Infective endocarditis (IE) is a rare but serious infectious disease that is defined by infection of the endocardial surface, native or prosthetic heart valves, or indwelling cardiac devices (1, 2). Although diagnostic technology and therapeutic strategies have improved significantly in recent decades, the prognosis of IE remains poor (3–5). Epidemiological data have indicated that the short-term mortality of IE is ~10% (6–8). Early identification of high-risk patients is essential for optimal therapeutic regimens.

Uric acid (UA) is the end product of purine nucleotides’ degradation and is mainly eliminated by the kidney and the intestinal tract (9). It functions as a potent antioxidant extracellularly to scavenge free radicals; however, as an intracellular prooxidant, it can disturb the bioavailability of nitric oxide in the endothelium, activate the renin-angiotensin system, stimulate the proliferation of vascular smooth muscle cells, and promote inflammation (10). Therefore, accumulating evidence suggests a J- or U-shaped relationship between UA level and prognosis (11–13).

A similar phenomenon also occurs in an infectious state. Hypouricemia has been reported to be associated with disease severity and poor prognosis in patients with coronavirus disease 2019 (COVID-19) (14). By contrast, hyperuricemia can result in high mortality rate in patients with acute respiratory distress syndrome (15). IE is also an infectious disease that is frequently complicated with cardiac dysfunction (3). Increased UA is common in the setting of heart failure because of the increased production resulting from oxidative stress and decreased excretion due to renal insufficiency (16). However, few studies have explored the prognostic value of UA in patients with IE. Here, we investigated the nature of the link between UA and an adverse prognosis in patients with IE.

To our knowledge, this is the first study to explore the prognostic role of serum UA levels in patients with IE. We discovered a U-shaped relationship between the UA level and in-hospital mortality. The current definition of hyperuricemia was not an independent risk factor for in-hospital death in patients with IE. Both UA>400 μmol/L and <250 μmol/L were independently associated with in-hospital and 6-month mortality, which could be considered an optimal threshold for predicting poor prognosis in IE patients.

In our analysis, 30.1% IE patients had hyperuricemia, which could be attributed to a high incidence of renal and cardiac insufficiency in IE. In healthy individuals, two-thirds of daily UA is excreted by the kidneys and the remaining one-third is eliminated through the intestinal tract. In renal dysfunction, the renal excretion of UA reduced and the intestinal excretion is compromised by impairment of UA transporters, resulting in a high serum UA levels (21). With respect to heart failure, increased production of UA because of increased xanthine-oxidase activity as well as decreased renal excretion of UA because of renal hypoperfusion together contribute to an increase in the UA level (16). In addition to clinical manifestations in these two conditions, hyperuricemia could serve as an important indicator for unfavorable outcomes. Hyperuricemia plays a part in the progression of chronic kidney diseases (13, 22), as well as potentiating the risk of acute kidney injury during hospitalization (23, 24). In patients with acute/chronic heart failure, an increased UA level is believed to correlate independently with increased short-term and long-term mortality as well as re-hospitalization (25–27). However, the clinical importance of hyperuricemia in IE is still unclear.

We showed that hyperuricemia was a risk factor for in-hospital mortality, but its significance was lost after multivariate regression analysis. A U-shaped relationship between the UA level and in-hospital mortality for IE patients was discovered, which was consistent with previous studies (11–13). It was believed that the previous definition of hyperuricemia (UA>420 μmol/L in men and >360 μmol/L in women) was not sufficiently valid for predicting clinical outcomes in certain pathological conditions. The J- or U-shaped relationship was gradually accepted. A recent study conducted by Chen et al. included 1,854 patients with COVID-19 infection and showed a U-shaped association between UA and composite outcomes (28). Their cut-off values were ≥423 µmol/L and ≤278 µmol/L, which was close to our findings.

This U-shaped relationship might be explained by the dual antioxidant and prooxidant effect of UA in inflammatory conditions. In humans, >50% antioxidant capacity in blood plasma comes from UA (29). In addition, UA has been shown to be effective in preventing viral infection by enhancing T-cell responses and secretion of type-I interferons (30, 31). However, UA levels have been observed to decrease continuously in people with infectious diseases (32, 33). Consistently, the UA level was lower in patients with a positive blood culture in our study. Hypouricemia has a prognostic value to some extent. An extremely low level of UA diminishes the antioxidant capacity of plasma in severe sepsis and indicates a poor outcome (34).

Despite its protective effect, an extremely high UA level may signify more harm than benefit during severe inflammation. Our results suggested that an increased UA level was associated with a poor outcome in IE. The latter is a microbial infection on the endocardial surface, wherein the spread of pathogenic organisms into the bloodstream can trigger a systemic inflammatory response syndrome. The incidence of sepsis in 294 IE patients was nearly 30% in a study conducted by Krajinovic et al. (35). Chuang et al. showed that the UA level was positively correlated with the Acute Physiology and Chronic Health Evaluation (APACHE) score in patients with sepsis, which supported its role in reflecting illness severity (36). Septic patients with hyperuricemia tend to require greater vasopressor support (37). Lee et al. found that in patients with acute respiratory distress syndrome, the mortality was higher in cases with normal-to-high UA level than in patients with a low UA level (15). The possible underlying mechanism might be explained by the excessive prooxidant effect in a hyperuricemia environment that leads to endothelial dysfunction, increased activity of xanthine oxidase, increased oxidative stress, inappropriate activation of the renin–angiotensin–aldosterone system, impaired renal autoregulatory response, and release of proinflammatory chemokines (38).

Our study has some limitations. First, this was a single-center study with a small sample size (1,117 cases with 69 events). We used package “pwr2ppl” (version 0.2.0) in R software to calculate power for logistic model. Our study included 1117 cases with 69 events that had 82% to 99% power for detecting ORs of 1.50 to 1.90 at an alpha level of 0.05, with 6% in-hospital mortality and 0.20 correlation between UA and other covariates. Therefore, we think that the sample size is relatively powerful to detect the association between UA and mortality. Second, this study was retrospective in nature. Although we adjusted for most potential confounding factors in the multivariate analysis, residual factors might have affected the results. Third, the UA level is different in male and female patients, but the newly identified cut-off value of UA was not distinguished based on because of the small study cohort. Last, telephone interviews, hospital-readmission records, and outpatient clinic interviews were employed during the follow-up period, but some patients showed poor compliance.

Low and high levels of UA were independent risk factors for in-hospital and 1-year mortality in patients with IE. The previous definition of hyperuricemia (UA>420 μmol/L in men and >360 μmol/L in women) was not suitable for risk stratification because of the U-shaped trend between the UA level and adverse outcomes. UA>400 or <250 μmol/L might be more valuable predictors of outcome than the previous cut-offs, especially for infectious diseases.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The study protocol was approved (GDREC2020098) by the Ethics Committee of Guangdong Provincial People’s Hospital (Guangdong, China). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

DY and JC contributed to the conception or design of the work. XW, BF, XC, and WC contributed to the acquisition or interpretation of data for the work. ZW and GJ contributed to statistical analysis. XW, BF, and XC drafted the manuscript. DY and JC critically revised the manuscript. Everyone gave final approval and agreed to be accountable for all aspects of the work ensuring integrity and accuracy. All authors contributed to the article and approved the submitted version.

This study was supported by grants from the National Natural Science Foundation of China (grant no. 82002014), Natural Science Foundation of Guangdong Province (grant no. 2021A1515010107), Science and Technology Projects of Guangzhou (grant no. 201903010097), and Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention (grant no. 2017B030314041). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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