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High levels of serum uric acid are associated with silent brain infarction
Journal of the Neurological Sciences 297 (2010) 6–10
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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
High levels of serum uric acid are associated with silent brain infarction Sung Hyuk Heo a, Seung-Hoon Lee b,⁎ a b
Department of Neurology, Kyunghee University College of Medicine, Seoul, Republic of Korea Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 17 December 2009 Received in revised form 13 June 2010 Accepted 13 July 2010 Available online 3 August 2010 Keywords: Stroke Uric acid Silent brain infarction Biomarker
a b s t r a c t Background: Uric acid has been known to exert neuroprotective effects by acting as a free radical scavenger; however, several observational studies indicated that high levels of serum uric acid increased the risk of cardiovascular events or stroke. We sought to determine whether increased levels of uric acid are associated with the presence of silent brain infarction (SBI). Methods: We recruited a consecutive series of non-stroke individuals who visited the Healthcare System in our hospital and underwent brain MRI (n = 1577). We conducted intensive interviews and laboratory examinations, including serum uric acid. We examined associations between SBI and vascular risk factors including uric acid by controlling possible confounders. Results: Of the 1577 subjects recruited, 921 were men and 656 were women, and the uric acid level was much higher in the men (6.3 ± 1.3) than in the women (4.7 ± 1.0). There was a strong dose–response relationship between the quartiles of uric acid and the presence of SBI in women (p = 0.001), but not in men. Multivariable analysis showed that the highest quartile of uric acid level was an independent risk factor for the presence of SBI in total patients (adjusted OR, 1.79; 95% CI, 1.11–2.91). However, this association remained significant in women (adjusted OR, 2.64; 95% CI, 1.17–5.91), but not in men. Conclusions: Our results suggest that an increased level of uric acid may be a risk factor for the presence of SBI. Serum uric acid level might be a good serum marker of underlying SBI or future stroke, especially in women. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Purines are produced by metabolism of dietary and endogenous nucleic acids, and they are ultimately degraded to uric acid by xanthine oxidase. In humans and higher primates, uric acid is the final oxidation product of purine catabolism, whereas the enzyme uricase further oxidizes uric acid to allantoin in most other mammals. Uric acid exists in the extracellular compartment as sodium urate, and it is cleared from the plasma through the kidney [1]. Thus, the serum level of uric acid is determined by a combination of purine metabolism and the renal clearance system. In addition, it has been reported that increased levels of uric acid are associated with elevated serum triglyceride and cholesterol concentrations, elevated blood glucose levels, and the metabolic syndrome [2–4]. Uric acid has been known to exert neuroprotective effects by acting as a free radical scavenger. Uric acid is a strong reducing agent (electron donor) and a potent antioxidant. In humans, approximately one half of the antioxidant capacity of plasma comes from uric acid [5]. Several experimental reports have shown beneficial effects in acute stroke animal models ⁎ Corresponding author. Department of Neurology, Seoul National University Hospital, 28 Yongon-dong, Jongno-gu, Seoul, 110-744, Republic of Korea. Tel.: + 82 2 2072 1014; fax: + 82 2 3672 7553. E-mail address: [email protected] (S.-H. Lee). 0022-510X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.07.007
[6], and a clinical trial on the neuroprotective effects of uric acid has been proposed especially in stroke patients [7,8]. The function of uric acid remains a matter of controversy. Silent brain infarction (SBI) is an incidental finding on CT or MR images of subjects without neurological symptoms, and this is clearly different to white matter lesions or leukoaraiosis because the SBI is a finding of real ischemic damage with tissue loss and perigliotic rims. SBI is common in the general population, and it is closely associated with vascular risk factors [9]. Subjects with SBI may have subtle deficits in physical or cognitive functions that commonly go unnoticed, and it may predict the likelihood of future stroke [9]. Therefore, SBI may be an excellent surrogate marker of stroke, and it has been frequently used to analyze the risk factors for stroke in a more sensitive manner. In this context, the association between the level of uric acid and stroke can be investigated through the use of SBI. There were a few recent reports on this issue, which did not show a strong relationship with the presence of SBI, but the studies have a limitation of small sample size [10,11]. In contrast, another two recent studies suggested a positive association between uric acid level and white matter hyperintensities on brain MR images [12,13]. Therefore, the effects of uric acid level on the presence of SBI remain to be solved. In this study, we sought to determine whether increased levels of uric acid are associated with the presence of SBI on MR images.
S.H. Heo, S.-H. Lee / Journal of the Neurological Sciences 297 (2010) 6–10
2. Methods 2.1. Enrolment of subjects We recruited a consecutive series of “neurologically healthy” subjects who visited Seoul National University Hospital (SNUH) Healthcare System Gangnam Centre, Republic of Korea for routine health check-up from October 2003 through December 2004 as the SNUH Gangnam MRI Survey [14]. We defined neurologically healthy subjects as those who did not experience a stroke or transient ischemic attack and did not have any symptom and sign of neurological manifestation. Among the entire study population (n= 1588), eleven subjects were excluded due to a lack of data on uric acid level, and the final study population included a total of 1577 subjects. All subjects provided informed consent, and the study was approved by the institutional review board at our hospital.
