Debbie S. Thompson

Impaired Cardiovascular Structure and Function in Adult Survivors of Severe Acute Malnutrition

Malnutrition below 5 years remains a global health issue. Severe acute malnutrition (SAM) presents in childhood as oedematous (kwashiorkor) or nonoedematous (marasmic) forms, with unknown long-term cardiovascular consequences. We hypothesized that cardiovascular structure and function would be poorer in SAM survivors than unexposed controls. We studied 116 adult SAM survivors, 54 after marasmus, 62 kwashiorkor, and 45 age/sex/body mass index–matched community controls who had standardized anthropometry, blood pressure, echocardiography, and arterial tonometry performed. Left ventricular indices and outflow tract diameter, carotid parameters, and pulse wave velocity were measured, with systemic vascular resistance calculated. All were expressed as SD scores. Mean (SD) age was 28.8±7.8 years (55% men). Adjusting for age, sex, height, and weight, SAM survivors had mean (SE) reductions for left ventricular outflow tract diameter of 0.67 (0.16; P<0.001), stroke volume 0.44 (0.17; P=0.009), cardiac output 0.5 (0.16; P=0.001), and pulse wave velocity 0.32 (0.15; P=0.03) compared with controls but higher diastolic blood pressures (by 4.3; 1.2–7.3 mm Hg; P=0.007). Systemic vascular resistance was higher in marasmus and kwashiorkor survivors (30.2 [1.2] and 30.8 [1.1], respectively) than controls 25.3 (0.8), overall difference 5.5 (95% confidence interval, 2.8–8.4 mm Hg min/L; P<0.0001). No evidence of large vessel or cardiac remodeling was found, except closer relationships between these indices in former marasmic survivors. Other parameters did not differ between SAM survivor groups. We conclude that adult SAM survivors had smaller outflow tracts and cardiac output when compared with controls, yet markedly elevated peripheral resistance. Malnutrition survivors are thus likely to develop excess hypertension in later life, especially when exposed to obesity.

Glucose metabolism in adult survivors of severe acute malnutrition

CONTEXT AND OBJECTIVES The clinical syndromes of severe acute malnutrition may have early life origins because children with marasmus have lower birth weight than those with kwashiorkor. We hypothesized that resultant metabolic effects may persist into adulthood. We investigated whether marasmus survivors (MS) are more insulin resistant and glucose intolerant than kwashiorkor survivors (KS). RESEARCH DESIGN AND SETTING This was a case-control study in Jamaican adults. SUBJECTS We performed oral glucose tolerance tests on 191 adults (aged 17-50 y; 52% male; body mass index 24.2 ± 5.5 kg/m(2)). There were 43 MS; 38 KS; 70 age-, sex-, and body mass index-matched community controls; and 40 age- and birth weight-matched controls. MEASUREMENTS We measured insulin sensitivity with the whole-body insulin sensitivity index, and β-cell function with the insulinogenic index and the oral disposition index. RESULTS Fasting glucose was comparable across groups, but glucose intolerance was significantly more common in MS (19%) than in KS (3%), community controls (11%), and birth weight-matched controls (10%). The whole-body insulin sensitivity index was lower in MS than KS (P = .06) but similar between MS and controls. The insulinogenic index and oral disposition index were lower in MS compared with all three groups (P < .01). CONCLUSIONS Marasmus survivors tend to be less insulin sensitive, but have significantly lower insulin secretion and are more glucose intolerant compared with kwashiorkor survivors and controls. This suggests that poor nutrition in early life causes β-cell dysfunction, which may predispose to the development of diabetes.

The effect of antenatal factors and postnatal growth on serum adiponectin levels in children

Low levels of serum adiponectin (i.e. hypoadiponectinaemia) are a marker of cardiometabolic risk in overweight children. It is not clear whether early-life factors may play a role in the development of hypoadiponectinaemia. We investigated whether antenatal factors and postnatal growth are associated with childhood adiponectin levels. This was an observational study in a birth cohort (Vulnerable Windows Cohort Study). Anthropometry was measured at birth, at 6 weeks, every 3 months up to 2 years and then every 6 months. Fasting glucose, insulin, lipids and adiponectin were measured at a mean age 11.5 years. Data on 323 children were analysed with age- and sex-adjusted multivariate analyses. The sizes of mother, placenta, fetus and newborn were not significantly associated with adiponectin levels. Current weight, body mass index (BMI), fat mass, waist circumference, glucose, insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)], triglycerides and systolic blood pressure were inversely related to adiponectin (P < 0.05). Faster growth in BMI during late infancy and childhood was associated with lower adiponectin levels (P < 0.05). After adjusting for current waist circumference, faster growth in BMI during early infancy was positively associated with adiponectin (P < 0.01). Faster growth in BMI during childhood was inversely associated (P < 0.001). These associations were similar after adjusting for HOMA-IR. We concluded that antenatal factors are not determinants of childhood adiponectin levels. Faster growth in BMI during infancy is associated with higher levels, whereas faster rates during childhood are associated with hypoadiponectinaemia. Hypoadiponectinaemia is a marker of a more adverse cardiometabolic profile in Afro-Caribbean children.

