Preoperative Uric Acid-to-albumin Ratio as a New Indicator for Predicting Long-term Prognosis in Patients With Acute Type a Aortic Dissection

Xue Wang First A liated Hospital of Xi'an Jiaotong University Chao Deng First A liated Hospital of Xi'an Jiaotong University Fengwei Guo First A liated Hospital of Xi'an Jiaotong University Liang Zhong First A liated Hospital of Xi'an Jiaotong University Ming Li First A liated Hospital of Xi'an Jiaotong University Yanbo Xue First A liated Hospital of Xi'an Jiaotong University Qiong Ma First A liated Hospital of Xi'an Jiaotong University Xiaopu Zheng First A liated Hospital of Xi'an Jiaotong University Heng Gao (  gaoheng19820109@163.com ) Shaanxi Provincial People's Hospital

Type A acute aortic dissection (AAD) is the most common and catastrophic presentation of acute aortic syndrome. Most type A AAD patients have severe and unbearable chest pain and rapidly developing complications including aortic dissection rupture, pericardial effusion and tamponade, and acute myocardial infarction. Despite aggressive surgical techniques, the prognosis of some patients remains poor, and the mortality can be as high as 30%. Moreover, it is di cult to identify patients at high risk of death, which is important for rapid decision making [1][2][3].
Serum albumin (SA) is the most important protein in human serum and has many important physiological functions. The catabolism of SA increases after the activation of in ammatory response. A low SA level can lead to enhanced platelet activation and aggregation along with increased blood viscosity, leading to the damage of endothelial cells [4]. Ronit studied 2240 individuals without cardiovascular diseases in Japan and found that low SA was linked to the occurrence of hypertension [5]. Furthermore, low SA levels can lead to pulmonary edema and uid retention, which aggravate primary cardiovascular disease and are independent predictors of ischemic heart disease [6-8].
Elevated serum uric acid concentrations can increase the expressions of chemokines and cytokines in the vascular system, activate the renin angiotensin system, and increase the expression of c-reactive protein, resulting in a cascade reaction of in ammation and oxidative stress and damage to vascular endothelial cells [9,10]. Uric acid has been shown to be an independent factor in the occurrence and development of cardiovascular events such as ascending aortic dilatation, hypertension, coronary heart disease, cerebrovascular disease and other cardiovascular diseases [11][12][13].Çakmak reported that the uric acid-toalbumin ratio (UAR) is a novel in ammatory marker that independently provides better predictive ability for outcomes than the C-reactive protein-to-albumin ratio; thus, UAR might be useful for predicting the extent of in on-ST-elevation myocardial infarction NSTEMI patients [14]. However, no studies have been conducted on the effect of UAR on the prognosis of patients with type A AAD, and whether the predictive value of UAR for prognosis differs from SA level or uric acid level. Therefore, we investigated the connection between preoperative UAR and the prognosis of patients with type A AAD. Moreover, the evaluated the predictive value of UAR by observing follow-up patients with type A AAD. Co., Ltd., China). CRP was detected using an automatic blood cell analyzer (Mindray, Model: CRP-M100, Shenzhen Mindray Bio-Medical Electronics Co., Ltd., China). Total bilirubin, albumin, globulin, total cholesterol, urea, creatinine, uric acid, and creatine kinase-MB CK-MB contents were detected using an automatic biochemical analyzer (HITACHI, Model: 008AS, Japan). The D-dimer and brinogen degradation products (FDP )contents were detected using a hemagglutination analyser-3 instrument (SYSMEX, Model: Cs-5100, Japan), high-sensitivity troponin were detected using automatic analyzer (RADIOMETER, model ABL90FLEX, Radomite Medical Equipment Co., LTD.)

Statistical Analysis
Summary statistics are presented as frequencies and percentages or as means ± standard deviation (SD). Differences between two groups were compared using unpaired Student's t tests or Mann-Whitney U tests for continuous variables and χ² tests for categorical variables. The COX proportional hazards model was used to identify predominant predictors for aortic events throughout the entire follow-up period based on univariate and stepwise multivariate analyses. Survival rate, dissection-related death-free rate, and aortic event-free rate were computed according to the Kaplan-Meier technique, and event-free curves were compared by log-rank test. For laboratory results, we also assessed whether measurements were outside the normal range. All statistical analyses were performed using IBM Statistics 26. A twotailed value of P < 0.05 was considered statistically signi cant.
Consent for publication. Our study does not contain any individual person's data in any form. All authors have signed a consent form for publication in case of acceptance.