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Haenszel's χ2 test was used to determine the correlation between the numbers of subjects with SBI and the uric acid quartiles. In addition, the level of uric acid was compared between subjects with SBI and subjects without SBI in men and women separately. Finally, multivariable logistic regression analysis was conducted to identify independent risk factors for the presence of SBI. In this model, uric acid level was entered as the highest quartile, and all of the demographic, clinical, and laboratory variables were entered together. Data from this model were presented as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). First, we conducted this work in the whole population, and then, separately conducted in men and women. All statistical analyses were conducted using SPSS for Windows version 12.0, and statistical significance was accepted at the p b 0.05 level. 3. Results
2.2. Vascular risk factors
3.1. Baseline characteristics
All subjects underwent an intensive interview and appropriate laboratory examinations to identify vascular risk factors. Hypertension was defined as follows: subjects with a prior history of hypertension and those who were prescribed any antihypertensive medications or subjects with a systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg at rest. We classified the subjects with diabetes as either alleged diabetes subjects or subjects with fasting glucose ≥7.0 mmol/L. Dyslipidemia was determined by a prior diagnosis of dyslipidemia, fasting serum low-density lipoprotein (LDL) cholesterol ≥4.1 mmol/L or total cholesterol ≥6.3 mmol/L. Information on past or current history of cigarette smoking was collected. A history of coronary artery disease was elicited based on interview questions on the experience of symptoms and on the previous diagnosis. Medication history included antihypertensive medications or aspirin medication. Resting blood pressure was recorded, and laboratory tests, including hemoglobin, glucose, glycated hemoglobin (hemoglobin A1c), creatinine, high sensitivityC-reactive protein (hs-CRP), total cholesterol, triglyceride, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and uric acid, were conducted. The laboratory tests were conducted after fasting for at least 8 h in order to avoid the effects of diet.
Of the 1577 subjects included in this study, 921 were men and 656 were women (Table 1). The subjects ranged in age from 20 to 86 years (mean, 53.7 ± 10.6 years). The uric acid level ranged from 1.7 to 11.5 mg/dL (mean, 5.6 ± 1.4 mg/dL). The uric acid level was much higher in the men (6.3 ± 1.3) than in the women (4.7 ± 1.0). SBI was identified in 88 subjects (5.6%). Subjects with SBI were more likely to be older and to have hypertension, diabetes, and a history of coronary artery disease. The subjects with SBI were also more likely to exhibit greater increases in blood pressure, glucose level, hemoglobin A1c level, triglyceride level and uric acid level than those without SBI. The level of HDL cholesterol was likely to be lower in subjects with SBI than in those without SBI.
2.3. Diagnosis of SBI MR images were obtained using a 1.5T superconducting magnet (GE Medical Systems, Milwaukee, WI, USA). The imaging protocol used was as follows: T2-weighted spin-echo [repetition time/echo time (TR/TE), 5800/96 ms), T1-weighted spin-echo (TR/TE, 520/ 14 ms), and fluid-attenuated inversion recovery (FLAIR; TR/TE, 8500/96 ms; inversion time, 2100 ms) imaging. The slice thickness was 5 mm, with no interslice gap. The diagnostic process was described in detail in a previous report [14]. In brief, two trained neurologists who were blind to the patients' clinical information assessed the presence of SBI, and the presence of SBI was finally determined by consensus. SBI was defined as a focal lesion measuring 3 mm or more in diameter with signal intensity corresponding to liquor (small cavitary lesions filled with cerebrospinal fluid) [15]. 2.4. Statistical analysis To analyze the baseline characteristics, unpaired student t-tests and χ2 tests were used to compare the prevalence of demographic, clinical, laboratory and radiological variables between men and women, as well as between subjects with SBI and those without. Because there is a substantial difference in the serum level of uric acid between men and women, we basically analyzed the levels of uric acid according to quartiles in men and women separately. Mantel–
3.2. Relationships between uric acid level and SBI We analyzed the uric acid levels according to quartiles in the entire group of subjects and separately in men and women. As illustrated in Fig 1., in the entire group of subjects, the number of subjects with SBI tended to be higher in the highest quartile of uric acid, but the relationship was not significant (Mantel–Haenszel χ2 test, p = 0.070). In the men, there was no difference in the number of subjects with SBI among the quartiles (p = 0.40), but in the women, there was a strong dose–response relationship (p = 0.002). In the men, there was no difference in the level of uric acid between the subjects with SBI (6.3 ± 1.3 mg/dL) and those without (6.3 ± 1.3 mg/dL; p = 0.851). However, in the women, the level of uric acid was significantly higher in the subjects with SBI (5.4 ± 1.2 mg/dL) than in the subjects without (4.6± 1.0 mg/dL; p b 0.001). 3.3. Independent effects of uric acid level on the presence of SBI We examined whether the increased level of uric acid according to the presence of SBI was independent of other important clinical variables. First, we conduct univariate and multivariate analyses in total subjects (Table 2). In this analysis, the highest quartile of uric acid level was an independent risk factor for the presence of SBI (adjusted OR, 1.79; 95% CI 1.11–2.91), and hypertension and history of coronary artery disease were another risk factors. Then, as described above, there were substantial differences in the clinical and laboratory values, including uric acid levels, between the men and women, and multivariable logistic regression analysis was conducted separately in men and women. As shown in Table 3, only age and hypertension were independent risk factors for the presence of SBI among men, and the highest quartile of uric acid level was not associated with the presence of SBI. However, in women, age and the highest quartile of uric acid level were significantly associated with the presence of SBI (adjusted OR, 2.62; 95% 1.17–5.91) (Table 4).
