Clinical relevance of serum uric acid and abdominal aortic‐calcification in a national survey

Abstract Background Hyperuricemia was often found in subjects with an elevated risk of cardiovascular disease (CVD). Abdominal aortic‐calcification (AAC) is significantly associated with subclinical atherosclerotic disease. Hypothesis The aim of this study is to evaluate the relationship between serum uric acid (SUA) level and AAC from a national database. Methods A total of 2765 eligible participants older than 40 years who received dual‐energy X‐ray absorptiometry (DXA) scans with SUA data were enrolled from the National Health and Nutrition Examination Survey (2013‐2014). The association between SUA level and AAC was analyzed using multivariate regression models for covariate adjustment. Results After categorizing SUA level into four quartiles, the odds ratios for the presence of subclinical atherosclerosis via contrasting the highest SUA quartile with the lowest SUA quartile were 1.876 (95% CI = 1.298‐2.711), 2.038 (95% CI = 1.303‐3.187), 1.935 (95% CI = 1.221‐3.065), and 1.956 (95% CI = 1.225‐3.124) (all, P value less than .05) in Model 1, Model 2, Model 3, and Model 4, respectively. The above relationship remained still in the fully adjusted model for the male but not female subjects. The optimal SUA cutoff value was 6.35 mg/dL for male and 5.25 mg/dL for female to predict the presence of subclinical atherosclerosis. Conclusions Our results explore the promising evidences that SUA level showed a positive correlation with AAC score in a dose‐response manner. These findings decisively indicated that SUA may act as a promising tool to forecast the incidence of subclinical atherosclerosis in males.

nowadays. 1 Atherosclerosis, among the wide array of problems that may arise within the cardiovascular system, has always been the underlying cause of about 50% of all deaths in westernized society. 2 For the purpose of evaluating the individualized cardiovascular risk, it's essential to recognize atherosclerosis in subclinical stages.
As the end product of purine catabolic metabolism, uric acid, which level in serum is influenced by multiple factors, including exogenous ingestion (particularly with an animal protein-rich diet), endogenous production by the liver, and renal excretion. 3 Serum uric acid (SUA) is an independent risk factor for CVD events including stroke, congestive heart failure, coronary heart disease, and even cardiovascular mortality in an elevated risk or general population. 4 Previous study by TavIl Y et al demonstrated that raised SUA level has been shown to be associated with atherogenesis, independent from hypertension. 5 Abdominal aortic-calcification (AAC), measured via AAC score described by Kauppila LI et al in 1997 6 or another semiquantitative method is significantly associated with subclinical atherosclerotic disease and an independent predictor of subsequent vascular morbidity and mortality. 7 To our knowledge, no nationally representative US studies on the relationship between SUA and AAC are available. Hence, we investi-  Diseases Control and Prevention using a stratified, multistage, clustered probability sample design. The survey contained a large-scale household interview (information on medical history, ethnicity/race, age, and gender) and a sequential physical examination at a particularly equipped Mobile Examination Center (MEC). In this cross-sectional study we included participants over the age of 40 who received dual-energy Xray absorptiometry (DXA) scans (n = 3140). We excluded subjects with lost information of SUA level, or other demographic or associated covariates. The final analytical sample of 2765 participants was composed of 1355 men and 1410 women who were categorized into tertile group based on the SUA level ( Figure 1). Ethics approval was approved by the National Center for Health Statistics Ethics Review Board. All participants had signed an informed consent before study participation.

| AAC score
As an acknowledged prognosticator of cardiovascular mortality, 7  Briefly, the abdominal aorta was divided into four parts immediately anterior to each of the lumbar vertebrae L1-L4. For each part, aorticcalcification severity in the anterior and posterior longitudinal walls was graded separately on a 0-3 scale. The calcium lesions are graded as follows: "0" represents no calcification; "1" represents calcification length less than 1/3 of vertebra; "2" represents the calcification length extended from 1/3 to 2/3 of vertebra; "3" represents calcification length more than 2/3 of vertebra. With this numerical grading, the score could vary from a minimum of 0 to a maximum of 24 points to form AAC-24 score. 9 On the other hand, ranging from "0" to "4" and the total score range is 0 to 8, AAC-8 score evaluates the entire length of calcification of the anterior and posterior aortic walls in front of L1 to L4. One grade is given for the presence of calcification in the abdominal aorta alongside one vertebra on either the anterior or posterior side. If the calcification has an aggregate length of more than one vertebra, the grade increases one point and so forth. 8 Subjects were ineligible for DXA examination in this research if they were younger than 40 years old, pregnant, weighed more than 450 pounds (DXA table limitation) or used radiographic contrast material in past 7 days. AAC Total 24 Score above the 75th percentile (2 points) was defined as subclinical atherosclerosis in the present study. While AAC total 24 score > 6 has been thought of as noteworthy calcification and used as a cutoff point in prior research. 7

