Acta Neurol Scand 2013: 130: 11–17 DOI: 10.1111/ane.12208
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Association of uric acid and carotid artery disease in patients with ischemic stroke Kumral E, Karaman B, Orman M, Kabaroglu C. Association of uric acid and carotid artery disease in patients with ischemic stroke. Acta Neurol Scand 2014: 130: 11–17. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background and purpose – Some previous studies reported an independent association between uric acid and coronary artery disease, while little is known on the association among uric acid and carotid artery disease (CAD). To address this issue, we investigated the association between CAD and higher uric acid level because of the well-known importance of the carotid artery pathologies for ischemic stroke. Methods – Between 2009 and 2012, we conducted a study among 406 consecutive first-ever ischemic stroke patients to assess the relationship between uric acid and carotid artery. A mean intimamedia thickness IMT was calculated for the wall of the left and right common carotid arteries (CCA) and IMT of the bifurcation of the carotid arteries. CAD was assessed by neuroimaging techniques in patients with carotid artery stenosis more than 50%. Logistic regression models were used to determine the relation among pathological changes of the carotid artery and higher uric acid level. Results – In patients with hyperuricemia, the frequency of age (>60 years), hypertriglyceridemia, higher apo B, renal failure were significantly higher than those with normal uric acid level. CAD was more frequent in patients with hyperuricemia than those with normal uric acid level (OR, 1.8, 95% CI, 1.1–3.1; P = 0.01). In patients with higher uric acid level, the mean of the IMT of the CCA and of the bifurcation of the carotid artery were higher than those with normal uric acid level (P = 0.001 for each). Covariance matrix analysis displayed a strong correlation between CAD and age (>60 years) (P < 0.05), sex (P < 0.01), hyperuricemia (P < 0.01), hypertension (P < 0.05), and hypercholesterolemia (P < 0.05). In the models of regression analysis, a strong association was found among patients with CAD and sex, renal failure, hyperuricemia, number of plaques, and size of plaques. Conclusion – Our study demonstrated that higher uric acid level is strongly associated with CAD. Elevated uric acid might be injurious for large cerebral arteries with some probable confounding risk factors. Further prospective large clinical trials will determine whether lowering uric acid level reduces the frequency of CAD and ischemic stroke.
Introduction
It is well known that higher uric acid level is associated with hypertension and kidney dysfunction (1–3). Some studies reported an independent association between uric acid and coronary heart disease (4–7), but others only found an association in women (8), and in yet others, the associations
E. Kumral1, B. Karaman1, M. Orman2, C. Kabaroglu3 1 Stroke Unit, Department of Neurology, School of Medicine, Ege University, _Izmir, Turkey; 2Department of Biostatistic, School of Medicine, Ege University, _Izmir, Turkey; 3Department of Clinical Biochemistry, School of Medicine, Ege University, _Izmir, Turkey
Key words: Carotis stenosis; Cerebrovascular diseases; Ischemic stroke E. Kumral, Stroke Unit, Department of Neurology, Ege University, Faculty of Medicine, Bornova, Izmir 35100, Turkey Tel.: +90-532.2165213 Fax: +90-232.4634626 e-mail: [email protected] Accepted for publication November 7, 2013
disappeared after adjustment for confounders (9, 10). There is relatively little information on the role of uric acid as a risk factor for stroke. For instance, hyperuricemia by itself has generally been regarded as insignificant or incidental for ischemic stroke. Previous studies showed an association between uric acid and stroke risk in diabetics (11), and between uric acid and fatal stroke in 11
Kumral et al. the general population (12); moreover, a population-based study in elderly persons demonstrated an association between uric acid and stroke (13). However, the role of uric acid as a risk factor for carotid artery disease (CAD) is not well known. We sought the association between higher uric acid level and CAD in patients with ischemic stroke because of the assumed importance of carotid disease in the pathogenesis of ischemic stroke.
apo B, lipoprotein (a), glucose, creatinine, fasting glucose, HbA1c, plasma homocysteine levels were measured with commercial chemistry kits (Modular, Roche, Boehringer-Mannheim, Germany). Hyperlipidemia was defined as total cholesterol ≥200 mg/dl, triglycerides ≥ 160 mgl/dl, HDL cholesterol ≤ 40 mg/dl, LDL cholesterol ≥ 160 mg/dl, apolipoprotein A (apo A) ≤ 110 mg/dl, apolipoprotein B (apo B) ≥ 120 mg/dl, lipoprotein (a) [Lp (a)] ≥ 30, or use of lipid-lowering drugs.
Materials and methods
Uric acid
Five hundred and seventy-five consecutive patients with first-ever ischemic stroke were studied in our Neurology Department, University Medical Center (14). We excluded 169 participants who had diagnosis of cryptogenic stroke and other type of stroke (hematological, dissections, vasculitis, etc.), because these participants were scarcely represented different pathophysiological mechanisms rather than CAD (or large artery disease), small artery disease (SAD), and cardioembolism (CE) (15, 16). Patients with no history of a gout attack for at least the previous 4 weeks and consumption of not more than 60 ml of alcohol per day were included. Four hundred and six patients were used in the present analyses. Prospectively recorded variables contained age, gender, blood pressure, cigarette smoking, blood chemistry, vascular risk factors, clinical subtypes, and topography of infarcts regarding to magnetic resonance imaging studies. The baseline examinations, definitions of vascular disease, risk factors, and carotid ultrasonography are described briefly below. Patients >90 years of age and those with a terminal malignancy were not enrolled. The study was approved by the Ethics Committee of the Ege University Medical Center, and written informed consent was obtained from all the participants.
