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

Abstract

Extensive rodent studies have shown that reduced perinatal nutrition programmes chronic cardiovascular disease. To enable translation to humans, we developed baboon offspring cohorts from mothers fed ad libitum (control) or 70% of the control ad libitum diet in pregnancy and lactation, which were growth restricted at birth. We hypothesized that intrauterine growth restriction (IUGR) offspring hearts would show impaired function and a premature ageing phenotype. We studied IUGR baboons (8 male, 8 female, 5.7 years), control offspring (8 male, 8 female, 5.6 years - human equivalent approximately 25 years), and normal elderly (OLD) baboons (6 male, 6 female, mean 15.9 years). Left ventricular (LV) morphology and systolic and diastolic function were evaluated with cardiac MRI and normalized to body surface area. Two-way ANOVA by group and sex (with P < 0.05) indicated ejection fraction, 3D sphericity indices, cardiac index, normalized systolic volume, normalized LV wall thickness, and average filling rate differed by group. Group and sex differences were found for normalized LV wall thickening and normalized myocardial mass, without interactions. Normalized peak LV filling rate and diastolic sphericity index were not correlated in control but strongly correlated in OLD and IUGR baboons. IUGR programming in baboons produces myocardial remodelling, reduces systolic and diastolic function, and results in the emergence of a premature ageing phenotype in the heart. To our knowledge, this is the first demonstration of the specific characteristics of cardiac programming and early life functional decline with ageing in an IUGR non-human primate model. Further studies across the life span will determine progression of cardiac dysfunction.

Maternal undernutrition in late gestation increases IGF2 signalling molecules and collagen deposition in the right ventricle of the fetal sheep heart

“…A more moderate (30%) maternal nutrient restriction in the non‐human primate causes signs of both left and right ventricle dysfunction in the offspring, including a decreased ejection fraction, wall shortening and increased chamber volume as assessed using magnetic resonance imaging (Kuo et al . , b ). Interestingly, these two partner studies highlighted that right ventricular function was more severely impacted by maternal nutrient restriction than left ventricular function.…”

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

“…We have also reported altered development of the placenta, fetal kidney, fetal brain, fetal liver, fetal skeletal muscle, and fetal heart . In postnatal life, these IUGR offspring show cognitive and behavioral changes, accelerated aging of the heart, and a pre‐diabetic metabolic phenotype when compared to controls. We present here the weights and morphometrics of control and IUGR fetuses over the second half of gestation, at birth, and over the first 3 years of life.…”

Neonatal Growth Restriction Slows Cardiomyocyte Development and Reduces Adult Heart Size

“…As seen with perinatal GR, adults with a history of preterm delivery have cardiac dysmorphology with foreshortened hearts and increased resting heart rates (Crispi et al, 2010; Johansson et al, 2007; Kowalski et al, 2016; Lewandowski et al, 2013; Rodriguez-Lopez et al, 2016). Investigations in baboons have explored the combined impact of intrauterine and neonatal GR through maternal caloric restriction, and analogous alterations in cardiac structure and function were demonstrated (Kuo et al, 2016). Unlike intrauterine GR, the neonatal GR seen in premature infants is not associated with hypoxia and the independent effect of neonatal GR on adult cardiac structure has not been determined.…”