Basic and clinical characteristics
A total of 289 patients were included in this study. Each patient received a surgical operation. Between January 2019 and September 2020, 213 men and 76 women were enrolled with an average age of 52 ± 11 years. All patients were divided into the UAR < 9.875 group (135 patients) and the UAR ≥ 9.875 group (154 patients) according to the optimal critical value of UAR in ROC analysis. The indicators of age, men, BMI, globulin, total bilirubin, BUN, Cr, creatinine clearance, HGB, WBC, RBC, total cholesterol, CK-MB, hypersensitive troponin T, ventilator-assisted time, length of stay in the ICU, and mortality) were signi cantly different between the two groups Table 1 . According to whether death occurred after the procedure during follow-up, the patients were further divided into the death and survival groups. The indicators of age, hypertension, albumin, UAR, Cr, creatinine, clearance, RB, CPLT, SBP, CK-MB, D-dimer, and FDP were signi cantly different between the two groups Table 2 . As shown in Figure 1, Kaplan-Meier survival analysis indicated that mortality in patients with type A AAD was higher in patients with high UAR (≥ 9.875μmol/g) compared to those with UAR (< 9.875μmol/g; log-rank x 2 = 20.68; P < 0.001). Table 1. Baseline and clinical characteristics of the UAR ≥ 9.875 and UAR < 9.875 groups. Data are mean ± SD or median (interquartile range), n (%). BMI, body mass index; CHD, coronary heart disease; BUN, urea nitrogen; Cr, creatinine; HGB, hemoglobin; HGB, hemoglobin; WBC, white blood cells;RBC, red blood cells; PLT: platelet; CRP, C reactive protein; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; CK-MB, creatine kinade MB; ICU, intensive care unit. Table 2. Baseline and clinical characteristics of the death and survival groups. Data are mean ± SD or median (interquartile range), n (%). FDP, brinogen degradation product.
Predicting factors for death COX regression multivariate analysis after univariate analysis of all-cause mortality indicated the following independent risk factors for mortality ( .875 group had a signi cantly higher death rate than those in the UAR < 9.875 group ( Figure 1; P< 0.001). The predictive values of UAR, D-dimer, age, hypertension, albumin, and uric acid for death was evaluated using the receiver operating characteristic (ROC) method, as shown in Table 4.
As shown in Figures 2 and 3, the patients were divided into two groups according to the optimal critical value of UAR: high UAR (≥ 9.875μmol/g) and low UAR (< 9.875μmol/g). Of the 135 patients in the low UAR group, 21 (13.6%) died during follow-up. In contrast, of the 154 patients in the high UAR group, 48 (31.2%) died during follow-up. Chi-square test showed a signi cant difference in mortality between the two groups (P = 0.002). For D-dimer, the patients were divided into two groups according to the optimal critical D-dimer content: high D-dimer (> 9.19 g/L) and low D-dimer (≤ 9.19 g/L). The percentages of patients that died during follow-up were 37.6% in the high D-dimer group but only 12.2% in the low Ddimer group, and the difference in mortality was signi cant based on Chi-square test (P = 0.000).
For age, the patients were divided into two groups according to the optimal cutoff value: high age (> 56 years) and low age (≤ 56 years , and the sensitivity and speci city were 59.4% and 75.9%, respectively (P = 0.000). Thus, the combination of UAR and D-dimer was best for predicting deaths (Figure 2 ).  Table 5.
Predictive values of different combinations of indicators (D-dimer + age, UAR + age + D-dimer, UAR + Ddimer, and UAR + age) for mortality in patients with type A AAD.