We defined hyperuricemia as a serum uric acid concentration of >7.2 mg/dl in men or >6.6 mg/ dl in women, as measured by enzymatic–colorimetric methods (11). None of the patients was being treated with either uricosuric agents or xanthine oxidase inhibitors. Of the hyperuricemic patients, 26% (18 of 69) received colchicine for the prevention of acute gout attack; no other medications or vasoactive agents were taken.
Vascular risk factors
Blood pressure, diabetes mellitus, obesity, physical activity, current cigarette smoking, uric acid were recorded. A venous blood sample was collected after an overnight fast of ≥8 h. Hypertension was presumed as systolic pressure ≥160 mmHg or diastolic pressure ≥95 mmHg or taking antihypertensive drugs. Diabetes mellitus was specified as fasting serum glucose ≥125 mg/dl, non-fasting serum glucose ≥200 mg/dl, or use of oral blood sugar-lowering drugs or insulin. Serum total cholesterol, LDL-C, HDL-C, triglycerides, apo A, 12
Stroke subtypes
Stroke subtype classification was primarily based on the etiological subtypes as defined before (16). Carotid artery disease (CAD) was presumed in patients with carotid artery stenosis >50%. Cardiac embolism (CE) included mainly nonvalvular atrial fibrillation, left ventricular akinetic segment, intracardiac thrombus or tumor, mitral stenosis, and other less common sources. Small artery disease (SAD) was defined in patients with infarcts of 7 MHz. Appropriate depth of focus (30–40 mm), frame rate optimally 25 Hz (1 15 Hz), and gain settings (minimal intraluminal artifacts) are recommended to obtain optimal image quality. An R-wave-triggered optimal longitudinal image of the far-wall was frozen.
Uric acid and carotid artery disease On this image, the sonographer traced the leading edges corresponding to the transition zones between lumen-intima and media-adventitia. The total intima-media surface of this selected area was calculated online by built-in software of the ultrasound system. A mean intima-media thickness (IMT) was calculated for each patient based on six far-wall measurements of the left and right CCA and IMT of the bifurcation at the beginning of the dilatation of the carotid arteries as described previously (17). In case of missing data at anyof the six measurements, the mean IMT of the available values was calculated. Plaque was defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the mediaadventitia interface to the intima-lumen interface. To define internal carotid artery stenosis ≥50%, we used the systolic velocity (>125 cm/s), and for the internal carotid artery/common carotid artery we used the systolic velocity ratio (>2) (18). In all patients, additional neurovascular explorations such as magnetic resonance angiography or CT angiography were performed. Statistics
Pearson chi-square test, Student’s t-test, one-way ANOVA or Fisher exact test when appropriate were used to assess relationships between variables. The post hoc analysis was made by Bonferroni and Tukey’s tests and pairwise multiple comparisons to assess which means differ. Significance was established at the P < 0.05 level. All relevant values were presented as the mean SD. The differences of carotid ultrasound findings in normal and hyperuricemic patients were examined by chi-square test and ANOVA test. In the second analysis, logistic regression analysis by forward stepwise method (likelihood ratio) was used to find the association among CAD and risk factors, etiologies of stroke and carotid artery examination findings. In the linear regression model, CAD was used as dependent variable, and covariates were age (>60 years old), sex, hypertension, diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, higher apo A and B, renal failure, IMT of the CCA and IMT of the bifurcation, size of plaques, and number of plaques. Pearson correlation analysis with a one-tailed significance level and the number of cases for each correlation are displayed. Regression coefficient B, t-value for B, and two-tailed significance level of t, confidence intervals for each regression coefficient were calculated. Linear
regression coefficients were used to estimate odds ratios for each of the independent variables in the model. All the statistical analyses were performed using SPSS 16.0 (SPSS Inc.) (19). Results
