Abstract
Objective
This study aimed to investigate the correlation of serum uric acid (SUA) with risk and dilatation diameter of ascending aortic dilatation (AAD) in Behçet's disease (BD) patients.
Methods
Seventeen BD patients complicated with AAD and 20 BD patients without AAD were consecutively enrolled and categorized into AAD group and control group, respectively. Ascending aortic dilatation was determined by two‐dimensional doppler echocardiographic examination, and AAD was defined as a diameter of ascending aorta ≥3.8 and <4.4 cm. SUA was detected by quantitative immunoassay method.
Results
Ascending aortic dilatation patients presented with higher proportion of male patients (P = 0.003), hypertension occurrence (P = 0.036) and increased diameter of ascending aorta (P < 0.001) compared to controls. SUA was elevated in AAD patients compared to controls (P = 0.002), and receiver operating characteristic curve displayed that SUA presented with great predictive value for AAD risk in BD patients with area under curve (AUC) 0.821 (95% CI 0.675‐0.966). Pearson's analysis also disclosed that SUA was positively correlated with ascending aortic diameter in total BD patients. However, no difference of CRP (P = 0.219) or ESR (P = 0.320) between AAD patients and controls was observed, and no correlation of CRP (R = −0.150, P = 0.377) or ESR (R = 0.067, P = 0.692) with ascending aortic diameter in total BD patients was discovered either. Further multivariate logistic regression illuminated that SUA was an independent factor predicting AAD risk in BD patients (P = 0.031).
Conclusions
Serum uric acid could be served as an independent marker for increased risk and severity of AAD in BD patients.
Keywords: ascending aorta dilatation, Behçet's disease, C‐reactive protein, erythrocyte sedimentation rate, serum uric acid
1. INTRODUCTION
Behçet's disease (BD), also called the silk route disease, is a rare immune‐mediated systemic vasculitis characterized by recurrently oral or genital ulcerations, uveitis, and erythema nodosum.1 Moreover, diverse systemic manifestations, such as arthritis, gastrointestinal lesions, and neurologic and cardiovascular complications, are also known to be accompanied with BD occurrence.2 Among all the complications, cardiovascular involvements especially the aortic aneurysm are considered as the most common cause of deaths in BD patients, thus special attention should be paid to ascending aortic dilatation (AAD), which is regarded as the possible forerunner of ascending aortic aneurysm.3, 4 However, the convincing markers for risk of AAD in BD patients are lacking; therefore, it is essential to explore more novel markers for predicting susceptibility and severity of AAD.
Several factors such as inflammatory cells/cytokines, smooth muscle cells, mechanical stretch, growth factors and lipid mediators have been proposed to affect the balance between destruction and regeneration of the aortic wall, thereby leading to aortic impairment and subsequent AAD.5, 6 And recently, the increment of serum uric acid (SUA) is observed to be correlated with higher risk of cardiovascular event and related mortality in several diseases, which would stimulate the nicotinamide adenine dinucleotide phosphate (NADPH) peroxidase, enhance oxidative stress, reduce activity of nitric oxide, impair mitochondrial function and adenosine triphosphate (ATP), therefore leading to impairment of vascular endothelial dysfunction.5, 6, 7, 8, 9 However, it still remains unclear whether SUA correlates with susceptibility and severity of AAD.
Thus, to address this aspect, this current study aimed to investigate the correlation of SUA with risk and dilatation diameters of AAD in BD patients.
2. MATERIALS AND METHODS
2.1. Patients
Seventeen BD patients complicated with AAD between December 2011 and December 2015 in Huadong Hospital were consecutively enrolled as AAD group in this case‐control study. The inclusion criteria were as follows: (a) Diagnosed as BD according to the International Criteria for Behçet's Disease (ICBD, 2006) or the revised ICBD (2010)10; (b) Complicated with AAD which was defined as a diameter of ascending aorta ≥3.8 and <4.4 cm according to previous studies11, 12, 13; (c) Age above 18 years. The main exclusion criteria were as follows: (a) clinical or laboratory evidence of congestive heart failure; (b) complicated with congenital heart disease, aneurysmal pericardial disease, renal failure (creatinine ≥ 1.5 mg/dL), moderate‐to‐severe liver dysfunction (alanine aminotransferase, aspartate aminotransferase more than or equal to three times the upper limit of normal), hemolytic disorders, other connective tissue disease, neoplastic disease, and documented coronary artery diseases; (c) receiving antioxidant medications or other drugs which may affect the SUA level such as thiazides and furosemides. In the meanwhile, 20 BD patients without AAD were also consecutively recruited as controls (control group) in this study, which shared the same inclusion and exclusion criteria as case group except for the diagnosis of AAD.
