Atul Singhal

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.

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.

How much loss to follow-up is acceptable in long-term randomised trials and prospective studies?

to test early nutritional interventions and prospective observational cohorts. RCTs are generally accepted as methodologically the best approach for informing health policy. They can equalise unknown as well as known confounding factors and so can demonstrate causation; they permit estimation of effect size and so can be used to assess likely economic

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.

Promotion of Faster Weight Gain in Infants Born Small for Gestational Age Is There an Adverse Effect on Later Blood Pressure

Background— Being born small for gestational age is associated with later risk factors for cardiovascular disease, such as high blood pressure. Promotion of postnatal growth has been proposed to ameliorate these effects. There is evidence in animals and infants born prematurely, however, that promotion of growth by increased postnatal nutrition increases rather than decreases later cardiovascular risk. We report the long-term impact of growth promotion in term infants born small for gestational age (birth weight <10th percentile). Methods and Results— Blood pressure was measured at 6 to 8 years in 153 of 299 (51%) of a cohort of children born small for gestational age and randomly assigned at birth to receive either a standard or a nutrient-enriched formula. The enriched formula contained 28% more protein than standard formula and promoted weight gain. Diastolic and mean (but not systolic) blood pressure was significantly lower in children assigned to standard compared with nutrient-enriched formula (unadjusted mean difference for diastolic blood pressure, −3.2 mm Hg; 95% CI, −5.8 to −0.5; P=0.02) independent of potential confounding factors (adjusted difference, −3.5 mm Hg; P=0.01). In observational analyses, faster weight gain in infancy was associated with higher later blood pressure. Conclusions— In the present randomized study targeted to investigate the effect of early nutrition on long-term cardiovascular health, we found that a nutrient-enriched diet increased later blood pressure. These findings support an adverse effect of relative “overnutrition” in infancy on long-term cardiovascular disease risk, have implications for the early origins of cardiovascular disease hypothesis, and do not support the promotion of faster weight gain in infants born small for gestational age.

Randomized Controlled Trial of the MEND Program: A Family‐based Community Intervention for Childhood Obesity

The aim of this study was to evaluate the effectiveness of the Mind, Exercise, Nutrition, Do it (MEND) Program, a multicomponent community‐based childhood obesity intervention (www.mendcentral.org). One hundred and sixteen obese children (BMI ≥ 98th percentile, UK 1990 reference data) were randomly assigned to intervention or waiting list control (6‐month delayed intervention). Parents and children attended eighteen 2‐h group educational and physical activity sessions held twice weekly in sports centers and schools, followed by a 12‐week free family swimming pass. Waist circumference, BMI, body composition, physical activity level, sedentary activities, cardiovascular fitness, and self‐esteem were assessed at baseline and at 6 months. Children were followed up 12 months from baseline (0 and 6 months postintervention for the control and intervention group, respectively). Participants in the intervention group had a reduced waist circumference z‐score (−0.37; P < 0.0001) and BMI z‐score (−0.24; P < 0.0001) at 6 months when compared to the controls. Significant between‐group differences were also observed in cardiovascular fitness, physical activity, sedentary behaviors, and self‐esteem. Mean attendance for the MEND Program was 86%. At 12 months, children in the intervention group had reduced their waist and BMI z‐scores by 0.47 (P < 0.0001) and 0.23 (P < 0.0001), respectively, and benefits in cardiovascular fitness, physical activity levels, and self‐esteem were sustained. High‐attendance rates suggest that families found this intensive community‐based intervention acceptable. Further larger controlled trials are currently underway to confirm the promising findings of this initial trial.

Fetal, infant and childhood growth: relationships with body composition in Brazilian boys aged 9 years

BACKGROUND:Early growth rate has been linked to later obesity categorised by body mass index (BMI), but the development of body composition has rarely been studied.METHODS:We tested the hypotheses that (1) birthweight and weight gain in (2) infancy or (3) childhood are associated with later body composition, in 172 Brazilian boys followed longitudinally since birth. Growth was assessed using measurements of weight and height at birth, 6 months, and 1 and 4 y. Measurements at 9 y comprised height, weight and body composition using foot–foot impedance.RESULTS:Birthweight was associated with later height and lean mass (LM), but not fatness. Weight gain 0–6 months was associated with later height and LM, and with obesity prevalence according to BMI, but not with fatness. Weight gain 1–4 y was associated with later fatness and LM. Weight gain 4–9 y was strongly associated with fatness but not LM. Early growth rate did not correlate positively with subsequent growth rate.CONCLUSIONS:Early rapid weight gain increased the risk of later obesity, but not through a direct effect on fatness. Childhood weight gain remained the dominant risk factor for later obesity. The reported link between early growth and later obesity may be due partly to hormonal programming, and partly to the contribution of LM to obesity indices based on weight and height. Whether our findings apply to other populations requires further research.