We studied 406 patients with a median age of 66 11 (range, 40–90 years), among them 243 (60%) were male. Vascular risk factors in patients with higher and normal uric acid level were presented in Table 1. In patients with higher uric acid, the frequency of age (>60 years), hypertriglyceridemia, higher apoB, renal failure were significantly higher than those with normal uric acid level. The frequency of CAD was significantly higher in patients with hyperuricemia than those with normal uric acid level (OR, 1.8, 95% CI, 1.1–3.1; P = 0.01), but not in patients with SAD (OR, 0.6 95% CI, 0.4–1.1; P = 0.053) and in those with CE (OR, 0.9, 95% CI, 0.5–1.5; P = 0.34). The mean of the IMT of the CCA was higher than those with normal uric acid level (0.8 0.3 vs 0.7 0.2; P = 0.001). In patients with hyperuricemia, the mean of the IMT of the bifurcation was significantly higher than those with normal uric acid level (0.9 0.3 vs 0.8 0.2; P = 0.001). The mean of the size of plaques and number of plaques in the CCA and bifurcation were also significantly higher in patients with hyperuricemia than those with normal uric acid level (P = 0.002 and P = 0.05, respectively) (Table 2). Pearson correlation analysis showed a significant correlation among CAD and age (>60 years), sex, hyperuricemia, hypertension, and hypercholesterolemia. There was a strong association between CAD and IMT of the CCA and bifurcation of the carotid artery, number of plaques, and size of plaques (Table 3). Linear regression analysis to predict the relationship between variables showed that CAD had significant association with hyperuricemia (P = 0.03), renal failure (P = 0.01), number of plaques (P = 0.001), and size of plaques (P = 0.001) after excluding other covariates in the first model. In the second model of the analysis, CAD was associated with sex (P = 0.04), renal failure (P = 0.001), hyperuricemia (P = 0.03), number of plaques (P = 0.001), and size of plaques (P = 0.003) (Table 4). Discussion
At the time that the first studies were published, uric acid was regarded as a biologically inert 13
Kumral et al. Table 1 Baseline characteristics of patients Characteristics
Patients with normal uric acid (n = 331)
TIA Retinal ischemia Male, No (%) Age, year [mean SD, (range)] Cause of stroke Carotid artery disease Small-artery disease Cardioembolism Hypertension1 Diabetes mellitus2 Cigarette smoking History of CHD3 Atrial fibrillation Hypercholesterolemia4 Hypertriglyceridemia Higher LDL-C Lower HDL-C Lower apo A Higher apo B Lipoprotein (a) Hyperhomocysteinemia Obesity Diabetic foot Physical activity absence5 Renal failure6
Patients with hyperuricemia (n = 75)
P
38 20 197 65
(12) (6) (60) 11 (40–90)
7 2 46 68
(10) (3) (61) 10 (44–87)
0.4 0.2 0.5 0.05
99 142 90 267 139 67 70 63 194 141 135 226 257 122 69 60 79 15 97 66
(30) (43) (27) (81) (42) (22) (21) (19) (59) (43) (41) (68) (78) (37) (21) (18) (24) (5) (29) (20)
33 24 18 62 30 15 22 13 45 42 30 50 55 36 21 15 20 4 20 22
(44) (32) (24) (83) (40) (13) (29) (19) (60) (56) (40) (67) (73) (48) (28) (20) (27) (6) (28) (30)
0.01 0.053 0.34 0.42 0.43 0.07 0.09 0.6 0.5 0.02 0.5 0.4 0.3 0.05 0.12 0.4 0.35 0.4 0.5 0.05
CHD, coronary heart disease; CAD, carotid artery disease; SAD, small artery disease. Values in parenthesis are percentage of column. Risk factors definition. 1 Systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 95 mmHg or taking antihypertensive drugs. 2 Fasting serum glucose ≥ 125 mg/dl, non-fasting serum glucose ≥ 200 mg/dl or taking insulin therapy or oral blood sugar-lowering drugs. 3 History of myocardial infarction or angina pectoris. 4 Total cholesterol ≥ 200 mg/dl, triglycerides ≥ 160 mgl/dl, HDL cholesterol ≤ 40 mg/dl, LDL cholesterol ≥ 160 mg/dl, apoA ≤ 110 mg/dl, apoB ≥ 120 mg/dl, Lp(a) ≥ 30 or taking lipid-lowering drugs. 5 Physical activity: walking 3–4 times/1 h/week. 6 Creatinine clearance (CLcr) < 30 ml/min.
Table 2 Doppler ultrasound findings in patients with higher uric acid level vs those with lower uric acid level Patients with normal uric acid level1 IMT-CCA (mm) IMT-Bif (mm) Number of plaques (N) Size of plaques (mm)
0.7 0.8 1.3 7.1
Patients with higher uric acid level
2
0.2 (0.1–1.3) 0.2 (0.1–1.4) 0.9 (0–3) 6 (1–20)
0.8 0.9 1.6 10
0.3 0.3 1.2 6.1
(0.1–1.3) (0.3–1.5) (0–4) (1–21)
P 0.001 0.001 0.05 0.002
Bif, Bifurcation of the carotid artery; CCA, Common carotid artery; IMT, Intima-media thickness; N, Number. Values are mean SD. 2 Values in parentheses are 95% CI for mean (upper bound-lower bound). 1
molecule. In course of time, an increasing evidence showed that an elevation of uric acid may cause primary hypertension which is the most common cause of stroke (20–25). However, we found that in patients with hyperuricemia and in those with normal uric acid level the frequency of hypertension was not significantly different. Regarding this finding, we can never be sure that hypertension is the only factor causing stroke in hyperuricemic subjects. Moreover, we do think that the impact of uric acid on the 14
CAD has been demonstrated convincingly regarding our results. The last studies noted that the association between uric acid and stroke is most pronounced in normotensive subjects (13). In addition, they found that the effect of uric acid on stroke risk was lower in persons with hypertension. This finding was supported by the observation in rats by a renal mechanism linked to inhibition of nitric oxide, activation of the renin–angiotensin system, and development of renal arteriolosclerosis (26).
