Hillary F. Huber

Cardiac remodelling in a baboon model of intrauterine growth restriction mimics accelerated ageing

Rodent models of intrauterine growth restriction (IUGR) successfully identify mechanisms that can lead to short‐term and long‐term detrimental cardiomyopathies but differences between rodent and human cardiac physiology and placental‐fetal development indicate a need for models in precocial species for translation to human development. We developed a baboon model for IUGR studies using a moderate 30% global calorie restriction of pregnant mothers and used cardiac magnetic resonance imaging to evaluate offspring heart function in early adulthood. Impaired diastolic and systolic cardiac function was observed in IUGR offspring with differences between male and female subjects, compared to their respective controls. Aspects of cardiac impairment found in the IUGR offspring were similar to those found in normal controls in a geriatric cohort. Understanding early cardiac biomarkers of IUGR using non‐invasive imaging in this susceptible population, especially taking into account sexual dimorphisms, will aid recognition of the clinical presentation, development of biomarkers suitable for use in humans and management of treatment strategies.

Maternal nutrient restriction during pregnancy and lactation leads to impaired right ventricular function in young adult baboons

Maternal nutrient restriction induces intrauterine growth restriction (IUGR) and leads to heightened cardiovascular risks later in life. We report right ventricular (RV) filling and ejection abnormalities in IUGR young adult baboons using cardiac magnetic resonance imaging. Both functional and morphological indicators of poor RV function were seen, many of which were similar to effects of ageing, but also with a few key differences. We observed more pronounced RV changes compared to our previous report of the left ventricle, suggesting there is likely to be a component of isolated RV abnormality in addition to expected haemodynamic sequelae from left ventricular dysfunction. In particular, our findings raise the suspicion of pulmonary hypertension after IUGR. This study establishes that IUGR also leads to impairment of the right ventricle in addition to the left ventricle classically studied.

Effect of moderate, 30 percent global maternal nutrient reduction on fetal and postnatal baboon phenotype

Most developmental programming studies on maternal nutrient reduction (MNR) are in altricial rodents whose maternal nutritional burden and offspring developmental trajectory differ from precocial non‐human primates and humans.

An assessment of gum‐based environmental enrichment for captive gummivorous primates

In the wild, many primates consume gums exuded from trees, and many species are gum specialists. In spite of this, few data exist concerning gum feeding in captivity. Using a web-based survey of 46 zoos in 12 countries, we evaluated the extent to which zoos feed gum to primates. We found that although callitrichids and galagos receive gum-based enrichment, cercopithecines generally do not. Environmental enrichment is important for stimulating naturalistic behavior to promote the psychological wellbeing of animals. Thus, gum-based enrichment is important for captive gummivores. Our study highlights the need to improve environmental enrichment for captive gummivores, in particular that of cercopithecines. This is most striking for the patas monkey (Erythrocebus patas), an obligate gummivore. The exchange of ecological data between field research and captive settings is crucial, and is just one way primate caretakers can contribute to the conservation and welfare of some of our closest living relatives.

Increased aggressive and affiliative display behavior in intrauterine growth restricted baboons

We hypothesized intrauterine growth restricted offspring (IUGR) demonstrate higher rates of aggression and higher dominance ranks than control (CTR) offspring with normal weight at term; if aggressive behavior is advantageous during resource scarcity, developmental programming may lead to an association between aggression and IUGR.

Prenatal steroid administration leads to adult pericardial and hepatic steatosis in male baboons

Developmental programming studies indicate that glucocorticoids modify fetal development. We hypothesized that administration of the synthetic glucocorticoid (sGC) betamethasone to pregnant baboons at doses and stages of fetal life equivalent to human obstetric practice to decrease premature offspring morbidity and mortality, programs lipid metabolism. In 10-year-old male baboons (human equivalent 40) exposed in fetal life to betamethasone or saline, we quantified pericardial fat and hepatic lipid content with magnetic resonance imaging and spectroscopy. sGC offspring delivered at term as do most sGC-exposed human neonates. Pericardial fat thickness (7.7±3.6 mm vs 3.1±1.1 mm, M±s.d.; P=0.022; n=5) and hepatic fatty acids (13.3±11.0% vs 2.5±2.2%; P=0.046; n=5) increased following sGC without birth weight or current body morphometric differences. Our results indicate that antenatal sGC therapy caused abnormal fat deposition and adult body composition in mid-life primate offspring. The concern raised is that this degree of pericardial and hepatic lipid accumulation can lead to harmful local lipotoxicity. In summary, developmental programing by sGC produces a mid-life metabolically obese but normal weight phenotype. Prior studies show sexually dimorphic responses to some programming challenges thus female studies are necessary.

Sex-dimorphic acceleration of pericardial, subcutaneous, and plasma lipid increase in offspring of poorly nourished baboons

Developmental programming by reduced maternal nutrition alters function in multiple offspring physiological systems, including lipid metabolism. We have shown that intrauterine growth restriction (IUGR) leads to offspring cardiovascular dysfunction with an accelerated aging phenotype in our nonhuman primate, baboon model. We hypothesized age-advanced pericardial fat and blood lipid changes. In pregnancy and lactation, pregnant baboons ate ad lib (control) or 70% ad lib diet (IUGR). We studied baboon offspring pericardial lipid deposition with magnetic resonance imaging at 5–6 years (human equivalent 20–24 years), skinfold thickness, and serum lipid profile at 8–9 years (human equivalent 32–36 years), comparing values with a normative life-course baboon cohort, 4–23 years. Increased pericardial fat deposition occurred in IUGR males but not females. Female but not male total cholesterol, low-density lipoprotein, and subcutaneous fat were increased with a trend of triglycerides increase. When comparing IUGR changes to values in normal older baboons, the increase in male apical pericardial fat was equivalent to advancing age by 6 years and the increase in female low-density lipoprotein to an increase of 3 years. We conclude that reduced maternal diet accelerates offspring lipid changes in a sex-dimorphic manner. The interaction between programming and accelerated lipogenesis warrants further investigation.

Intrauterine growth restriction results in persistent vascular mismatch in adulthood.

Intrauterine growth restriction (IUGR) increases offspring risk of chronic diseases later in life, including cardiovascular dysfunction. Our prior studies suggest biventricular cardiac dysfunction and vascular impairment in baboons who were IUGR at birth because of moderate maternal nutrient reduction. The current study reveals changes in artery sizes, distensibility, and blood flow pattern in young adult IUGR baboons, which may contribute to cardiac stress. The pattern of abnormality observed suggests that vascular redistribution seen with IUGR in fetal life may continue into adulthood.

Ageing changes in biventricular cardiac function in male and female baboons (Papio spp.)

Life course changes in cardiovascular function in a non‐human primate have been comprehensively characterized. Age‐related declines in normalized left ventricular stroke volume and cardiac output were found with corresponding decreases in biventricular ejection fractions and filling rates. There were age‐related decreases in male and female baboon normalized left ventricular myocardial mass index, which declined at similar rates. Systolic functional declines in right ventricular function were observed with age, similar to the left ventricle. Sex differences were found in the rates and directions of right ventricular volume changes along with decreased end‐systolic right ventricular sphericity. The results validate the baboon as an appropriate model for translational studies of cardiovascular functional decline with ageing.

Maternal activity, anxiety, and protectiveness during moderate nutrient restriction in captive baboons (Papio sp.)

We hypothesized that maternal nutrient restriction (NR) would increase activity and behavioral indicators of anxiety (self‐directed behaviors, SDBs) in captive baboons (Papio sp.) and result in more protective maternal styles.