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Table 1 Baseline characteristics. Gender
Gender Age, years Hypertension Diabetes Dyslipidemia History of smoking History of coronary artery disease Medication history Anti-hypertensive agents Aspirin Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Hemoglobin, % Glucose, mg/dL Hemoglobin A1C, % Creatinine Hs-CRP Total cholesterol, mg/dL Triglyceride, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL Uric acid, mg/dL SBI
SBI
Women (n = 656)
Men (n = 921)
None (n = 1489)
Present (n = 88)
NA 54.0 ± 10.4 264 (40.2) 51 (7.8) 110 (16.8) 60 (9.1) 21 (3.2)
NA 53.5 ± 10.7 532 (57.8)a 136 (14.8)a 165 (17.9) 718 (78.0)a 40 (4.3)
621 (41.7) 53.3 ± 10.5 723 (48.6) 162 (10.9) 259 (17.4) 729 (49.0) 50 (3.4)
35 (39.8) 60.7 ± 10.0a 73 (83.0)a 25 (28.4)a 16 (18.2) 49 (55.7) 11 (12.5)a
130 (19.8) 51 (7.8) 120 ± 18 76 ± 12 13.2 ± 1.0 98.5 ± 20.0 5.7 ± 0.8 0.9 ± 0.3 0.13 ± 0.31 202 ± 35 96 ± 60 124 ± 32 58 ± 13a 4.7 ± 1.0 35 (5.3)
192 (20.8) 117 (12.7)a 126 ± 16a 84 ± 12a 15.3 ± 1.2a 107.3 ± 7.9a 5.8 ± 0.9a 1.1 ± 0.2a 0.19 ± 0.49a 200 ± 35 127 ± 81a 125 ± 33a 50 ± 12 6.3 ± 1.3a 53 (5.8)
279 (18.7) 153 (10.3) 126 ± 17 80 ± 12 14.5 ± 1.6 103.0 ± 24.6 5.8 ± 0.9 1.0 ± 0.2 0.16 ± 0.43 201 ± 35 113 ± 72 125 ± 32 53 ± 14a 5.6 ± 1.5 NA
43 (48.9)a 15 (17.0) 135 ± 19a 86 ± 12a 14.3 ± 1.6 114.8 ± 1.6a 6.2 ± 1.2 1.1 ± 0.5 0.20 ± 0.32 204 ± 38 138 ± 105a 127 ± 38 50 ± 9 6.0 ± 1.3a NA
Numbers are presented as means ± standard deviations or frequencies (percentages), as appropriate. χ2 tests were used for categorical variables and student t-tests were used for continuous variables. Hs-CRP indicates high sensitivity-C-reactive protein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; SBI, silent brain infarction; NA, not applicable. a Indicates a significantly higher value after statistical analysis.
4. Discussion Our results revealed a dose-dependent relationship between the serum level of uric acid and the presence of SBI in adult women. There was a substantial difference in uric acid level between the women and men, and the highest quartile of uric acid was an independent risk factor for the presence of SBI in women, but not in men. To our knowledge, this is the first study to show gender differences in the association between uric acid and SBI. Many epidemiological studies have reported that increased levels of uric acid might be associated with an increased risk of cardiovascular disease or stroke [16]. Multivariable analysis of data from the MONICA study (1044 men) showed an independent association between serum uric acid and cardiovascular mortality [17]. A prospective study in the Netherlands recently showed that uric acid was a strong predictor of myocardial infarction and stroke during the
long follow-up period (8.4 years, mean) [18]. In contrast, another retrospective study, which analyzed data from a consecutive series of 881 acute ischemic stroke patients, indicated that there was a 12% increase in the odds of achieving a good clinical outcome at discharge for each milligram per deciliter increase in serum uric acid [7]. In addition, a small randomized controlled study indicated that administration of uric acid and vitamin C selectively improved acetylcholine responses in patients with type 1 diabetes and in regular smokers [19]. Moreover, it is important to consider the substantial experimental evidence that uric acid was beneficial in vitro and in vivo. Uric acid might suppress the accumulation of reactive oxygen species and lipid peroxidation after cerebral ischemia or exposure to glutamate [6], and the administration of uric acid to adult rats before or after focal cerebral ischemia resulted in a significant Table 2 Univariate and multivariate analyses in total patients.
Age (per year) Hypertension Diabetes Dyslipidemia History of smoking History of coronary artery disease Medication of aspirin Systolic blood pressure Diastolic blood pressure Hemoglobin Glucose Hemoglobin A1C Creatinine hs-CRP HDL cholesterol Highest quartile of uric acid Fig. 1. Distribution of the percentages of subjects in each quartile of uric acid level in the entire study group, men and women.
Univariate
Multivariate
Unadjusted OR 95% CI
Adjusted OR 95% CI
1.07 5.16 3.25 1.06 1.31 4.11
(1.05–1.10) (2.93–9.07) (1.99–5.31) (0.60–1.84) (0.85–2.02) (2.06–8.21)
1.05 2.58 1.63 0.91 1.20 2.53
(1.02–1.08) (1.26–5.30) (0.80–3.29) (0.50–1.65) (0.72–1.99) (1.18–5.40)
1.79 1.04 1.04 0.96 1.01 1.44 1.69 1.18 0.98 1.80
(1.00–3.21) (1.03–1.05) (1.02–1.06) (0.84–1.09) (1.01–1.02) (1.21–1.70) (1.05–2.73) (0.83–1.68) (0.96–0.99) (1.15–2.82)
0.85 1.01 1.00 0.91 1.01 0.96 1.33 0.94 0.98 1.79
(0.45–1.59) (0.99–1.03) (0.97–1.03) (0.78–1.06) (0.99–1.02) (0.66–1.39) (0.77–2.30) (0.59–1.51) (0.97–1.00) (1.11–2.91)
Hs-CRP indicates high sensitivity-C-reactive protein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; SBI, silent brain infarction.
S.H. Heo, S.-H. Lee / Journal of the Neurological Sciences 297 (2010) 6–10 Table 3 Multivariable analysis in men.