Table 4 Linear regression models of findings in patients with carotid artery disease
0172** 0.193** 0.012 0.077 0.041 0.069 0.065 0.089* 0.178** 0.628** 1.000
Number of plaques
Uric acid and carotid artery disease
Standardized coefficients
0.165** 0.085* 0.003 0.079 0.167** 0.03 0.032 0.837** 1.000 0.138** 0.071 0.002 0.041 0.163** 0.028 0.003 1.000
0.538** 0.82* 0.125** 0.069 0.044 0.049 0.024 0.109* 0.185** 1.000
Model 1 Renal failure Hyperuricemia Size of plaques Number of plaques Model 2 Sex Renal failure Hyperuricemia Size of plaques Number of plaques
IMT, intima-media thickness; CAD, Coronary artery disease; CCA, common carotid artery. *P < 0.05. **P < 0.01.
Carotid artery disease Age Sex Hypertension Hyperuricemia Hypercholesterolemia CAD IMT-CCA IMT-bifurcation Size of plaques Number of plaques
1.000
0.085* 1.000
0.161** 0.036 1.000
0.81* 0.18** 0.04 1.000
0.124** 0.106* 0.009 0.03 1.000
0.104* 0.009 0.06 0.055 0.006 1.000
0.037 0.158** 0.001 0.052 0.061 0.058 1.000
IMT – bifurcation Hypercholesterolemia Hyperuricemia Hypertension Sex Age Carotid artery disease
Table 3 Pearson correlation analysis of patients with carotid artery disease regarding to vascular risk factors and carotid artery findings
CAD
IMT-CCA
Size of plaques
Exp (B)
95% Confidence interval for B
Significance
Lower bound
Upper bound
0.117 0.104 0.516 0.28
0.01 0.03 0.001 0.001
0.03 0.01 0.59 0.18
0.21 0.19 0.44 0.38
0.08 0.134 0.1 0.5 0.27
0.04 0.001 0.03 0.001 0.001
0.003 0.62 0.009 0.58 0.18
0.16 0.24 0.2 0.43 0.37
Once the renal arteriolosclerosis develops, the kidney drives the hypertension, and lowering uric acid is no longer protective. A study reported that the admission serum uric acid also independently predicted worse outcome and a higher rate of repeated stroke or other cardiovascular event (23). Others have also reported that a higher uric acid level in patients with acute stroke is associated with poorer outcome (24). These studies suggest that uric acid may be a true risk factor for stroke and for a poor outcome after stroke. But none of the studies has explained why and how the uric acid may cause poor outcome and higher rate of repeated stroke. Regarding to our finding, pathological changes in the carotid artery were significantly associated with higher uric acid level. Moreover, IMT of the wall of the bifurcation is strongly associated with hyperuricemia suggesting the accelerating role of higher uric acid level on the process of carotid atherosclerosis. Large vessel involvement may be the consequence of hyperuricemia which stimulates synthesis of monocyte chemoattractant protein-1 by rat vascular smooth muscle cells (27), which is known to have a key role in stimulating macrophage infiltration in atherosclerotic vessels (28, 29), particularly in the large vessels of the brain. There is also other potential pathogenetic mechanism to explain why an elevated serum uric acid at the time of stroke may be injurious. Recent evidence suggests that acute ischemic stroke results in generation of local oxidants that augment local injury and increase infarct size (30). Acute stroke is associated with a rapid decrease in serum antioxidants (31, 32) which recover slowly over the subsequent week (33, 34). Uric acid is often considered an antioxidant and has been shown to scavenge hydrogen 15
Kumral et al. peroxide and hydroxyl radicals, to block nitrotyrosine formation from peroxynitrite, and to preserve extracellular superoxide dismutase (35, 36). One might therefore expect that having elevated uric acid during an acute stroke would be beneficial. However, only one small study has reported that elevated uric acid is associated with good outcome after an ischemic stroke (37), whereas three other studies found the opposite (23, 33, 38). A recent study showed that low serum uric acid concentration is modestly associated with a very good short-term outcome supporting the hypothesis that uric acid is more a marker of the magnitude of the cerebral infarction than an independent predictor of stroke outcome (39). We did not assess the magnitude of the cerebral infarction at acute stroke period; howbeit, our study showed strong evidence that an elevated uric acid is associated with CAD (large artery disease) which may yield to large cerebral lesions. In our study, we limited analysis to three stroke subtypes, and there was no follow-up of patients to determine repeated stroke and outcome. While our stringent stroke monitoring procedures allowed us to include stroke patients with definite diagnosis of stroke subtypes and carotid pathologies, while most of the previous studies neuroimaging was often lacking and examinations not thorough enough to classify strokes. Uric acid examinations were performed in the first week of stroke in all patients and we think that this provided a homogeneity for the study. In conclusion, our data suggest that higher uric acid level is strongly associated with CAD promoting IMT and plaque formation changes in patients with ischemic stroke. Additional prospective large clinical trials are required to determine whether lowering uric acid level reduces the frequency of the CAD and stroke. Authors contribution
Principal author: Emre Kumral M.D., Study concept or design: Emre Kumral M.D., Acquisition of data: Ceyda Kabaroglu M.D., Bedriye Karaman M.D., Analysis or interpretation of data: Bedriye Karaman M.D., Statistical analysis: Mehmet Orman M.D. PhD., Study supervision or coordination: Emre Kumral M.D., Ceyda Kabaroglu M.D. Conflict of interest
We have no actual or potential conflicts of interest for all authors involved in this paper. 16
Funding
Emre Kumral M.D., Bedriye Karaman M.D., Mehmet Orman M.D., Ceyda Kabaroglu M.D. did not receive funding disclosure Ethical committee approval