| Biochemical measurements
Peripheral blood was commenced from all subjects in the morning after an overnight fast about 12 to 14 hours to obtain biochemical analysis. probably to be older, have more history of congestive heart failure, higher BMI, and higher CREA level (all, P < .05).

| Discussion
In the US adult population, the aim of the present study was to investigate the association between SUA level and AAC. We provided the evidences that SUA level revealed a positive correlation with AAC score in a dose-response manner. To the best of our knowledge, ours is the first study that evaluated the relationship between SUA and AAC.
Emerging evidences addressed that AAC was a recognized predictor of cardiovascular mortality. 6 In the same paper, Kiss et al illustrated that SUA level was associated with calcium scores and the third SUA tercile was an independent predictor for the presence of high-risk coronary calcification. In contrast to the above study, we investigated not only the subsistence of overall AAC through four different AAC scores (AAC total 24 score, AAC anterior 8 score, AAC posterior 8 score and AAC total 8 score), but we also utilized the cutoff value of 2 for AAC total 24 score which defines subclinical atherosclerosis and found a strong and independent association in the male participants. The Framingham study also reported that gout had a significant effect on the preceding coronary events in male but not in female. 15 This gender difference may be due to the action of the hormone estrogen. 16 Estrogens have an impact on the renal tubular handling of uric acid and premenopausal levels of estrogen in women cause a greater T A B L E 4 Association between SUA cutoff value and subclinical atherosclerosis categorized by gender renal clearance of uric acid. 17 Little has been known why estrogen increases renal uric acid excretion. However, recently it has been revealed that estradiol suppressed the protein levels of urate reabsorptive transporters urate transporter 1 and glucose transporter 9 (Urat1 and Glut9), and that of urate efflux transporter ATPbinding cassette subfamily G member 2 (Abcg2). 18 Prior research has proven elevated SUA level to be an independent risk factor of atherosclerosis. 19 There are several possible pathophysiological mechanisms linking SUA to atherosclerosis. First, SUA may result in the activation of local platelet aggregation and lysis, 20,21 which are related to an elevated risk of vulnerable plaque formation. Second, during the production of uric acid catalyzed by xanthine-oxidase (XO), reactive oxygen species (ROS) are generated as by product, which have a significant role in the increased vascular oxidative stress. 22 Third, SUA could also bring about stimulation of inflammatory pathways in vascular smooth muscle cell (VSMC) proliferation contributing to dysfunction of endothelium. 23 The above-mentioned alterations could take an important part in illustrating the possible pathophysiological mechanism between SUA and atherosclerosis in the abdominal aorta.
Several limitations still existed in this study. First, as the initial research in humans to investigate the association between SUA and AAC. Second, AAC data derived from NHANES were acquired through only participants 40 years of age and older; therefore, patients with lowest SUA level are excluded from this research. Third, we did not have data on frequency/precise amount of physical exertion, dietary intake, or medication, all of which can alter SUA level.

| Conclusions
Our results highlighted the promising evidences that SUA level demonstrated a positive correlation with AAC score in a dose-response manner. These findings decisively indicated that SUA may act as a promising tool to forecast the incidence of subclinical atherosclerosis in males.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest

AUTHOR CONTRIBUTIONS
Yen-Wei Li contributed to the design of the study, was responsible for the management and retrieval of data, contributed to initial dataanalysis and interpretation, and drafted the initial manuscript. Yen-Wei Li and Wei-Liang Chen decided upon the data collection methods. Yen-Wei Li and Wei-Liang Chen were also responsible for the data-analysis decisions. Wei-Liang Chen conceptualized and designed the study, supervised all aspects of the study, critically reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors meet the ICMJE criteria for authorship.

ETHICS STATEMENT
IRB information: NCHS IRB granted an exemption from requiring ethics approval.