Age (per year) Hypertension Diabetes Dyslipidemia History of smoking History of coronary artery disease Medication of aspirin Systolic blood pressure Diastolic blood pressure Hemoglobin Glucose Hemoglobin A1C Creatinine hs-CRP HDL cholesterol Highest quartile of uric acid
Adjusted OR
95% CI
p
1.04 3.01 1.27 0.64 1.62 2.48 1.24 1.02 0.99 1.04 1.01 1.02 2.58 0.93 1.00 1.25
(1.00–1.08) (1.09–8.28) (0.51–3.15) (0.27–1.52) (0.73–3.60) (0.98–6.27) (0.60–2.57) (0.99–1.04) (0.96–1.03) (0.81–1.33) (0.99–1.02) (0.65–1.60) (0.94–7.10) (0.48–1.81) (0.97–1.03) (0.63–2.49)
0.03 0.03 0.61 0.31 0.24 0.05 0.57 0.30 0.76 0.78 0.25 0.94 0.07 0.83 0.95 0.53
Hs-CRP indicates high sensitivity-C-reactive protein; HDL, high-density lipoprotein; SBI, silent brain infarction.
reduction of the infarction volume and improved behavioral scale scores [6]. Despite these observations, a previous study suggested that uric acid is likely to be harmful, at least in humans, especially in patients with cardiovascular disease or stroke [16], and our results support this suggestion. Although serum uric acid possesses antioxidant properties, several harmful mechanisms have been proposed experimentally. Uric acid was found to promote LDL oxidation in vitro [20] and to stimulate granulocyte adherence to the endothelium [21], as well as peroxide and superoxide free radical liberation [21]. However, another plausible explanation is that tissue injury, especially in ischemic lesions, may increase the level of uric acid [22]. Adenosine, which serves as an arteriolar vasodilator, is increasingly generated by cardiac and visceral ischemia, and it is in turn rapidly degraded by the endothelium to uric acid, which undergoes rapid efflux to the vascular lumen [23]. Therefore, serum uric acid may act as a marker of underlying tissue ischemia, but there has been no evidence to support this claim found in the brain. The results of this study indicated that an increased level of uric acid might not be a risk factor for SBI, but rather a product of SBI. According to this hypothesis, uric acid might not be an active substance that is either harmful or beneficial to the brain, but rather just a serum marker of SBI. However, we do not believe that this was the case in this study because the association between uric acid and SBI was present only in women. The absence of an association in men cannot be easily understood. Even if the increased level of uric acid was only a product of an underlying ischemic lesion in the brain, Table 4 Multivariable analysis in women.
Age (per year) Hypertension Diabetes Dyslipidemia History of smoking History of coronary artery disease Medication of aspirin Systolic blood pressure Diastolic blood pressure Hemoglobin Glucose Hemoglobin A1C Creatinine hs-CRP HDL cholesterol Highest quartile of uric acid
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it may not change the hypothesis that uric acid may be a serum marker of future stroke because SBI is a well-established, radiologic marker of future stroke [9]. It is very interesting that the increased level of uric acid was associated with SBI only in women. Generally speaking, there has been no difference in the association between uric acid and SBI in men and women, but our results showed a clear difference between genders. A post hoc analysis of the LIFE trial indicated that the association between the level of uric acid and cardiovascular outcomes was significant only in women after adjustment of the Framingham risk score [24]. Uric acid levels generally increase with age, and premenopausal women have lower levels of uric acid than age-matched men because of the uricosuric effect of estrogen [25]. It may be associated with the differences in the effect of uric acid between men and women, but the exact underlying mechanisms should be further investigated. Our study has some caveats to be acknowledged. First, our database did not include information on the patients' history of diuretics or statins. Some prior results indicated that thiazide diuretics may be an important confounder of the association between uric acid and cardiovascular risk [26–28]. In addition, the effects of statins on SBI have not yet been established, but the information would have improved our results. Second, this study collected data on a consecutive series, but they were recruited from a single health care centre, which was not representative of the general population. Moreover, number of subjects with SBI was only 88 patients among a total of 1577 subjects. This small positivity might limit the power of the study results to be generalized. Finally, uric acid has a very low solubility, which might be a barrier to use of uric acid as a neuroprotective agent [29]. In this context, due to this limited solubility, there might be less scope for uric acid concentrations to rise in men who have higher baseline concentrations than women. Our results suggest that the increased level of uric acid may be a risk factor for the presence of SBI in women. The presence of SBI is an excellent radiologic marker of future stroke [9], but general application of MR imaging is limited because of its high cost. Serum uric acid level would be a good serum marker of underlying SBI or future stroke in women. In addition, clinical trials on lowering uric acid level to prevent incident vascular events should be conducted in this context. Acknowledgements This study was supported by grants of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A090529). We specially thank to Dr. Beom Joon Kim for his intellectual comments. References
Adjusted OR
95% CI
p
1.06 2.62 2.42 1.49 1.72 1.92 0.30 1.01 1.01 0.84 1.00 0.89 0.48 1.06 0.96 2.62
(1.01–1.11) (0.86–7.98) (0.74–7.96) (0.61–3.65) (0.51–5.72) (0.44–8.34) (0.06–1.44) (0.97–1.04) (0.96–1.06) (0.60–1.16) (0.97–1.03) (0.46–1.75) (0.02–15.58) (0.47–2.43) (0.93–0.99) (1.17–5.91)
0.01 0.09 0.15 0.38 0.38 0.38 0.13 0.77 0.73 0.29 0.95 0.74 0.68 0.88 0.02 0.02
Hs-CRP indicates high sensitivity-C-reactive protein; HDL, high-density lipoprotein; SBI, silent brain infarction.