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© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Association of uric acid and carotid artery disease in patients with ischemic stroke Kumral E, Karaman B, Orman M, Kabaroglu C. Association of uric acid and carotid artery disease in patients with ischemic stroke. Acta Neurol Scand 2014: 130: 11–17. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background and purpose – Some previous studies reported an independent association between uric acid and coronary artery disease, while little is known on the association among uric acid and carotid artery disease (CAD). To address this issue, we investigated the association between CAD and higher uric acid level because of the well-known importance of the carotid artery pathologies for ischemic stroke. Methods – Between 2009 and 2012, we conducted a study among 406 consecutive first-ever ischemic stroke patients to assess the relationship between uric acid and carotid artery. A mean intimamedia thickness IMT was calculated for the wall of the left and right common carotid arteries (CCA) and IMT of the bifurcation of the carotid arteries. CAD was assessed by neuroimaging techniques in patients with carotid artery stenosis more than 50%. Logistic regression models were used to determine the relation among pathological changes of the carotid artery and higher uric acid level. Results – In patients with hyperuricemia, the frequency of age (>60 years), hypertriglyceridemia, higher apo B, renal failure were significantly higher than those with normal uric acid level. CAD was more frequent in patients with hyperuricemia than those with normal uric acid level (OR, 1.8, 95% CI, 1.1–3.1; P = 0.01). In patients with higher uric acid level, the mean of the IMT of the CCA and of the bifurcation of the carotid artery were higher than those with normal uric acid level (P = 0.001 for each). Covariance matrix analysis displayed a strong correlation between CAD and age (>60 years) (P < 0.05), sex (P < 0.01), hyperuricemia (P < 0.01), hypertension (P < 0.05), and hypercholesterolemia (P < 0.05). In the models of regression analysis, a strong association was found among patients with CAD and sex, renal failure, hyperuricemia, number of plaques, and size of plaques. Conclusion – Our study demonstrated that higher uric acid level is strongly associated with CAD. Elevated uric acid might be injurious for large cerebral arteries with some probable confounding risk factors. Further prospective large clinical trials will determine whether lowering uric acid level reduces the frequency of CAD and ischemic stroke.
Introduction
It is well known that higher uric acid level is associated with hypertension and kidney dysfunction (1–3). Some studies reported an independent association between uric acid and coronary heart disease (4–7), but others only found an association in women (8), and in yet others, the associations
E. Kumral1, B. Karaman1, M. Orman2, C. Kabaroglu3 1 Stroke Unit, Department of Neurology, School of Medicine, Ege University, _Izmir, Turkey; 2Department of Biostatistic, School of Medicine, Ege University, _Izmir, Turkey; 3Department of Clinical Biochemistry, School of Medicine, Ege University, _Izmir, Turkey
Key words: Carotis stenosis; Cerebrovascular diseases; Ischemic stroke E. Kumral, Stroke Unit, Department of Neurology, Ege University, Faculty of Medicine, Bornova, Izmir 35100, Turkey Tel.: +90-532.2165213 Fax: +90-232.4634626 e-mail: [email protected] Accepted for publication November 7, 2013
disappeared after adjustment for confounders (9, 10). There is relatively little information on the role of uric acid as a risk factor for stroke. For instance, hyperuricemia by itself has generally been regarded as insignificant or incidental for ischemic stroke. Previous studies showed an association between uric acid and stroke risk in diabetics (11), and between uric acid and fatal stroke in 11
Kumral et al. the general population (12); moreover, a population-based study in elderly persons demonstrated an association between uric acid and stroke (13). However, the role of uric acid as a risk factor for carotid artery disease (CAD) is not well known. We sought the association between higher uric acid level and CAD in patients with ischemic stroke because of the assumed importance of carotid disease in the pathogenesis of ischemic stroke.
apo B, lipoprotein (a), glucose, creatinine, fasting glucose, HbA1c, plasma homocysteine levels were measured with commercial chemistry kits (Modular, Roche, Boehringer-Mannheim, Germany). Hyperlipidemia was defined as total cholesterol ≥200 mg/dl, triglycerides ≥ 160 mgl/dl, HDL cholesterol ≤ 40 mg/dl, LDL cholesterol ≥ 160 mg/dl, apolipoprotein A (apo A) ≤ 110 mg/dl, apolipoprotein B (apo B) ≥ 120 mg/dl, lipoprotein (a) [Lp (a)] ≥ 30, or use of lipid-lowering drugs.
Materials and methods
Uric acid
Five hundred and seventy-five consecutive patients with first-ever ischemic stroke were studied in our Neurology Department, University Medical Center (14). We excluded 169 participants who had diagnosis of cryptogenic stroke and other type of stroke (hematological, dissections, vasculitis, etc.), because these participants were scarcely represented different pathophysiological mechanisms rather than CAD (or large artery disease), small artery disease (SAD), and cardioembolism (CE) (15, 16). Patients with no history of a gout attack for at least the previous 4 weeks and consumption of not more than 60 ml of alcohol per day were included. Four hundred and six patients were used in the present analyses. Prospectively recorded variables contained age, gender, blood pressure, cigarette smoking, blood chemistry, vascular risk factors, clinical subtypes, and topography of infarcts regarding to magnetic resonance imaging studies. The baseline examinations, definitions of vascular disease, risk factors, and carotid ultrasonography are described briefly below. Patients >90 years of age and those with a terminal malignancy were not enrolled. The study was approved by the Ethics Committee of the Ege University Medical Center, and written informed consent was obtained from all the participants.