Socioeconomic factors associated with severe acute malnutrition in Jamaica

Objectives Severe acute malnutrition (SAM) is an important risk factor for illness and death globally, contributing to more than half of deaths in children worldwide. We hypothesized that SAM is positively correlated to poverty, low educational attainment, major crime and higher mean soil concentrations of lead, cadmium and arsenic. Methods We reviewed admission records of infants admitted with a diagnosis of SAM over 14 years (2000–2013) in Jamaica. Poverty index, educational attainment, major crime and environmental heavy metal exposure were represented in a Geographic Information System (GIS). Cases of SAM were grouped by community and the number of cases per community/year correlated to socioeconomic variables and geochemistry data for the relevant year. Results 375 cases of SAM were mapped across 204 urban and rural communities in Jamaica. The mean age at admission was 9 months (range 1–45 months) and 57% were male. SAM had a positive correlation with major crime (r = 0.53; P < 0.001), but not with educational attainment or the poverty index. For every one unit increase in the number of crimes reported, the rate of occurrence of SAM cases increased by 1.01% [Incidence rate ratio (IRR) = 1.01 (95% CI = 1.006–1.014); P P<0.001]. The geochemistry data yielded no correlation between levels of heavy metals and the prevalence of malnutrition. Conclusion Major crime has an independent positive association with severe acute malnutrition in Jamaican infants. This could suggest that SAM and major crime might have similar sociological origins or that criminality at the community level may be indicative of reduced income opportunities with the attendant increase in poor nutrition in the home.

Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition

Background Severe acute malnutrition (SAM) in infants may present as one of two distinct syndromic forms: non-edematous (marasmus), with severe wasting and no nutritional edema; or edematous (kwashiorkor) with moderately severe wasting. These differences may be related to developmental changes prior to the exposure to SAM and phenotypic changes appear to persist into adulthood with differences between the two groups. We examined whether the different response to SAM and subsequent trajectories may be explained by developmentally-induced epigenetic differences. Methods We extracted genomic DNA from muscle biopsies obtained from adult survivors of kwashiorkor (n = 21) or marasmus (n = 23) and compared epigenetic profiles (CpG methylation) between the two groups using the Infinium® 450 K BeadChip array. Findings We found significant differences in methylation of CpG sites from 63 genes in skeletal muscle DNA. Gene ontology studies showed significant differential methylation of genes in immune, body composition, metabolic, musculoskeletal growth, neuronal function and cardiovascular pathways, pathways compatible with the differences in the pathophysiology of adult survivors of SAM. Interpretation These findings suggest persistent developmental influences on adult physiology in survivors of SAM. Since children who develop marasmus have lower birth weights and after rehabilitation have different intermediary metabolism, these studies provide further support for persistent developmentally-induced phenomena mediated by epigenetic processes affecting both the infant response to acute malnutrition and later life consequences. Funding Supported by a Grant from the Bill and Melinda Gates Foundation (Global Health OPP1066846), Grand Challenge “Discover New Ways to Achieve Healthy Growth.” Evidence Before This Study Previous research has shown that infants who develop either kwashiorkor or marasmus in response to SAM differ in birth weight and subsequently have different metabolic patterns in both infancy and adulthood. Added Value of This Study This study demonstrates epigenetic differences in the skeletal muscle of adult survivors of marasmus versus kwashiorkor and these differences are in genes that may underlie the longer-term consequences. Implications of All the Available Evidence These data are compatible with the different clinical responses to SAM arising from developmentally-induced epigenetic changes laid down largely before birth and provide evidence for the predictive adaptive response model operating in human development.

Early‐life factors are associated with nocturnal cortisol and glucose effectiveness in Afro–Caribbean young adults

Early‐life factors (including intrauterine growth retardation) may influence the development of type 2 diabetes. We postulated that birth size is associated with cortisol levels, which itself could alter serum adipomyokines (i.e. adiponectin, IGF‐I, myostatin) and glucose metabolism.