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Background: The prevalence of obesity in long-term survivors with complex congenital heart disease may be increasing, and little is known about the timing and onset of weight gain and growth patterns in these high-risk patients. Methods and Results: Prevalence rates of overweight/obesity and longitudinal changes in body mass index (BMI) with age were determined in 606 patients with Fontan circulation seen at a tertiary care cardiology center from 1992 – 2012. The number of clinic encounters (n) was stratified by age group (n=401, 2–5y; n= 333, 6–11y; n=217, 12–19y; and n=129, >20y). Among adults, 39% were overweight/obese at last clinic visit; 22% overweight and 17% obese. Childhood anthropometric data were available for 82 adults; of which 15% (n=12/82) were overweight/obese in childhood. The likelihood of being overweight/ obese as an adult was 3 times higher if there was a BMI ≥ 85th percentile in childhood (CI 2.1–4.5, p <0.01). Overweight/obesity in adulthood was associated with lower heart failure rates (4% vs. 19%, P=0.03). Pediatric rates of overweight/obesity were comparable to national data (NHANES 2011–2012) in every age group: at 2–5y, (25 vs. 23%), 6–11y (26 vs. 34%), and 12–19y (15 vs. 35%). Systolic blood pressure was higher in overweight/obese children as young as 2–5 years of age. Conclusions: Childhood and adult survivors with Fontan circulation have high rates of overweight/obesity. Childhood obesity is a strong predictor of future adiposity and is linked to changes in systolic blood pressure at a very young age.

Intrauterine growth restriction (IUGR) induced by uterine artery ligation in pregnant rats leads to low birth weight and early insulin secretory defects followed by the development of insulin resistance, decline in ␤-cell mass, and diabetes in adulthood. Neonatal administration of Exendin-4 (Ex-4) prevents the deterioration of ␤-cell mass and the onset of adult-onset diabetes. Our aim was to determine whether this effect occurs through preservation of islet vascularization. In 2 wk-old IUGR rats, endothelial-specific lectin staining revealed a 40% reduction in islet vascular density (p ϭ 0.027), which was normalized by neonatal Ex-4. VEGF-A protein expression was reduced in IUGR islets compared with controls at postnatal d 1 (P). Neonatal Ex-4 normalized islet VEGF protein expression at P7. Neither IUGR nor Ex-4 administration to IUGR rats affected relative VEGF splice isoform RNA levels. Together, the reduced vascularity in IUGR islets before the deterioration of ␤-cell mass, and the enhancement of VEGF expression and normalization of islet vascularity by neonatal Ex-4, suggest islet vascularity as an early determinant of ␤-cell mass and as a potential therapeutic target for diabetes prevention. Uteroplacental insufficiency, leading to reduced delivery of nutrients, oxygen, growth factors, and hormones to the developing fetus, is a common cause of fetal growth restriction. Epidemiologic studies in humans have established a correlation between intrauterine growth restriction (IUGR) and an increased risk of type 2 diabetes, obesity, and coronary artery disease in later life (1). This demonstration of the fetal origins hypothesis, the idea that the fetal environment has a crucial influence on development of adult-onset disease, has been reproduced in multiple human populations and in various animal models (1). In a rat model of uteroplacental insufficiency, bilateral uterine artery ligation in late gestation results in IUGR and low birth weight (2). IUGR rats develop a phenotype similar to that of type 2 diabetes in humans, with the development of obesity, insulin resistance, and insulinsecretory deficits. Although normal early in life, there is a progressive decline in ␤-cell mass of IUGR rats, preceding the development of hyperglycemia and diabetes by several weeks of age (2).Extensive islet remodeling occurs during the immediate postnatal period in rodent pancreatic development, with waves of ␤-cell proliferation, apoptosis, and neogenesis in the first weeks of life (3,4). Similar to the impact that a negative fetal environment has on future pancreatic function, therapeutic intervention within this critical neonatal period may permanently improve ␤-cell mass throughout adulthood. The incretin hormone glucagon-like peptide-1 (GLP-1) and the long-acting GLP-1 receptor agonist, Exendin-4 (Ex-4), augment insulin secretion and improve glucose tolerance in diabetes (5). GLP-1 also promotes expansion of ␤-cell mass by increasing proliferation and stimulating neogenesis (5). Importantly, Ex-4 when given in t...