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inflammation and fibrosis. SUA concentration also interferes with blood vessel expansion by decreasing the response of blood vessels to acetylcholine and to increase blood pressure by endothelial dysfunction through the interference in the excretion process of nitric oxide from vascular endothelial cells.
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Uric acid has also been found to promote low-density lipoprotein (LDL) oxidation and promote lipid peroxidation, which in turn increases the thickness of intima to produce atherosclerosis,176 and these effects are inhibited by vitamin C177 indicating an important interaction between aqueous anti-oxidants.
UA can also stimulate granulocyte adherence to the endothelium,178 and peroxide and superoxide and superoxide free radical liberation.176 Therefore UA may have deleterious effect on the endothelium through leukocyte activation and, interestingly, a consistent relationship has been noted between elevated SUA concentration and circulating inflammatory markers.179, 180
UA traverses’ dysfunctional endothelial cells and accumulates as crystal within atherosclerotic plaques.181 These crystals may contribute to local inflammation and plaque formation and progression. Thus, while UA appears to make a significant contribution to serum anti-oxidant capacity, it could also lead directly or indirectly to vascular injury. It is also interesting to note that treatment of chronic cardiac failure within allopurinol restored endothelial function.182
The first clinical manifestation of cardiovascular disease often arises in a stage of well-advanced atherosclerosis. However, arterial vessel wall changes occur during a presumably long subclinical lag phase characterized by endothelial dysfunction and gradual thickening of intima. In recent years, research on atherosclerosis has been mainly towards identifying markers of early atherosclerosis. Various non-invasive markers of early arterial wall alteration are currently available, such as arterial wall thickening and stiffening, endothelial dysfunction and coronary artery calcification.183 Of all the non-invasive markers, intima-media thickness of large peripheral arteries, especially the carotids, can be assessed by B-mode ultrasound. This technique yields information on atherosclerotic wall changes that cannot be obtained by
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conventional contrast angiography or MRI. Owing to its non-invasive character and easy applicability, quantitative carotid B-mode ultrasonography has emerged as one of the methods of choice for determining the anatomic extent of atherosclerosis and its progression, and for assessing cardiovascular risk.184 In vitro and in vivo studies indicate that carotid artery IMT measurements obtained by ultrasonography correlate very well with pathophysiologic measurements, 185 and numerous investigators have demonstrated the reproducibility of this technique. CIMT is a good marker of early atherosclerotic changes and its progression.186 CIMT is increased in groups of patients with several cardiovascular risk factors187 and it has proved to be an independent risk factor for myocardial infarction and stroke.188 This explains why CIMT is increasingly been used in clinical research: to test the value of new and emerging risk factors based on observational or epidemiological studies in groups of patients or in the general population, and to evaluate the effects of risk factor modification on the progression of early arterial wall alteration in therapeutic trials.189
A possible association between UA and carotid atherosclerosis has been most intensively analyzed in the Atherosclerosis Risk in Communities (ARIC) Study, which included more than10, 000 subjects. In that study, Iribarren and collaborators showed that the association between UA and carotid atherosclerosis, assessed by the average CIMT, was statistically significant in white men but not women after adjusting for age, BMI, waist-to-hip ratio, systolic blood pressure, fibrinogen, low-density-lipoprotein cholesterol, and HDL-C.190
Elsayed et al reported that CIMT that was higher in patients with hypertension, with or without hyperuricemia, compared with the control group, while it was
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higher in hypertensive hyperuricemic than hypertensive non hyperuricemic patients. They also observed a higher CIMT in hyperuricemic normotensive patients than the control group.191 It therefore means that hyperuricemia per se could be a risk factor for atherosclerosis in both hypertensive as well as normotensive patients.
Chen et al in a study involving 10,281 persons also reported that SUA levels were positively associated with elevated CIMT. An important point of their study that should be highlighted is that, in the subgroup analysis, the positive association between the SUA level and the risk of elevated CIMT was not affected by the use of diuretics.192
CIMT is a well-established measure for assessing the degree of atherosclerosis,
184 which has also been found to be associated with cardiovascular alterations or organ damage. Therefore, B-mode ultrasonography may be useful in detecting high-risk subjects in primary prevention and in the decision to treat aggressively those patients at high risk with medication.
2.4 CAROTID INTIMA-MEDIA THICKNESS (CIMT) AS A MARKER OF