An investigation into whether an exercise intervention during pregnancy can prevent the programming of cardiovascular disease in the offspring of obese mothers

A strong body of evidence suggests that environmental insults from the point of fertilisation to birth and neonatal life can shape the health of the individual for many years to come. Adverse exposures, such as maternal overnutrition, in the early life environment increase the risk of traditionally adult-onset diseases such as cardiovascular disease and type 2 diabetes adding greatly to the next generation’s burden of disease. Studies in animal models provide strong evidence that these effects are mediated by non-genetic programmed mechanisms. This is of particular concern, as recent studies in the UK suggest that over half of women are now overweight or obese during pregnancy. Current preventative strategies for adult cardiovascular disease have, thus far, focused on reducing an individual’s modifiable risk factors. However, given growing evidence that risk of cardiovascular disease is determined in utero, there is strong rationale that disease risk from mother to child could be reduced prior to birth, through targeted interventions in the mother before and during pregnancy. Using an established murine model of maternal diet-induced obesity during pregnancy, the first aim of this thesis was to characterise potential programming factors in the obese mother and identify those that were targeted by a treadmill exercise intervention. Through feeding of an obesogenic diet, dams became heavier, with increased fat mass, and showed insulin resistance at weaning. Previous work has shown the intervention improved maternal insulin sensitivity during pregnancy (E19) and data from this thesis revealed that this was not accompanied by any changes to body composition. Previous data using this model showed that male offspring born to obese dams have pathological cardiac hypertrophy and ex vivo cardiac dysfunction. A second aim of this thesis was to establish if exercise intervention in obese dams was protective to the cardiovascular health of the offspring. These studies revealed that maternal exercise intervention during obese pregnancy had a positive impact by preventing pathological left ventricular cardiac hypertrophy and in vivo dysfunction, but did not prevent programmed hypertension in the male offspring. This demonstrates that offspring cardiac hypertrophy and dysfunction can be programmed independently of hypertension by maternal diet-induced obesity. The third aim of this thesis was to establish how female offspring were impacted by maternal obesity. The results demonstrated that female offspring born to obese dams were hypertensive and displayed right ventricular cardiac hypertrophy. However, there was no observable effect of maternal obesity on cardiac function in female offspring at this age. This highlights the potential sexually dimorphic effects of developmental programming by maternal obesity. A final aim of this thesis was to assess the immediate consequences of maternal obesity on the fetal heart and whether maternal exercise had any impact. This showed that in late gestation (E19), cardiac remodelling were already present in the male fetuses of obese dams, and the exercise intervention did not fully prevent this adverse finding. In conclusion, this thesis highlights that the cardiovascular health legacy of an individual is determined by maternal nutrition before birth and by the intrauterine environment. Just a small improvement in offspring risk could have important implications for the future prevalence of cardiovascular disease worldwide. Importantly this thesis highlights a potential need for combination intervention strategies to tackle the epidemic of obesity in pregnancy, as maternal exercise alone was not sufficient to reduce all aspects of the future burden of cardiovascular disease.British Heart Foundatio