Uric Acid and Coronary Collateral Circulation

Coronary collateral (CC) artery development is usually attributed to ischemia, but these anastomotic channels are also present in individuals who do not have coronary artery disease (CAD). The CCs are present in one-fourth of the patients with normal coronary arteries or nonobstructive CAD. Currently, there is no noninvasive method for evaluating CC circulation in humans. The most widely used strategy is visual assessment of collateral arteries as described by Rentrop et al. This method involves balloon occlusion of the contralateral coronary artery, which is rarely performed. In clinical practice, this method is applied without occluding the contralateral vessels. As a result, underestimation of collateralization is inevitable. Other limitations of this visual method include observer variability, influence by the blood pressure, and the force of contrast injection as well as the duration of filming. The most accurate assessment could be obtained by measuring the pressure-derived collateral flow index. Several clinical and angiographic variables including the degree of coronary stenosis, proximal lesion location, longer duration of symptoms, and occlusion as well as resting bradycardia have been reported as variables that correlated with the degree of collateralization. Also, in patients without CAD, the baseline heart rate has been described as the main predictor of collateralization. The most important trigger for collateral growth is tangential (radial) fluid shear stress at the endothelial level with the recruitment of bone marrow-derived mononuclear cells. It is a remodeling process of preexisting small collateral arterioles rather than the growth of new capillary vessels, which is induced by ischemia. Collateral growth is induced by fluid shear stress in preformed collateral vessels caused by a pressure gradient between the area proximal to a coronary stenosis and the low-pressure poststenotic area. The CCs play a role in preserving myocardial function, limiting infarct size, and increasing survival. However, a meta-analysis showed that a well-developed collateral circulation was a risk factor for restenosis after coronary revascularization. In humans, uric acid (UA) is generated from purine catabolism with the conversion of hypoxanthine to xanthine and of xanthine to UA by the enzyme xanthine oxidoreductase. It is further oxidized to allantoin in most species except humans and some higher primates who lack uricase. Therefore, serum UA (SUA) levels in humans are appreciably higher than in other mammals. Because of this difference in urate metabolism, the results of animal studies can be difficult to interpret. Also, different methods of measuring collateral flow may be applied in animal studies. Many patients with CAD use at least 1 drug that can influence SUA levels (eg, aspirin, statins, fibrates, and some antihypertensive agents). The SUA levels are higher in men than in women at all ages due to gender steroids. Sumino et al showed that hormone replacement therapy in postmenopausal women was associated with a significant reduction in SUA level. Also, dietary, environmental, and genetic factors are important determinants of SUA levels. It is important to note that UA is a potent antioxidant, but it can also be a prooxidant if the level is >6 mg/dL in women and 6.5 to 7.0 mg/dL in men. Therefore, elevated SUA level might be an indicator of increased burden of oxidant attack. Besides its dual oxidant effect, if UA is a harmful product, why do our kidneys recover 90% of filtered UA instead of eliminating it? Despite the antioxidant properties of UA, several studies have indicated that high SUA levels are associated with several disorders, including CAD, peripheral arterial disease, heart failure, metabolic syndrome, hypertension, and stroke. These associations have been mainly attributed to upregulation of renin release and the subsequent cascade-related reduction in endothelial function. However, instead of proven causal associations, possible explanations with small study groups could be reverse causality. For example, preclinical atherosclerosis could lead to higher levels of SUA. In contrast, experts from the Framingham Heart Study group have reported no association between the SUA and the cardiovascular disease. In a recently published study, Palmer et al investigated the association of plasma UA with CAD and hypertension using Mendelian randomization. They found no evidence of a causal effect of UA or hyperuricemia on the risk of CAD and hypertension. Recently, some studies have demonstrated an association between SUA and CC development in patients with CAD and