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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
High levels of serum uric acid are associated with silent brain infarction Sung Hyuk Heo a, Seung-Hoon Lee b,⁎ a b
Department of Neurology, Kyunghee University College of Medicine, Seoul, Republic of Korea Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 17 December 2009 Received in revised form 13 June 2010 Accepted 13 July 2010 Available online 3 August 2010 Keywords: Stroke Uric acid Silent brain infarction Biomarker
a b s t r a c t Background: Uric acid has been known to exert neuroprotective effects by acting as a free radical scavenger; however, several observational studies indicated that high levels of serum uric acid increased the risk of cardiovascular events or stroke. We sought to determine whether increased levels of uric acid are associated with the presence of silent brain infarction (SBI). Methods: We recruited a consecutive series of non-stroke individuals who visited the Healthcare System in our hospital and underwent brain MRI (n = 1577). We conducted intensive interviews and laboratory examinations, including serum uric acid. We examined associations between SBI and vascular risk factors including uric acid by controlling possible confounders. Results: Of the 1577 subjects recruited, 921 were men and 656 were women, and the uric acid level was much higher in the men (6.3 ± 1.3) than in the women (4.7 ± 1.0). There was a strong dose–response relationship between the quartiles of uric acid and the presence of SBI in women (p = 0.001), but not in men. Multivariable analysis showed that the highest quartile of uric acid level was an independent risk factor for the presence of SBI in total patients (adjusted OR, 1.79; 95% CI, 1.11–2.91). However, this association remained significant in women (adjusted OR, 2.64; 95% CI, 1.17–5.91), but not in men. Conclusions: Our results suggest that an increased level of uric acid may be a risk factor for the presence of SBI. Serum uric acid level might be a good serum marker of underlying SBI or future stroke, especially in women. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Purines are produced by metabolism of dietary and endogenous nucleic acids, and they are ultimately degraded to uric acid by xanthine oxidase. In humans and higher primates, uric acid is the final oxidation product of purine catabolism, whereas the enzyme uricase further oxidizes uric acid to allantoin in most other mammals. Uric acid exists in the extracellular compartment as sodium urate, and it is cleared from the plasma through the kidney [1]. Thus, the serum level of uric acid is determined by a combination of purine metabolism and the renal clearance system. In addition, it has been reported that increased levels of uric acid are associated with elevated serum triglyceride and cholesterol concentrations, elevated blood glucose levels, and the metabolic syndrome [2–4]. Uric acid has been known to exert neuroprotective effects by acting as a free radical scavenger. Uric acid is a strong reducing agent (electron donor) and a potent antioxidant. In humans, approximately one half of the antioxidant capacity of plasma comes from uric acid [5]. Several experimental reports have shown beneficial effects in acute stroke animal models ⁎ Corresponding author. Department of Neurology, Seoul National University Hospital, 28 Yongon-dong, Jongno-gu, Seoul, 110-744, Republic of Korea. Tel.: + 82 2 2072 1014; fax: + 82 2 3672 7553. E-mail address: [email protected] (S.-H. Lee). 0022-510X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.07.007
[6], and a clinical trial on the neuroprotective effects of uric acid has been proposed especially in stroke patients [7,8]. The function of uric acid remains a matter of controversy. Silent brain infarction (SBI) is an incidental finding on CT or MR images of subjects without neurological symptoms, and this is clearly different to white matter lesions or leukoaraiosis because the SBI is a finding of real ischemic damage with tissue loss and perigliotic rims. SBI is common in the general population, and it is closely associated with vascular risk factors [9]. Subjects with SBI may have subtle deficits in physical or cognitive functions that commonly go unnoticed, and it may predict the likelihood of future stroke [9]. Therefore, SBI may be an excellent surrogate marker of stroke, and it has been frequently used to analyze the risk factors for stroke in a more sensitive manner. In this context, the association between the level of uric acid and stroke can be investigated through the use of SBI. There were a few recent reports on this issue, which did not show a strong relationship with the presence of SBI, but the studies have a limitation of small sample size [10,11]. In contrast, another two recent studies suggested a positive association between uric acid level and white matter hyperintensities on brain MR images [12,13]. Therefore, the effects of uric acid level on the presence of SBI remain to be solved. In this study, we sought to determine whether increased levels of uric acid are associated with the presence of SBI on MR images.
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2. Methods 2.1. Enrolment of subjects We recruited a consecutive series of “neurologically healthy” subjects who visited Seoul National University Hospital (SNUH) Healthcare System Gangnam Centre, Republic of Korea for routine health check-up from October 2003 through December 2004 as the SNUH Gangnam MRI Survey [14]. We defined neurologically healthy subjects as those who did not experience a stroke or transient ischemic attack and did not have any symptom and sign of neurological manifestation. Among the entire study population (n= 1588), eleven subjects were excluded due to a lack of data on uric acid level, and the final study population included a total of 1577 subjects. All subjects provided informed consent, and the study was approved by the institutional review board at our hospital.