2.2. Ethics approval
This study was approved by the Human Ethics Committee of Huadong Hospital, and all patients signed the informed consents before recruitment.
2.3. Data collection
Comprehensive information of patients was collected including age, gender, complications, body mass index (BMI), diameter of ascending aorta, left ventricle ejection fraction (LVEF), white blood cell (WBC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, total triglyceride, total cholesterol, low‐density lipoprotein (LDL) cholesterol, high‐density lipoprotein (HDL) cholesterol, blood urea nitrogen, creatinine, HbA1c, prothrombin time (PT), activated partial thromboplastin time (APTT), blood K+, blood Na+ and New York Heart Association (NYHA) class, erythrocyte sedimentation rate (ESR), and C‐reactive protein (CRP).
2.4. Echocardiography
A two‐dimensional (2‐D) doppler echocardiographic examination was performed on a GE Sonoline echocardiograph with a cardiologic probe of variable frequency from 2 to 2.5 MHz (GE, vivid E9, Boston, MA, USA) after enrolment. The measurement of ascending aortic diameter referred to the guidelines of the American Society of echocardiography, and in the parasternal long‐axis view, the diameter of aorta perpendicular to the long axis of aorta was recorded as the largest aortic diameter.11, 13 AAD was defined as a diameter of ascending aorta ≥3.8 and <4.4 cm according to previous studies.11, 12, 13 In addition, LVEF was also determined and documented by Simpson's modified formula according to the American Society of Echocardiography guidelines.13
2.5. Serum uric acid detection
Blood sample from each patient was obtained after enrollment and serum was subsequently isolated by centrifugation at 1000 g for 10 minutes. SUA was detected by quantitative immunoassay method using Cobas Integra 400 Plus TQ (Roche Diagnostics Ltd., Basel, Basel State, Switzerland).
2.6. Statistical analysis
Statistical analysis was conducted using the SPSS 20.0 software (IBM, Chicago, IL, USA) and GraphPad Prism 6.01 software (GraphPad, San Diego, CA, USA). Continuous variables were presented as mean ± standard deviation, and categorical variables were presented as count (percentage). Comparison between two groups was determined by t test or chi‐square test; correlation was determined by Pearson's test; receiver operating characteristic (ROC) curve was drawn to assess the ability of SUA in distinguishing AAD patients from controls; multivariate logistic regression analysis (forward) was performed to evaluate the independent factors predicting AAD risk. P < 0.05 was considered significant.
3. RESULTS
3.1. Patients’ characteristics
Seventeen eligible AAD patients aged 38.53 ± 7.78 years with 16 males and 1 female, and 20 eligible controls aged 37.05 ± 7.32 years with 10 males and 10 females, were included into the analysis. AAD patients presented with higher proportion of male patients (P = 0.003), hypertension occurrence (P = 0.036), and increased diameter of ascending aorta (P < 0.001) compared to controls as displayed in Table 1, while no difference of other features between the two group was observed. The detailed characteristics of AAD patients and controls are shown in Table 1.
Table 1.
Characteristics of AAD patients and controls
| Parameters | Controls (N = 20) | AAD patients (N = 17) | P Value |
|---|---|---|---|
| Age (y) | 37.05 ± 7.32 | 38.53 ± 7.78 | 0.563 |
| Gender (male/female) | 10/10 | 16/1 | 0.003 |
| Hypertension (n, %) | 4 (20) | 9 (53) | 0.036 |
| Diabetes mellitus (n, %) | 2 (10) | 3 (18) | 0.498 |
| BMI (kg/m2) | 22.52 ± 1.54 | 22.48 ± 1.56 | 0.934 |
| Diameter of ascending aorta (mm) | 35.9 ± 1.1 | 40.8 ± 2.1 | <0.001 |
| LEVF (%) | 59.53 ± 2.04 | 59.06 ± 2.34 | 0.552 |
| WBC (109/L) | 5.86 ± 0.84 | 5.57 ± 0.68 | 0.264 |
| ALT (U/L) | 21.95 ± 5.59 | 21.71 ± 6.55 | 0.901 |
| AST (U/L) | 24.27 ± 5.86 | 23.82 ± 6.16 | 0.850 |
| Total bilirubin (μmol/L) | 9.49 ± 3.31 | 9.79 ± 3.90 | 0.803 |
| Total triglyceride(mmol/L) | 1.15 ± 0.30 | 1.06 ± 0.33 | 0.395 |
| Total cholesterol (mmol/L) | 4.06 ± 0.56 | 4.26 ± 0.67 | 0.337 |
| LDL cholesterol(mmol/L) | 2.07 ± 0.26 | 2.18 ± 0.39 | 0.283 |