Discussion
Type A AAD is one of the most common and critical diseases in cardiovascular surgery. The early identi cation of risk factors in patients with type A AAD may help reduce the risk of death in these patients. Old age, a history of hypertension, cardiac tamponade, shock, coronary tear, acute renal failure, acute liver failure, stroke, mesenteric ischemia, and other risk factors have been considered as independent predictors of death in patients with type A AAD [15]; however, these risk factors cannot meet the needs of early diagnosis in clinical practice. In this study, we found that age, history of hypertension, preoperative UAR, serum albumin, D-dimer, and FDP in patients with Type A AAD were associated with the risk of one-year mortality in type A AAD patients, and preoperative UAR, D-dimer, and age were identi ed as independent risk factors. These ndings agree with other studies that identi ed D-dimer and age as independent predictors of death in type A AAD patients [16,17]. This is the rst study to evaluate the predictive effect of UAR for mortality in type A AAD. Thus, UAR can be considered as a new independent predictor of death in type A AAD.
SA is likely protection factors to be the type A AAD.when type A AAD occurs, a large number of in ammatory cytokines release, increase SA decomposition and led to lower SA. lower SA caused oedema after large amounts of uid leakage and reduced the blood volume. ,AKI, pulmonary edema, cerebral edema and other serious complications can further affect the postoperative outcome of patients with Type A AAD. Low SA reduces the ability of scavenging oxygen free radicals and inhibiting in ammatory response, and endothelial cells are damaged, and the elasticity of aortic vascular wall decreases. Ultimately affecting the outcome of Type A AAD [18,19].
Uric acid, which is the nal product of purine metabolism, is produced by a xanthine oxidoreductasecatalyzed oxidation reaction. The concentration of uric acid in serum is related to the total antioxidant capacity and aortic dilation [20] along with pathological processes such as endothelial dysfunction, oxidative stress, systemic in ammation, and renin-angiotensin system activation [21][22]. These pathologic processes further lead to endothelial dysfunction, vascular smooth muscle cell proliferation, and increased arterial stiffness. Uric acid can also increase the serum contents of IL-1β and nucleotide binding oligomerization domain-like receptor 3 along with blood pressure variability. Hyperuricemia can participate in aortic vascular endothelial injury through an oxidative stress pathway, resulting in increased serum endothelin -1 ET-1 and ICAM and decreased carbon monoxide. Increased uric acid concentration led to a decrease in ENOS expression, increased ET-1 and ICAM expressions, and a signi cant increase in the apoptosis rate of aortic cells [23]. Zhang reported that preoperative uric acid was an independent risk factor for postoperative in-hospital death in type A AAD [24]. However, Zhang's study considered few risk factors for type A AAD, did not exclude confounding factors, involved only a small number of patients, and did not include long-term follow-up. In clinical practice, many factors affect the production and excretion of SA and uric acid [25].
Çakmak reported that UAR was an independent predictor of the severity of coronary artery disease but did not assess type A AAD speci cally [14]. In this study, we focused on patients diagnosed with type A AAD and treated with surgery. Follow-up over one year after surgery revealed that UAR can better predict the mortality than the serum albumin or uric acid content. We also assessed the values of age and D-dimer for predicting death in type A AAD patients since these indicators have been identi ed as important risk factors in previous studies. We found that the combination of UAR, age, and D-dimer had better predictive value for death than separate of UAR, age, and D-dimer. This may be due to the exposure of subcutaneous tissue caused by intima tear during aortic dissection, resulting in the release of tissue factors that increase the consumption and metabolism of albumin [26]. In ammation plays an important role in the entire pathophysiological continuum of type A AAD, and the severity of in ammation is related to type A AAD rupture and prognosis [27]. SA is an important inhibitor of platelet activation and aggregation, and reduced SA levels may be associated with an increased risk of thrombotic events associated with increased PLT activation and aggregation [28]. Low serum albumin concentration leads to reduced antioxidant activity, and oxidative stress is important in the pathology of type A AAD [29].
Renal insu ciency is a part of complications of type A AAD, and uric acid is one of the indexes of early renal damage. In addition, uric acid can damage endothelial function and lead to oxidative stress, systemic in ammation, renin-angiotensin system activation, and increased apoptosis rate. In our study, uric acid and SA were combined to exclude confounding factors. Serum albumin or uric acid alone has poor speci city in predicting death, while albumin combined with uric acid can predict the outcome of type A AAD. However, the combination of UAR, age, and D-dimer was a better predictor of death.

Conclusions
In patients with type A AAD, UAR may be considered as an independent risk factor for long-term mortality.
The predictive value of UAR was superior to that of albumin and uric acid. Among the tested indicators and their combinations, the combination of UAR, age, and D-dimer was the best predictor of death. UAR may improve the accuracy of clinical prognosis and shows promise for clinical application because its determination is low cost, quick, and simple. Therefore, UAR shows value for evaluating the prognosis in type A AAD patients to guide future clinical research and treatment strategy.

Abbreviations
AAD acute aortic dissection UAR uric acid-to-albumin Ratio COX proportional hazards model ROC receiver operating characteristic AUC receiver operating characteristic curve SA serum albumin Limitations First, this study was a single-center observational study. Although follow-up was conducted, no further review was carried out. Therefore, a prospective, large-scale, and multi-center study is needed to con rm our conclusions. Second, this study was failed to consider only preoperative UAR, future research is to consider more center more number of patients, prospective study, calculation UAR with dynamic monitoring, to evaluate UAR affecting type A AAD patient outcome in different time points.

Figure 1
Cumulative survival in each group.  Mortality rates in patients with type A AAD in different groups based on UAR, D-dimer, age, hypertension, albumin, and uric acid.