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Haenszel's χ2 test was used to determine the correlation between the numbers of subjects with SBI and the uric acid quartiles. In addition, the level of uric acid was compared between subjects with SBI and subjects without SBI in men and women separately. Finally, multivariable logistic regression analysis was conducted to identify independent risk factors for the presence of SBI. In this model, uric acid level was entered as the highest quartile, and all of the demographic, clinical, and laboratory variables were entered together. Data from this model were presented as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). First, we conducted this work in the whole population, and then, separately conducted in men and women. All statistical analyses were conducted using SPSS for Windows version 12.0, and statistical significance was accepted at the p b 0.05 level. 3. Results
2.2. Vascular risk factors
3.1. Baseline characteristics
All subjects underwent an intensive interview and appropriate laboratory examinations to identify vascular risk factors. Hypertension was defined as follows: subjects with a prior history of hypertension and those who were prescribed any antihypertensive medications or subjects with a systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg at rest. We classified the subjects with diabetes as either alleged diabetes subjects or subjects with fasting glucose ≥7.0 mmol/L. Dyslipidemia was determined by a prior diagnosis of dyslipidemia, fasting serum low-density lipoprotein (LDL) cholesterol ≥4.1 mmol/L or total cholesterol ≥6.3 mmol/L. Information on past or current history of cigarette smoking was collected. A history of coronary artery disease was elicited based on interview questions on the experience of symptoms and on the previous diagnosis. Medication history included antihypertensive medications or aspirin medication. Resting blood pressure was recorded, and laboratory tests, including hemoglobin, glucose, glycated hemoglobin (hemoglobin A1c), creatinine, high sensitivityC-reactive protein (hs-CRP), total cholesterol, triglyceride, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and uric acid, were conducted. The laboratory tests were conducted after fasting for at least 8 h in order to avoid the effects of diet.
Of the 1577 subjects included in this study, 921 were men and 656 were women (Table 1). The subjects ranged in age from 20 to 86 years (mean, 53.7 ± 10.6 years). The uric acid level ranged from 1.7 to 11.5 mg/dL (mean, 5.6 ± 1.4 mg/dL). The uric acid level was much higher in the men (6.3 ± 1.3) than in the women (4.7 ± 1.0). SBI was identified in 88 subjects (5.6%). Subjects with SBI were more likely to be older and to have hypertension, diabetes, and a history of coronary artery disease. The subjects with SBI were also more likely to exhibit greater increases in blood pressure, glucose level, hemoglobin A1c level, triglyceride level and uric acid level than those without SBI. The level of HDL cholesterol was likely to be lower in subjects with SBI than in those without SBI.
2.3. Diagnosis of SBI MR images were obtained using a 1.5T superconducting magnet (GE Medical Systems, Milwaukee, WI, USA). The imaging protocol used was as follows: T2-weighted spin-echo [repetition time/echo time (TR/TE), 5800/96 ms), T1-weighted spin-echo (TR/TE, 520/ 14 ms), and fluid-attenuated inversion recovery (FLAIR; TR/TE, 8500/96 ms; inversion time, 2100 ms) imaging. The slice thickness was 5 mm, with no interslice gap. The diagnostic process was described in detail in a previous report [14]. In brief, two trained neurologists who were blind to the patients' clinical information assessed the presence of SBI, and the presence of SBI was finally determined by consensus. SBI was defined as a focal lesion measuring 3 mm or more in diameter with signal intensity corresponding to liquor (small cavitary lesions filled with cerebrospinal fluid) [15]. 2.4. Statistical analysis To analyze the baseline characteristics, unpaired student t-tests and χ2 tests were used to compare the prevalence of demographic, clinical, laboratory and radiological variables between men and women, as well as between subjects with SBI and those without. Because there is a substantial difference in the serum level of uric acid between men and women, we basically analyzed the levels of uric acid according to quartiles in men and women separately. Mantel–
3.2. Relationships between uric acid level and SBI We analyzed the uric acid levels according to quartiles in the entire group of subjects and separately in men and women. As illustrated in Fig 1., in the entire group of subjects, the number of subjects with SBI tended to be higher in the highest quartile of uric acid, but the relationship was not significant (Mantel–Haenszel χ2 test, p = 0.070). In the men, there was no difference in the number of subjects with SBI among the quartiles (p = 0.40), but in the women, there was a strong dose–response relationship (p = 0.002). In the men, there was no difference in the level of uric acid between the subjects with SBI (6.3 ± 1.3 mg/dL) and those without (6.3 ± 1.3 mg/dL; p = 0.851). However, in the women, the level of uric acid was significantly higher in the subjects with SBI (5.4 ± 1.2 mg/dL) than in the subjects without (4.6± 1.0 mg/dL; p b 0.001). 3.3. Independent effects of uric acid level on the presence of SBI We examined whether the increased level of uric acid according to the presence of SBI was independent of other important clinical variables. First, we conduct univariate and multivariate analyses in total subjects (Table 2). In this analysis, the highest quartile of uric acid level was an independent risk factor for the presence of SBI (adjusted OR, 1.79; 95% CI 1.11–2.91), and hypertension and history of coronary artery disease were another risk factors. Then, as described above, there were substantial differences in the clinical and laboratory values, including uric acid levels, between the men and women, and multivariable logistic regression analysis was conducted separately in men and women. As shown in Table 3, only age and hypertension were independent risk factors for the presence of SBI among men, and the highest quartile of uric acid level was not associated with the presence of SBI. However, in women, age and the highest quartile of uric acid level were significantly associated with the presence of SBI (adjusted OR, 2.62; 95% 1.17–5.91) (Table 4).
