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Title: The role of the bone mineral axis in non-uraemic vascular disease
Author: Ellam, Timothy
ISNI:       0000 0004 5346 2719
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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Higher serum phosphate concentration and dietary phosphate intake are independent predictors of cardiovascular mortality. Variations in the hormones that regulate serum phosphate (higher fibroblast growth factor-23 and parathyroid hormone, lower active vitamin D) also predict adverse cardiovascular events. If these observations reflect causal relationships then manipulating this bone mineral axis might help prevent cardiovascular disease. Firstly, the effects of manipulating dietary phosphate content on metabolic profile and atherosclerosis were studied in an apolipoprotein E-knockout (ApoE-/-) mouse model of atherosclerosis. Low dietary phosphate content induced greater obesity and insulin resistance, reproducing clinical associations between lower serum phosphate and components of the metabolic syndrome. However, higher dietary phosphate content significantly increased aortic sinus atheroma burden. In a second study, vitamin D deficiency was induced in ApoE-/- mice. Despite a sufficiently severe degree of vitamin D deficiency to modify bone structure, there was no significant change in atheroma burden, left ventricular morphology/function or metabolic profile. Diffuse atherosclerotic calcification was, however, increased by vitamin D deficiency and to a similar extent as with a hypercalcaemic dose of active vitamin D analogue. Using a representative sample of the US population, associations between bone mineral axis parameters and higher-normal albuminuria (considered a marker of subclinical vascular disease) were examined. Higher parathyroid hormone (PTH) was the only parameter associated with greater albuminuria, suggesting higher-normal PTH is accompanied by vascular pathology, perhaps reflecting a mis-setting of the ‘normal’ range of PTH. However, manipulating PTH, phosphate, fibroblast growth factor-23 and active vitamin D had no effects on endothelial cell apoptosis, oxidative stress or nitric oxide generation in vitro. In conclusion, interventions to re-set the bone mineral axis, particularly via limiting dietary phosphate exposure, might be of cardiovascular benefit. However, evidence that subtle differences in bone mineral axis parameters contribute to clinical disease remains elusive. Clinical interventional studies are required to clarify this and are in progress.
Supervisor: Chico, Timothy ; Francis, Sheila Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available