We defined hyperuricemia as a serum uric acid concentration of >7.2 mg/dl in men or >6.6 mg/ dl in women, as measured by enzymatic–colorimetric methods (11). None of the patients was being treated with either uricosuric agents or xanthine oxidase inhibitors. Of the hyperuricemic patients, 26% (18 of 69) received colchicine for the prevention of acute gout attack; no other medications or vasoactive agents were taken.
Vascular risk factors
Blood pressure, diabetes mellitus, obesity, physical activity, current cigarette smoking, uric acid were recorded. A venous blood sample was collected after an overnight fast of ≥8 h. Hypertension was presumed as systolic pressure ≥160 mmHg or diastolic pressure ≥95 mmHg or taking antihypertensive drugs. Diabetes mellitus was specified as fasting serum glucose ≥125 mg/dl, non-fasting serum glucose ≥200 mg/dl, or use of oral blood sugar-lowering drugs or insulin. Serum total cholesterol, LDL-C, HDL-C, triglycerides, apo A, 12
Stroke subtypes
Stroke subtype classification was primarily based on the etiological subtypes as defined before (16). Carotid artery disease (CAD) was presumed in patients with carotid artery stenosis >50%. Cardiac embolism (CE) included mainly nonvalvular atrial fibrillation, left ventricular akinetic segment, intracardiac thrombus or tumor, mitral stenosis, and other less common sources. Small artery disease (SAD) was defined in patients with infarcts of 7 MHz. Appropriate depth of focus (30–40 mm), frame rate optimally 25 Hz (1 15 Hz), and gain settings (minimal intraluminal artifacts) are recommended to obtain optimal image quality. An R-wave-triggered optimal longitudinal image of the far-wall was frozen.
Uric acid and carotid artery disease On this image, the sonographer traced the leading edges corresponding to the transition zones between lumen-intima and media-adventitia. The total intima-media surface of this selected area was calculated online by built-in software of the ultrasound system. A mean intima-media thickness (IMT) was calculated for each patient based on six far-wall measurements of the left and right CCA and IMT of the bifurcation at the beginning of the dilatation of the carotid arteries as described previously (17). In case of missing data at anyof the six measurements, the mean IMT of the available values was calculated. Plaque was defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the mediaadventitia interface to the intima-lumen interface. To define internal carotid artery stenosis ≥50%, we used the systolic velocity (>125 cm/s), and for the internal carotid artery/common carotid artery we used the systolic velocity ratio (>2) (18). In all patients, additional neurovascular explorations such as magnetic resonance angiography or CT angiography were performed. Statistics
Pearson chi-square test, Student’s t-test, one-way ANOVA or Fisher exact test when appropriate were used to assess relationships between variables. The post hoc analysis was made by Bonferroni and Tukey’s tests and pairwise multiple comparisons to assess which means differ. Significance was established at the P < 0.05 level. All relevant values were presented as the mean SD. The differences of carotid ultrasound findings in normal and hyperuricemic patients were examined by chi-square test and ANOVA test. In the second analysis, logistic regression analysis by forward stepwise method (likelihood ratio) was used to find the association among CAD and risk factors, etiologies of stroke and carotid artery examination findings. In the linear regression model, CAD was used as dependent variable, and covariates were age (>60 years old), sex, hypertension, diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, higher apo A and B, renal failure, IMT of the CCA and IMT of the bifurcation, size of plaques, and number of plaques. Pearson correlation analysis with a one-tailed significance level and the number of cases for each correlation are displayed. Regression coefficient B, t-value for B, and two-tailed significance level of t, confidence intervals for each regression coefficient were calculated. Linear
regression coefficients were used to estimate odds ratios for each of the independent variables in the model. All the statistical analyses were performed using SPSS 16.0 (SPSS Inc.) (19). Results