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Table 1 Baseline characteristics. Gender
Gender Age, years Hypertension Diabetes Dyslipidemia History of smoking History of coronary artery disease Medication history Anti-hypertensive agents Aspirin Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Hemoglobin, % Glucose, mg/dL Hemoglobin A1C, % Creatinine Hs-CRP Total cholesterol, mg/dL Triglyceride, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL Uric acid, mg/dL SBI
SBI
Women (n = 656)
Men (n = 921)
None (n = 1489)
Present (n = 88)
NA 54.0 ± 10.4 264 (40.2) 51 (7.8) 110 (16.8) 60 (9.1) 21 (3.2)
NA 53.5 ± 10.7 532 (57.8)a 136 (14.8)a 165 (17.9) 718 (78.0)a 40 (4.3)
621 (41.7) 53.3 ± 10.5 723 (48.6) 162 (10.9) 259 (17.4) 729 (49.0) 50 (3.4)
35 (39.8) 60.7 ± 10.0a 73 (83.0)a 25 (28.4)a 16 (18.2) 49 (55.7) 11 (12.5)a
130 (19.8) 51 (7.8) 120 ± 18 76 ± 12 13.2 ± 1.0 98.5 ± 20.0 5.7 ± 0.8 0.9 ± 0.3 0.13 ± 0.31 202 ± 35 96 ± 60 124 ± 32 58 ± 13a 4.7 ± 1.0 35 (5.3)
192 (20.8) 117 (12.7)a 126 ± 16a 84 ± 12a 15.3 ± 1.2a 107.3 ± 7.9a 5.8 ± 0.9a 1.1 ± 0.2a 0.19 ± 0.49a 200 ± 35 127 ± 81a 125 ± 33a 50 ± 12 6.3 ± 1.3a 53 (5.8)
279 (18.7) 153 (10.3) 126 ± 17 80 ± 12 14.5 ± 1.6 103.0 ± 24.6 5.8 ± 0.9 1.0 ± 0.2 0.16 ± 0.43 201 ± 35 113 ± 72 125 ± 32 53 ± 14a 5.6 ± 1.5 NA
43 (48.9)a 15 (17.0) 135 ± 19a 86 ± 12a 14.3 ± 1.6 114.8 ± 1.6a 6.2 ± 1.2 1.1 ± 0.5 0.20 ± 0.32 204 ± 38 138 ± 105a 127 ± 38 50 ± 9 6.0 ± 1.3a NA
Numbers are presented as means ± standard deviations or frequencies (percentages), as appropriate. χ2 tests were used for categorical variables and student t-tests were used for continuous variables. Hs-CRP indicates high sensitivity-C-reactive protein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; SBI, silent brain infarction; NA, not applicable. a Indicates a significantly higher value after statistical analysis.
4. Discussion Our results revealed a dose-dependent relationship between the serum level of uric acid and the presence of SBI in adult women. There was a substantial difference in uric acid level between the women and men, and the highest quartile of uric acid was an independent risk factor for the presence of SBI in women, but not in men. To our knowledge, this is the first study to show gender differences in the association between uric acid and SBI. Many epidemiological studies have reported that increased levels of uric acid might be associated with an increased risk of cardiovascular disease or stroke [16]. Multivariable analysis of data from the MONICA study (1044 men) showed an independent association between serum uric acid and cardiovascular mortality [17]. A prospective study in the Netherlands recently showed that uric acid was a strong predictor of myocardial infarction and stroke during the
long follow-up period (8.4 years, mean) [18]. In contrast, another retrospective study, which analyzed data from a consecutive series of 881 acute ischemic stroke patients, indicated that there was a 12% increase in the odds of achieving a good clinical outcome at discharge for each milligram per deciliter increase in serum uric acid [7]. In addition, a small randomized controlled study indicated that administration of uric acid and vitamin C selectively improved acetylcholine responses in patients with type 1 diabetes and in regular smokers [19]. Moreover, it is important to consider the substantial experimental evidence that uric acid was beneficial in vitro and in vivo. Uric acid might suppress the accumulation of reactive oxygen species and lipid peroxidation after cerebral ischemia or exposure to glutamate [6], and the administration of uric acid to adult rats before or after focal cerebral ischemia resulted in a significant Table 2 Univariate and multivariate analyses in total patients.
Age (per year) Hypertension Diabetes Dyslipidemia History of smoking History of coronary artery disease Medication of aspirin Systolic blood pressure Diastolic blood pressure Hemoglobin Glucose Hemoglobin A1C Creatinine hs-CRP HDL cholesterol Highest quartile of uric acid Fig. 1. Distribution of the percentages of subjects in each quartile of uric acid level in the entire study group, men and women.
Univariate
Multivariate
Unadjusted OR 95% CI
Adjusted OR 95% CI
1.07 5.16 3.25 1.06 1.31 4.11
(1.05–1.10) (2.93–9.07) (1.99–5.31) (0.60–1.84) (0.85–2.02) (2.06–8.21)
1.05 2.58 1.63 0.91 1.20 2.53
(1.02–1.08) (1.26–5.30) (0.80–3.29) (0.50–1.65) (0.72–1.99) (1.18–5.40)
1.79 1.04 1.04 0.96 1.01 1.44 1.69 1.18 0.98 1.80
(1.00–3.21) (1.03–1.05) (1.02–1.06) (0.84–1.09) (1.01–1.02) (1.21–1.70) (1.05–2.73) (0.83–1.68) (0.96–0.99) (1.15–2.82)
0.85 1.01 1.00 0.91 1.01 0.96 1.33 0.94 0.98 1.79
(0.45–1.59) (0.99–1.03) (0.97–1.03) (0.78–1.06) (0.99–1.02) (0.66–1.39) (0.77–2.30) (0.59–1.51) (0.97–1.00) (1.11–2.91)
Hs-CRP indicates high sensitivity-C-reactive protein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; SBI, silent brain infarction.
S.H. Heo, S.-H. Lee / Journal of the Neurological Sciences 297 (2010) 6–10 Table 3 Multivariable analysis in men.