| HDL cholesterol (mmol/L) | 1.36 ± 0.04 | 1.35 ± 0.05 | 0.571 |
| Blood urea nitrogen (mmol/L) | 6.14 ± 1.49 | 6.26 ± 1.40 | 0.796 |
| Creatinine (μmol/L) | 61.17 ± 9.81 | 62.81 ± 10.19 | 0.628 |
| HbA1c(%) | 5.53 ± 0.40 | 5.51 ± 0.32 | 0.913 |
| PT(s) | 12.05 ± 0.83 | 12.18 ± 0.81 | 0.644 |
| APTT(s) | 35.22 ± 0.19 | 34.63 ± 2.60 | 0.492 |
| Blood K+(mmol/L) | 3.89 ± 0.19 | 3.93 ± 0.27 | 0.563 |
| Blood Na+ (mmol/L) | 140.35 ± 1.87 | 140 ± 1.66 | 0.559 |
| NYHA class | |||
| Class I | 18 (90) | 14 (82) | 0.498 |
| Class II | 2 (10) | 3 (18) | |
Data were presented as mean ± standard deviation or count (percentage), comparison between two groups was determined by t test or chi‐square test. P < 0.05 was considered as significant, and P value with bold font represented P < 0.05.AAD, ascending aortic dilatation; BMI, body mass index; WBC, white blood cell; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; PT, prothrombin time; APTT, activated partial thromboplastin time; LVEF, left ventricle ejection fraction; GFR, estimated glomerular filtration rate using modification of diet in renal disease formula; NYHA, New York Heart Association.
3.2. SUA level in AAD patients and controls
Serum uric acid was elevated in AAD patients (394.1 ± 20.37 μmol/L) compared to controls (304.1 ± 17.11 μmol/L) (P = 0.002, Figure 1A). ROC curve displayed that SUA presented with great predictive value for AAD risk in BD patients with area under curve (AUC) 0.821 (95% CI 0.675‐0.966), and sensitivity was 70.6% and specificity was 95.0% at best cutoff value 339.4 μmol/L (Figure 1B). Best cutoff value was defined as the point on ROC curve which realized the maximum of sensitivity plus specificity. In addition, Pearson's analysis also disclosed that SUA was positively correlated with ascending aortic diameter in total BD patients (Figure 1C).
Figure 1.
Correlation of SUA with AAD risk and severity. A, SUA was increased in AAD patients than controls. B, ROC curve analysis revealed SUA had good value in distinguishing AAD from control. C, Pearson's analysis revealed SUA correlated with ascending aortic diameter. SUA, serum uric acid; AAD, ascending aortic dilatation; ROC, receiver operating characteristic
3.3. CRP and ESR levels in AAD patients and controls
As inflammation was considered as a core factor for cardiovascular impairment, we next determined the levels of CRP and ESR levels in AAD patients and controls. And no difference of CRP (P = 0.219, Figure 2A) or ESR (P = 0.320, Figure 2C) between AAD patients and controls was observed. Furthermore, no correlation of CRP (R = −0.150, P = 0.377, Figure 2B) or ESR (R = 0.067, P = 0.692, Figure 2D) with ascending aortic diameter in total BD patients was discovered either.
Figure 2.
Correlation of CRP/ESR with AAD risk and severity. A, CRP level was similar between AAD patients and controls. B, CRP did not correlate with ascending aortic diameter. C, ESR level was similar between AAD patients and controls. D, ESR did not correlated with ascending aortic diameter. CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; AAD, ascending aortic dilatation
3.4. Independent factors affecting AAD risk
In order to further validate the independent factors affecting AAD risk in BD patients, multivariate logistic regression analysis (forward) was performed, which revealed that SUA (P = 0.031) and gender‐male (P < 0.001) were independent factors for predicting higher AAD risk in BD patients (Table 2).
Table 2.
Multivariate logistic regression analysis (Forward) for independent factors predicting AAD risk
| Parameters | Multivariate logistic regression | |||
|---|---|---|---|---|
| P value | OR | 95% CI | ||
| Lower | Higher | |||
| Gender (male) | <0.001 | 47.045 | 1.672 | 1364.3 |
| SUA | 0.031 | 1.013 | 1.001 | 1.228 |
Data were presented as P value, OR value, and 95% CI. Independent factors predicting AAD risk was detected by multivariate logistic regression analysis (Forward). P < 0.05 was considered as significant, and P value with bold font represented P < 0.05. AAD, ascending aortic dilatation; OR, odds ratio; CI, confidence interval; SUA, serum uric acid.
