The prevalence of obesity has increased worldwide at an alarming rate over the past four decades. Obesity is a major risk factor for various non-communicable diseases including cardiovascular disease, type 2 diabetes mellitus and certain types of cancer. In parallel with the global obesity epidemic, rates of maternal obesity and gestational diabetes mellitus have risen, both of which are associated with long-term adverse health outcomes for the affected offspring.
There is a robust body of epidemiological evidence, supported by experimental animal models, that fetal growth has a profound influence on adult diseases. For instance, the environment to which a fetus is exposed in the womb contributes to long-term risks of cardiovascular disease in adulthood. Both fetal growth restriction (predominantly due to poor nutrition resulting from placental insufficiency) and excessive fetal growth (predominantly due to over nutrition resulting from GDM or maternal obesity) are associated with higher risk of cardiovascular disease during adulthood. Birth weight is a widely used marker of fetal growth, albeit crude. Measures of newborn body composition, such as fat mass, may identify ‘high risk’ infants more accurately.
Postmenopausal women with obesity, are at a particularly high risk of cardiovascular disease. While on average obesity is associated with a greater severity of atherosclerosis and poorer arterial function, many postmenopausal women with obesity will never be affected by atherosclerosis-related cardiovascular disease. A better understanding of the risk factors for atherosclerosis in postmenopausal women with obesity will contribute to improved prediction of high-risk people and enable more effective disease management.
The studies undertaken as part of this thesis aimed to improve early identification of cardiovascular risk on the basis of advanced measures of body composition, and to trial preventive strategies for reducing the burden of atherosclerosis. Non-invasive measures of vascular health that enabled age-appropriate assessment of atherosclerosis across the life course was applied in order to achieve the following specific objectives.
To examine whether a low Glycaemic Index (GI) diet during pregnancy could improve vascular health of the offspring of women with a high risk of gestational diabetes;
To determine whether body composition in newborn infants, especially body fatness of neonates, is a stronger predictor of arterial wall thickness than birth weight;
To determine the predictors of vascular structure in postmenopausal women with obesity;
To determine theeffects of fast vsslow weight loss intervention strategies on vascular function.
Chapter 3,published in the American Journal of Clinical Nutrition,reports the vascular sub-study of a randomized controlledtrial of a low-GI diet during pregnancy in women at high risk of gestational diabetes mellitus (GDM). The low-GI diet improved offspring arterial wall thickness at 1-year of age, independent of birth weight, body fatness and growth during infancy. This suggests that the vascular effects of a low maternal GI diet are acting via mechanisms that do not involve fetal growth.
Chapter 4, published in Journal of Clinical Medicine,reports aortic intima-media thickness (AoIMT), an age-appropriate marker of vascular health, in newborns with high or low body fat, compared to those with average body fat. Infants with low body fat had higher AoIMT than controls, butinfants with high body fat showed no differences in AoIMT compared to controls. In contrast, AoIMT was significantly higher in those babies born at either end of the birth weight spectrum. The association of birth weight £10th percentile with AoIMT was independent of body fatness, but the association of birth weight >90thpercentile with AoIMT was weakened after controlling for body fatness.Accordingly, this suggests thatnewborns with low body fat have increased AoIMT, which is consistent with a higher risk of future cardiovascular disease, however birth weight appears to be a stronger predictor of aortic IMT.
Chapter 5reports an analysis ofthe best predictors of atherosclerosisin postmenopausal women with obesity. We demonstrated that waist circumference (WC), subcutaneous adipose tissue(SAT) and intrahepatic lipid content were significantly associated with carotid intima-media thickness (CIMT) after controlling for age, lipid lowering medications, diastolic blood pressure and BMI. This suggests that waist circumference may represent a cost-effective measure for identifying those postmenopausal women with obesity who are at the highest risk of atherosclerosis-related cardiovascular disease.
Finally,Chapter 6reports the vascular sub-study of a randomized controlled trial of weight loss in postmenopausal women with obesity. The trial examined the effects on arterial endothelial function measured by flow mediated dilatation (FMD), after 4-6 months on one of two intervention strategies; fast weight loss (very low energy diet-based diet), and slow weight loss (food-based diet). Both interventions produced meaningful weight loss, although greater weight loss was achieved at both 4 and 6 months in the fast weight loss intervention group. Only the fast weight loss group showed improvements in FMD. The strongest correlate of improvements in FMD over 4-6 months was concurrent reduction in VAT, suggesting that changes in this adipose tissue depot may mechanistically link weight loss with improvements in atherosclerotic cardiovascular disease.
The studies presented in this thesis suggest that body composition hasa profound influence on vascular health from birth through adulthood. Intervention strategies aimed at reducing cardiovascular risk should begin in the womb and focus on strategies that produce vascular health benefits. In order to treat obesity and cardiovascular disease, further research should take a holistic approach to integrate various evidences among different populations at risks with a focus on early detection and prevention.
Keywords:atherosclerosis, body composition, fetal growth, obesity, vascular health