We studied 406 patients with a median age of 66 11 (range, 40–90 years), among them 243 (60%) were male. Vascular risk factors in patients with higher and normal uric acid level were presented in Table 1. In patients with higher uric acid, the frequency of age (>60 years), hypertriglyceridemia, higher apoB, renal failure were significantly higher than those with normal uric acid level. The frequency of CAD was significantly higher in patients with hyperuricemia than those with normal uric acid level (OR, 1.8, 95% CI, 1.1–3.1; P = 0.01), but not in patients with SAD (OR, 0.6 95% CI, 0.4–1.1; P = 0.053) and in those with CE (OR, 0.9, 95% CI, 0.5–1.5; P = 0.34). The mean of the IMT of the CCA was higher than those with normal uric acid level (0.8 0.3 vs 0.7 0.2; P = 0.001). In patients with hyperuricemia, the mean of the IMT of the bifurcation was significantly higher than those with normal uric acid level (0.9 0.3 vs 0.8 0.2; P = 0.001). The mean of the size of plaques and number of plaques in the CCA and bifurcation were also significantly higher in patients with hyperuricemia than those with normal uric acid level (P = 0.002 and P = 0.05, respectively) (Table 2). Pearson correlation analysis showed a significant correlation among CAD and age (>60 years), sex, hyperuricemia, hypertension, and hypercholesterolemia. There was a strong association between CAD and IMT of the CCA and bifurcation of the carotid artery, number of plaques, and size of plaques (Table 3). Linear regression analysis to predict the relationship between variables showed that CAD had significant association with hyperuricemia (P = 0.03), renal failure (P = 0.01), number of plaques (P = 0.001), and size of plaques (P = 0.001) after excluding other covariates in the first model. In the second model of the analysis, CAD was associated with sex (P = 0.04), renal failure (P = 0.001), hyperuricemia (P = 0.03), number of plaques (P = 0.001), and size of plaques (P = 0.003) (Table 4). Discussion
At the time that the first studies were published, uric acid was regarded as a biologically inert 13
Kumral et al. Table 1 Baseline characteristics of patients Characteristics
Patients with normal uric acid (n = 331)
TIA Retinal ischemia Male, No (%) Age, year [mean SD, (range)] Cause of stroke Carotid artery disease Small-artery disease Cardioembolism Hypertension1 Diabetes mellitus2 Cigarette smoking History of CHD3 Atrial fibrillation Hypercholesterolemia4 Hypertriglyceridemia Higher LDL-C Lower HDL-C Lower apo A Higher apo B Lipoprotein (a) Hyperhomocysteinemia Obesity Diabetic foot Physical activity absence5 Renal failure6
Patients with hyperuricemia (n = 75)
P
38 20 197 65
(12) (6) (60) 11 (40–90)
7 2 46 68
(10) (3) (61) 10 (44–87)
0.4 0.2 0.5 0.05
99 142 90 267 139 67 70 63 194 141 135 226 257 122 69 60 79 15 97 66
(30) (43) (27) (81) (42) (22) (21) (19) (59) (43) (41) (68) (78) (37) (21) (18) (24) (5) (29) (20)
33 24 18 62 30 15 22 13 45 42 30 50 55 36 21 15 20 4 20 22
(44) (32) (24) (83) (40) (13) (29) (19) (60) (56) (40) (67) (73) (48) (28) (20) (27) (6) (28) (30)
0.01 0.053 0.34 0.42 0.43 0.07 0.09 0.6 0.5 0.02 0.5 0.4 0.3 0.05 0.12 0.4 0.35 0.4 0.5 0.05
CHD, coronary heart disease; CAD, carotid artery disease; SAD, small artery disease. Values in parenthesis are percentage of column. Risk factors definition. 1 Systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 95 mmHg or taking antihypertensive drugs. 2 Fasting serum glucose ≥ 125 mg/dl, non-fasting serum glucose ≥ 200 mg/dl or taking insulin therapy or oral blood sugar-lowering drugs. 3 History of myocardial infarction or angina pectoris. 4 Total cholesterol ≥ 200 mg/dl, triglycerides ≥ 160 mgl/dl, HDL cholesterol ≤ 40 mg/dl, LDL cholesterol ≥ 160 mg/dl, apoA ≤ 110 mg/dl, apoB ≥ 120 mg/dl, Lp(a) ≥ 30 or taking lipid-lowering drugs. 5 Physical activity: walking 3–4 times/1 h/week. 6 Creatinine clearance (CLcr) < 30 ml/min.
Table 2 Doppler ultrasound findings in patients with higher uric acid level vs those with lower uric acid level Patients with normal uric acid level1 IMT-CCA (mm) IMT-Bif (mm) Number of plaques (N) Size of plaques (mm)
0.7 0.8 1.3 7.1
Patients with higher uric acid level
2
0.2 (0.1–1.3) 0.2 (0.1–1.4) 0.9 (0–3) 6 (1–20)
0.8 0.9 1.6 10
0.3 0.3 1.2 6.1
(0.1–1.3) (0.3–1.5) (0–4) (1–21)
P 0.001 0.001 0.05 0.002
Bif, Bifurcation of the carotid artery; CCA, Common carotid artery; IMT, Intima-media thickness; N, Number. Values are mean SD. 2 Values in parentheses are 95% CI for mean (upper bound-lower bound). 1
molecule. In course of time, an increasing evidence showed that an elevation of uric acid may cause primary hypertension which is the most common cause of stroke (20–25). However, we found that in patients with hyperuricemia and in those with normal uric acid level the frequency of hypertension was not significantly different. Regarding this finding, we can never be sure that hypertension is the only factor causing stroke in hyperuricemic subjects. Moreover, we do think that the impact of uric acid on the 14
CAD has been demonstrated convincingly regarding our results. The last studies noted that the association between uric acid and stroke is most pronounced in normotensive subjects (13). In addition, they found that the effect of uric acid on stroke risk was lower in persons with hypertension. This finding was supported by the observation in rats by a renal mechanism linked to inhibition of nitric oxide, activation of the renin–angiotensin system, and development of renal arteriolosclerosis (26).