Age (per year) Hypertension Diabetes Dyslipidemia History of smoking History of coronary artery disease Medication of aspirin Systolic blood pressure Diastolic blood pressure Hemoglobin Glucose Hemoglobin A1C Creatinine hs-CRP HDL cholesterol Highest quartile of uric acid
Adjusted OR
95% CI
p
1.04 3.01 1.27 0.64 1.62 2.48 1.24 1.02 0.99 1.04 1.01 1.02 2.58 0.93 1.00 1.25
(1.00–1.08) (1.09–8.28) (0.51–3.15) (0.27–1.52) (0.73–3.60) (0.98–6.27) (0.60–2.57) (0.99–1.04) (0.96–1.03) (0.81–1.33) (0.99–1.02) (0.65–1.60) (0.94–7.10) (0.48–1.81) (0.97–1.03) (0.63–2.49)
0.03 0.03 0.61 0.31 0.24 0.05 0.57 0.30 0.76 0.78 0.25 0.94 0.07 0.83 0.95 0.53
Hs-CRP indicates high sensitivity-C-reactive protein; HDL, high-density lipoprotein; SBI, silent brain infarction.
reduction of the infarction volume and improved behavioral scale scores [6]. Despite these observations, a previous study suggested that uric acid is likely to be harmful, at least in humans, especially in patients with cardiovascular disease or stroke [16], and our results support this suggestion. Although serum uric acid possesses antioxidant properties, several harmful mechanisms have been proposed experimentally. Uric acid was found to promote LDL oxidation in vitro [20] and to stimulate granulocyte adherence to the endothelium [21], as well as peroxide and superoxide free radical liberation [21]. However, another plausible explanation is that tissue injury, especially in ischemic lesions, may increase the level of uric acid [22]. Adenosine, which serves as an arteriolar vasodilator, is increasingly generated by cardiac and visceral ischemia, and it is in turn rapidly degraded by the endothelium to uric acid, which undergoes rapid efflux to the vascular lumen [23]. Therefore, serum uric acid may act as a marker of underlying tissue ischemia, but there has been no evidence to support this claim found in the brain. The results of this study indicated that an increased level of uric acid might not be a risk factor for SBI, but rather a product of SBI. According to this hypothesis, uric acid might not be an active substance that is either harmful or beneficial to the brain, but rather just a serum marker of SBI. However, we do not believe that this was the case in this study because the association between uric acid and SBI was present only in women. The absence of an association in men cannot be easily understood. Even if the increased level of uric acid was only a product of an underlying ischemic lesion in the brain, Table 4 Multivariable analysis in women.
Age (per year) Hypertension Diabetes Dyslipidemia History of smoking History of coronary artery disease Medication of aspirin Systolic blood pressure Diastolic blood pressure Hemoglobin Glucose Hemoglobin A1C Creatinine hs-CRP HDL cholesterol Highest quartile of uric acid
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it may not change the hypothesis that uric acid may be a serum marker of future stroke because SBI is a well-established, radiologic marker of future stroke [9]. It is very interesting that the increased level of uric acid was associated with SBI only in women. Generally speaking, there has been no difference in the association between uric acid and SBI in men and women, but our results showed a clear difference between genders. A post hoc analysis of the LIFE trial indicated that the association between the level of uric acid and cardiovascular outcomes was significant only in women after adjustment of the Framingham risk score [24]. Uric acid levels generally increase with age, and premenopausal women have lower levels of uric acid than age-matched men because of the uricosuric effect of estrogen [25]. It may be associated with the differences in the effect of uric acid between men and women, but the exact underlying mechanisms should be further investigated. Our study has some caveats to be acknowledged. First, our database did not include information on the patients' history of diuretics or statins. Some prior results indicated that thiazide diuretics may be an important confounder of the association between uric acid and cardiovascular risk [26–28]. In addition, the effects of statins on SBI have not yet been established, but the information would have improved our results. Second, this study collected data on a consecutive series, but they were recruited from a single health care centre, which was not representative of the general population. Moreover, number of subjects with SBI was only 88 patients among a total of 1577 subjects. This small positivity might limit the power of the study results to be generalized. Finally, uric acid has a very low solubility, which might be a barrier to use of uric acid as a neuroprotective agent [29]. In this context, due to this limited solubility, there might be less scope for uric acid concentrations to rise in men who have higher baseline concentrations than women. Our results suggest that the increased level of uric acid may be a risk factor for the presence of SBI in women. The presence of SBI is an excellent radiologic marker of future stroke [9], but general application of MR imaging is limited because of its high cost. Serum uric acid level would be a good serum marker of underlying SBI or future stroke in women. In addition, clinical trials on lowering uric acid level to prevent incident vascular events should be conducted in this context. Acknowledgements This study was supported by grants of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A090529). We specially thank to Dr. Beom Joon Kim for his intellectual comments. References
Adjusted OR
95% CI
p
1.06 2.62 2.42 1.49 1.72 1.92 0.30 1.01 1.01 0.84 1.00 0.89 0.48 1.06 0.96 2.62
(1.01–1.11) (0.86–7.98) (0.74–7.96) (0.61–3.65) (0.51–5.72) (0.44–8.34) (0.06–1.44) (0.97–1.04) (0.96–1.06) (0.60–1.16) (0.97–1.03) (0.46–1.75) (0.02–15.58) (0.47–2.43) (0.93–0.99) (1.17–5.91)
0.01 0.09 0.15 0.38 0.38 0.38 0.13 0.77 0.73 0.29 0.95 0.74 0.68 0.88 0.02 0.02
Hs-CRP indicates high sensitivity-C-reactive protein; HDL, high-density lipoprotein; SBI, silent brain infarction.
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