There are strong epidemiological associations between high serum uric acid
concentrations and increased cardiovascular risk. However, it is unclear if uric acid is
an independent causal risk factor, serves a protective role due to its antioxidant
properties, or simply acts as a passive marker of risk through association with other
factors. The distinction is important because, if acting as a causal risk factor,
treatment to lower uric acid concentrations might reduce cardiovascular risk.
To study the cardiovascular effects of raising and lowering circulating uric acid
concentrations, so as to identify potential mechanisms by which uric acid could
impair cardiovascular function or, as an antioxidant, serve a protective role.
I developed a technique of uric acid administration that allowed the effects of raised concentrations to be examined in vivo. The potential impact on serum antioxidant
capacity, plasma viscosity, platelet aggregability, systemic haemodynamics,
baroreflex sensitivity, large arterial stiffness, and endothelial function were studied in
healthy subjects. The effects of high uric acid concentrations were studied in a model
of acute exercise-induced oxidative stress, and in regular smokers and patients with
type 1 diabetes who are ordinarily exposed to chronic oxidative stress. The effects of
lowering uric acid, by means of urate oxidase, were studied in patients with type 2
diabetes to explore whether this might improve vascular function in these patients.
Raising and lowering uric acid concentrations had no effect on vascular function in
healthy subjects. Uric acid administration significantly increased serum antioxidant
capacity, reduced oxidative stress during acute aerobic exercise, and improved
endothelium-dependent vascular responses in regular smokers and patients with type
1 diabetes. Lowering uric acid concentrations did not influence vascular function in
healthy subjects or patients with type 2 diabetes.
High uric acid concentrations did not impair vascular function, at least in the acute
situation, and appear to preserve vascular function by protecting against oxidative
stress in smokers and patients with type 1 diabetes. These findings do not support a
causal link between high serum uric acid concentrations and increased cardiovascular
risk. Further research is required to define the mechanisms by which high uric acid
concentrations ameliorate endothelial dysfunction, and to examine whether these
properties have therapeutic potential in diseases characterised by oxidative stress.