Table 4 Linear regression models of findings in patients with carotid artery disease
0172** 0.193** 0.012 0.077 0.041 0.069 0.065 0.089* 0.178** 0.628** 1.000
Number of plaques
Uric acid and carotid artery disease
Standardized coefficients
0.165** 0.085* 0.003 0.079 0.167** 0.03 0.032 0.837** 1.000 0.138** 0.071 0.002 0.041 0.163** 0.028 0.003 1.000
0.538** 0.82* 0.125** 0.069 0.044 0.049 0.024 0.109* 0.185** 1.000
Model 1 Renal failure Hyperuricemia Size of plaques Number of plaques Model 2 Sex Renal failure Hyperuricemia Size of plaques Number of plaques
IMT, intima-media thickness; CAD, Coronary artery disease; CCA, common carotid artery. *P < 0.05. **P < 0.01.
Carotid artery disease Age Sex Hypertension Hyperuricemia Hypercholesterolemia CAD IMT-CCA IMT-bifurcation Size of plaques Number of plaques
1.000
0.085* 1.000
0.161** 0.036 1.000
0.81* 0.18** 0.04 1.000
0.124** 0.106* 0.009 0.03 1.000
0.104* 0.009 0.06 0.055 0.006 1.000
0.037 0.158** 0.001 0.052 0.061 0.058 1.000
IMT – bifurcation Hypercholesterolemia Hyperuricemia Hypertension Sex Age Carotid artery disease
Table 3 Pearson correlation analysis of patients with carotid artery disease regarding to vascular risk factors and carotid artery findings
CAD
IMT-CCA
Size of plaques
Exp (B)
95% Confidence interval for B
Significance
Lower bound
Upper bound
0.117 0.104 0.516 0.28
0.01 0.03 0.001 0.001
0.03 0.01 0.59 0.18
0.21 0.19 0.44 0.38
0.08 0.134 0.1 0.5 0.27
0.04 0.001 0.03 0.001 0.001
0.003 0.62 0.009 0.58 0.18
0.16 0.24 0.2 0.43 0.37
Once the renal arteriolosclerosis develops, the kidney drives the hypertension, and lowering uric acid is no longer protective. A study reported that the admission serum uric acid also independently predicted worse outcome and a higher rate of repeated stroke or other cardiovascular event (23). Others have also reported that a higher uric acid level in patients with acute stroke is associated with poorer outcome (24). These studies suggest that uric acid may be a true risk factor for stroke and for a poor outcome after stroke. But none of the studies has explained why and how the uric acid may cause poor outcome and higher rate of repeated stroke. Regarding to our finding, pathological changes in the carotid artery were significantly associated with higher uric acid level. Moreover, IMT of the wall of the bifurcation is strongly associated with hyperuricemia suggesting the accelerating role of higher uric acid level on the process of carotid atherosclerosis. Large vessel involvement may be the consequence of hyperuricemia which stimulates synthesis of monocyte chemoattractant protein-1 by rat vascular smooth muscle cells (27), which is known to have a key role in stimulating macrophage infiltration in atherosclerotic vessels (28, 29), particularly in the large vessels of the brain. There is also other potential pathogenetic mechanism to explain why an elevated serum uric acid at the time of stroke may be injurious. Recent evidence suggests that acute ischemic stroke results in generation of local oxidants that augment local injury and increase infarct size (30). Acute stroke is associated with a rapid decrease in serum antioxidants (31, 32) which recover slowly over the subsequent week (33, 34). Uric acid is often considered an antioxidant and has been shown to scavenge hydrogen 15
Kumral et al. peroxide and hydroxyl radicals, to block nitrotyrosine formation from peroxynitrite, and to preserve extracellular superoxide dismutase (35, 36). One might therefore expect that having elevated uric acid during an acute stroke would be beneficial. However, only one small study has reported that elevated uric acid is associated with good outcome after an ischemic stroke (37), whereas three other studies found the opposite (23, 33, 38). A recent study showed that low serum uric acid concentration is modestly associated with a very good short-term outcome supporting the hypothesis that uric acid is more a marker of the magnitude of the cerebral infarction than an independent predictor of stroke outcome (39). We did not assess the magnitude of the cerebral infarction at acute stroke period; howbeit, our study showed strong evidence that an elevated uric acid is associated with CAD (large artery disease) which may yield to large cerebral lesions. In our study, we limited analysis to three stroke subtypes, and there was no follow-up of patients to determine repeated stroke and outcome. While our stringent stroke monitoring procedures allowed us to include stroke patients with definite diagnosis of stroke subtypes and carotid pathologies, while most of the previous studies neuroimaging was often lacking and examinations not thorough enough to classify strokes. Uric acid examinations were performed in the first week of stroke in all patients and we think that this provided a homogeneity for the study. In conclusion, our data suggest that higher uric acid level is strongly associated with CAD promoting IMT and plaque formation changes in patients with ischemic stroke. Additional prospective large clinical trials are required to determine whether lowering uric acid level reduces the frequency of the CAD and stroke. Authors contribution
Principal author: Emre Kumral M.D., Study concept or design: Emre Kumral M.D., Acquisition of data: Ceyda Kabaroglu M.D., Bedriye Karaman M.D., Analysis or interpretation of data: Bedriye Karaman M.D., Statistical analysis: Mehmet Orman M.D. PhD., Study supervision or coordination: Emre Kumral M.D., Ceyda Kabaroglu M.D. Conflict of interest
We have no actual or potential conflicts of interest for all authors involved in this paper. 16
Funding
Emre Kumral M.D., Bedriye Karaman M.D., Mehmet Orman M.D., Ceyda Kabaroglu M.D. did not receive funding disclosure Ethical committee approval
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