabolic, and nutritional insults would lead to reduced hippocampal volumes and to deficits in memory because of the role of the hippocampus in this domain of cognition. Neuropsychological and magnetic resonance imaging methods were used to investigate this hypothesis in adolescents born preterm (≤30 wk gestation, n = 11) or full-term (n = 8). The preterm group had significantly smaller hippocampal volumes bilaterally, despite equivalent head size, and showed specific deficits in certain aspects of everyday memory, both on objective testing and as indicated by parental questionnaires. The preterm group also had a specific deficit in numeracy. The reduced hippocampal volumes and deficits in everyday memory have previously been unrecognized, but their prevalence in a group of neurologically normal children is striking.

Breastmilk feeding and lipoprotein profile in adolescents born preterm: follow-up of a prospective randomised study

BACKGROUND Breastfeeding is associated with reduced cholesterol concentration later in life, but previous studies have not used random assignment of infant diet with prospective follow-up. We tested the hypothesis that breastmilk feeding benefits the lipoprotein profile in adolescents born preterm, in whom randomisation to different diets at birth is feasible. METHODS 926 infants born preterm were randomly assigned in two parallel trials to receive (trial 1) donated banked breastmilk or preterm formula, or (trial 2) standard term formula or preterm formula, as sole diet or as supplements to mothers milk in both trials. We followed up 216 participants at age 13-16 years and measured ratio of low-density to high-density lipoprotein cholesterol (LDL to HDL), ratio of apolipoprotein B to apolipoprotein A-1 (apoB to apoA-1), and concentration of C-reactive protein (CRP; a measure of the inflammatory process associated with atherosclerosis). RESULTS Adolescents who had been randomised to banked breastmilk had a lower CRP concentration (p=0.006) and LDL to HDL ratio (mean difference 0.34 [14% lower], 95% CI -0.67 to -0.01; p=0.04) than those given preterm formula. A greater proportion of human milk intake in infancy was associated with lower ratios of LDL to HDL (p=0.03) and apoB to apoA-1 (p=0.004)--independent of gestation and potential confounding factors--and with lower CRP concentration (p=0.03). CRP concentration correlated with the two lipoprotein ratios (p<0.0001 and p=0.003, respectively). INTERPRETATION Our data provide experimental evidence for the long-term benefits of breastmilk feeding on the risk of atherosclerosis.

Flow-Mediated Dilation in 9- to 11-Year-Old Children The Influence of Intrauterine and Childhood Factors

BACKGROUND Early life factors, particularly size at birth, may influence later risk of cardiovascular disease, but a mechanism for this influence has not been established. We have examined the relation between birth weight and endothelial function (a key event in atherosclerosis) in a population-based study of children, taking into account classic cardiovascular risk factors in childhood. METHODS AND RESULTS We studied 333 British children aged 9 to 11 years in whom information on birth weight, maternal factors, and risk factors (including blood pressure, lipid fractions, preload and postload glucose levels, smoking exposure, and socioeconomic status) was available. A noninvasive ultrasound technique was used to assess the ability of the brachial artery to dilate in response to increased blood flow (induced by forearm cuff occlusion and release), an endothelium-dependent response. Birth weight showed a significant, graded, positive association with flow-mediated dilation (0.027 mm/kg; 95% CI, 0.003 to 0.051 mm/kg; P=.02). Childhood cardiovascular risk factors (blood pressure, total and LDL cholesterol, and salivary cotinine level) showed no relation with flow-mediated dilation, but HDL cholesterol level was inversely related (-0.067 mm/mmol; 95% CI, -0.021 to -0.113 mm/mmol; P=.005). The relation between birth weight and flow-mediated dilation was not affected by adjustment for childhood body build, parity, cardiovascular risk factors, social class, or ethnicity. CONCLUSIONS Low birth weight is associated with impaired endothelial function in childhood, a key early event in atherogenesis. Growth in utero may be associated with long-term changes in vascular function that are manifest by the first decade of life and that may influence the long-term risk of cardiovascular disease.