4. DISCUSSION
In this study, we observed that SUA correlated with increased risk of AAD independently, and it also positively associated with ascending aortic diameter in BD patients. While inflammation indexes including CRP and ESR were not correlated with risk or severity of AAD in BD patients.
Chronic inflammation in BD patients affects multiple organs or systems including joints, blood vessels, intestines, central nervous system (CNS), and so on, among which cardiovascular lesions are associated with higher risk of AAD, aneurysms, and regurgitation that leads to a high mortality rate of approximate 20% after diagnosis.14, 15, 16, 17 However, the etiology of AAD in BD patients remains unknown. Previous studies revealed that age, BMI, and blood pressure positively correlate with increased ascending aortic diameter in patients without cardiac disease,18 and the vascular aneurysms in BD are more common in men than women.19 In line with these researches, we observed that AAD group illuminated increased male percentage and hypertension percentage compared to control group in BD patients. These results might result from that (a) male patients with BD are often complicated with severer disease condition especially higher possibility of smoke, hypertension, and hyperlipidemia which increase the risk of AAD; (b) hypertension is a key factor for increased risk of cardiovascular and cerebrovascular diseases including AAD.
Accumulating studies reveal that high SUA correlates with elevated cardiovascular lesions or events in several diseases. A previous study discloses that SUA positively associates with left ventricular mass index in women with obstructive hypertrophic cardiomyopathy20; another research illustrates that SUA positively associates with cardiometabolic risk factors and metabolic syndrome risk in adolescents21; and a recent investigation based on large sample‐size Chinese populations observes that SUA could be served as a cardio‐cerebrovascular event risk factor in middle‐aged and nonobese Chinese men.6 However, seldom study exploring the correlation of SUA with AAD in BD patients has been reported. In this present study, we observed that SUA correlated with increased risk of AAD independently, and it also positively associated with ascending aortic diameter in BD patients. There were several possible explanations to our results: (a) increased SUA induces NADPH peroxidase, increases oxidative stress, then attenuates activity of nitric oxide, subsequently damages mitochondrial function, and adenosine triphosphate (ATP), therefore results in the impairment of vascular endothelial dysfunction and corresponding higher risk of AAD7; (b) SUA level serves as an indicator of the underlying oxidative stress and total antioxidant capacity which are involved in the development of AAD and aortic aneurysms, therefore higher SUA correlates with increased risk of AAD.22
Previous reports disclose that systemic inflammation correlates with increased risk of AAD.23, 24 For example, a case‐control study reveals that hs‐CRP is increased in AAD patients compared to age‐ and gender‐matched health controls while no association of Hs‐CRP level with ascending aortic diameter in AAD patients is observed23; another case‐control study also presented that hs‐CRP level is raised in AAD patients than subjects with normal aortic diameters.24 While no study has been reported about the correlation of inflammation indexes with AAD risk in BD patients until now. In this present study, we discovered that inflammation indexes including CRP and ESR were not correlated with risk or severity of AAD in BD patients, which was in discrepancy with previous opinion that increased inflammation associates with higher risk of cardiovascular lesion, the result might be on account of that CRP (<10 mg/L) and ESR (<20 mm/H) were both well controlled in BD patients in our study; thus, their effects on development or progression of AAD in BD patients were attenuated.
There were still some limitations in this study: (a) Sample size of this study was small; however, BD patients complicated with AAD were very rare; although our Hospital had the most BD patients in China, we only enrolled 17 eligible BD patients with AAD in this study for 4 years; (b) the effect of SUA on prognosis such as cardiovascular mortality and all‐cause mortality in BD patients with AAD was not investigated.
In conclusion, SUA could be served as an independent marker for increased risk and severity of AAD in BD patients.
ACKNOWLEDGMENTS
This study was funded by (a) Shanghai Pujiang Young Rheumatologists Training Program (SPROG), No. SPROG201707; (b) Clinical Science Innovation Program of Shanghai Shenkang Hospital Development Center, No. SHDC1207129; (c) Shanghai Municipal Commission of Health and Family Planning, Key developing disciplines, No. 2015ZB0501.
Cai J, Zhang Y, Zou J, et al. Serum uric acid could be served as an independent marker for increased risk and severity of ascending aortic dilatation in Behçet's disease patients. J Clin Lab Anal. 2019;33:e22637 10.1002/jcla.22637
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