The global expansion of the elderly population ​has been accompanied by a rising incidence of stroke. Despite significant advancements in stroke treatment and prevention strategies, ​stroke-related mortality and disability rates remain persistently high (1). Atherosclerotic plaques, ​a predominant precursor of ischemic stroke, predominantly occur in the internal carotid artery distal to the bifurcation of the common carotid artery in Western populations. ​This anatomical predilection may be associated with reduced shear stress at this arterial segment. ​Compromised endothelial function, characterized by increased intimal thickness and diminished nitric oxide release under low shear stress conditions, ​contributes to the susceptibility to cholesterol plaque formation. ​Since 2015, stroke ​has emerged as the leading cause of mortality and disability in China, posing substantial threats to public health and socioeconomic stability (2).

Atherosclerosis serves as the principal pathological foundation for cardiovascular and cerebrovascular diseases (3, 4). Carotid intima-media thickness (CIMT), ​a non-invasive ultrasonographic marker, provides reliable assessment of subclinical atherosclerosis and endothelial dysfunction (5, 6). Growing evidence supports CIMT ​as a predictive biomarker for cardiovascular events and stroke (7–9). While traditional risk factors for atherosclerosis ​are well-characterized, ​the pathophysiological contributions of certain metabolic parameters ​require further elucidation.

Urine is the main route for excreting serum uric acid (UA), which is the final byproduct of purine metabolism synthesized in the liver (10).The elevation of UA concentration in human plasma is influenced by factors such as diet, alcohol consumption, fructose intake, obesity, and ethnicity (11).Many studies have demonstrated that an excess of uric acid can lead to conditions such as gout, kidney stones, and inflammatory reactions (12–15).There is an increasing body of evidence supporting the promotive role of UA in atherosclerosis. However, it is noteworthy that some studies have indicated its antioxidative effects in oxidative stress (16), suggesting a protective role for blood vessels in the human body (17, 18). Contradictory data (19–21) characterizes the involvement of UA in the development of atherosclerosis. Furthermore, there is no consensus on the optimal UA level control in healthy populations to manage atherosclerosis. Hence, it is crucial to further explore the connection between UA and CIMT in people undergoing health examinations, providing a basis for future medication interventions that aim to regulate UA levels in order to prevent the onset and progression of atherosclerosis.

Elevated levels of UA in the human body have been associated with multiple pathological processes. ​Epidemiological studies consistently identify hyperuricemia as an independent risk factor for cardiovascular events. For instance, Bos et al. demonstrated that hyperuricemia independently predicts myocardial infarction and stroke (22). ​Epidemiological studies consistently identify hyperuricemia as an independent risk factor for cardiovascular events. For instance, Bos et al. demonstrated that hyperuricemia independently predicts myocardial infarction and stroke (23).Research conducted on endothelial cells from the human umbilical vein discovered that elevated levels of UA trigger oxidative stress and inflammation by impacting the signaling pathway of HMGB1/RAGE, the pathway of NF-κB, the activation of the renin-angiotensin system, the reduction of NO, and the expression of inflammatory cytokines (24–26). These mechanisms collectively promote endothelial dysfunction and vascular remodeling, accelerating atherosclerosis.

In our study involving a healthy check-up population, we identified an independent correlation between UA and increased CIMT (β = 0.037; 95% CI = 0.021-0.052, p < 0.00001).The correlation remained significant even after accounting for other variables (β = 0.033; 95% CI = 0.015-0.050, p = 0.00032).The association between increased UA from Q1 to Q4 and CIMT was significant in both minimally adjusted and fully adjusted models ( Table 3 ). Significantly, we noticed an inverse correlation between UA and CIMT, exhibiting a critical threshold at 3.15 mg/dL. Below this threshold, UA levels were not statistically associated with CIMT, while above this threshold, a significant positive correlation was observed, suggesting a hormesis phenomenon.

Subsequent analysis using smoothing functions and segmented linear regression models confirmed the threshold effect at 3.15 mg/dL. According to our research, there is a nonlinear correlation between UA and CIMT in the population undergoing regular health check-ups, with a critical value at 3.15 mg/dL. There is no significant correlation between CIMT and UA when UA is less than 3.15 mg/dL, but a significant positive correlation with CIMT is observed when UA is 3.15 mg/dL or higher. Reducing uric acid through treatment can help alleviate factors that cause arterial inflammation and the formation of neointimal lesions in a mouse model induced with carotid atherosclerosis (27).To reduce the risk of increased CIMT, it is suggested that individuals without symptoms should maintain UA levels below 3.15 mg/dL, taking into account the potential advantages of prolonged non-bisphosphonate therapy in preventing arterial stiffness caused by hyperuricemia (28).

The innovation of this study is primarily reflected in the following aspects:​Revealing the nonlinear relationship between UA and CIMT: While previous studies have investigated the association between hyperuricemia and atherosclerosis, few have systematically analyzed the nonlinear relationship between uric acid (UA) and carotid intima-media thickness (CIMT). By employing generalized additive models (GAMs) and piecewise linear regression models, we successfully demonstrated this nonlinear relationship, overcoming the limitations of traditional linear models. Furthermore, a threshold effect of UA levels was identified, providing a more precise reference for clinical intervention.​Highlighting the potential of UA as an early biomarker for arteriosclerosis: Through our analysis, we observed a significant association between elevated UA levels and increased CIMT, particularly when UA concentrations exceeded 3.15 mg/dL. These findings provide a theoretical foundation for the potential application of UA as a biomarker in early arteriosclerosis screening. This discovery may offer new directions for the prevention and intervention of early-stage cardiovascular and cerebrovascular diseases.

Despite these findings, our study has certain limitations. Initially, as a cross-sectional study, it solely illustrates a non-linear correlation between UA and CIMT and cannot establish causation, necessitating prospective studies for verification. Secondly, averaging the measurements of CIMT at six locations on both sides of the neck may not fully reflect the thickness at other locations if there is severe thickening beyond these measured locations. Thirdly, due to collinearity, the use of statin drugs, total cholesterol, and estimated glomerular filtration rate were not adequately adjusted and may influence the results. Additionally, our study population had a high proportion of individuals over 60 years old (67.73%), possibly influenced by factors such as social, economic, and family values, making them more willing to undergo health check-ups. In conclusion, since this study was conducted retrospectively on a population undergoing routine health check-ups, the findings may not be applicable to individuals suffering from different medical conditions.