Association of Serum Uric Acid With Blood Pressure in Japanese Men

Transcription

1 Circulation Journal Official Journal of the Japanese Circulation Society Advance Publication by J-STAGE Association of Serum Uric Acid With Blood Pressure in Japanese Men Cross-Sectional Study in Work-Site Group Yasuo Kansui, MD, PhD; Toshio Ohtsubo, MD, PhD; Kenichi Goto, MD, PhD; Satoko Sakata, MD; Kunihiko Ichishima, MD, PhD; Masayo Fukuhara, MD, PhD; Yuko Ohta, MD, PhD; Kiyoshi Matsumura, MD, PhD Background: It has been reported that elevated levels of serum uric acid are related to hypertension and cardiovascular disease. Recent studies, however, have found little association between hyperuricemia and hypertension. Methods and Results: The association of serum uric acid with blood pressure was examined in 3,960 Japanese male workers (18 64 years of age; mean age, 42.3±0.2 years). Systolic blood pressure was significantly correlated with serum uric acid. Multiple regression analysis also showed that both systolic and diastolic blood pressures were independently associated with serum uric acid. When subjects were divided into 6 groups according to blood pressure on the basis of the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009), serum uric acid was elevated in a linear fashion as blood pressure increased. A similar relationship was found even in 3,608 subjects who were not taking anti-hypertensive or uric acid-lowering agents. In contrast, no relation was found between serum uric acid and blood pressure in 352 subjects taking anti-hypertensive medicine. Conclusions: Blood pressure is closely associated with serum uric acid. Serum uric acid might be associated with the increase in blood pressure, because there is no relation between serum uric acid and blood pressure in the subjects treated with anti-hypertensive medications. Key Words: Blood pressure; Cross-sectional study; Hypertension; Serum uric acid Hypertension is one of the most prevalent and important risk factors for cardiovascular disease, affecting approximately one-third of the population, and leads to cardiovascular mortality and morbidity. 1,2 Anti-hypertensive treatment has reduced cardiovascular disease in a number of clinical trials. 3,4 The etiology of hypertension is still unknown in the majority, but recent clinical evidence and experimental studies suggest that uric acid per se might contribute to incident hypertension. 5 Furthermore, some epidemiological studies have also suggested that increased serum uric acid level is associated with cardiovascular disease independently of other risk factors. 6 Editorial p???? Hyperuricemia is well known as the cause of gout and thus leads to gouty arthritis, kidney stones, and renal disease. 7,8 Even in the absence of gout, patients with asymptomatic hyperuricemia accumulate risk factors for cardiovascular disease, such as hypertension, impaired glucose tolerance, and dyslipidemia. 9,10 The incidence of hyperuricemia was high among untreated patients with essential hypertension, ranging from 25% to 50%. 11 In addition, many hypertensive patients with hyperuricemia have obesity or metabolic syndrome. These characteristics of patients with hyperuricemia have yielded conflicting results as to whether serum uric acid is an independent risk factor for cardiovascular disease or simply a marker of impaired metabolism and disease severity. 6,12 14 Furthermore, little association between hyperuricemia and incident hypertension was observed in recent studies in a meta-analysis. 5 In order to elucidate the association between blood pressure and serum uric acid, we carried out a cross-sectional study in a working population. In addition, we discuss the possibility that serum uric acid is associated with increased blood pressure. Methods Subjects The study group consisted of 3,960 male employees, ranging in age from 18 to 64 years old (mean age, 42.3±0.2 years), of a bus and railway company in Japan. Women were excluded Received June 6, 2011; accepted August 18, 2011; released online October 15, 2011 Time for primary review: 37 days Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Mailing address: Kiyoshi Matsumura, MD, PhD, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka , Japan. matsumk@intmed2.med.kyushu-u.ac.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 KANSUI Y et al. Table 1. Baseline Subject Characteristics Age (years) 42.3±0.2 Serum uric acid (mg/dl) 6.03±0.02 BMI (kg/m 2 ) 23.8±0.05 SBP (mmhg) 122.4±0.2 DBP (mmhg) 77.6±0.2 AST (IU/L) 22.7±0.2 ALT (IU/L) 29.3±0.3 γ-gtp (IU/L) 50.2±1.0 LDL-cholesterol (mg/dl) 122.1±0.5 HDL-cholesterol (mg/dl) 56.5±0.2 Triglyceride (mg/dl) 154.9±1.9 Hemoglobin (g/dl) 14.9±0.02 Hematocrit (%) 45.8±0.04 Hemoglobin A1c (%) 5.19±0.01 Creatinine (mg/dl) 0.80±0.003 hscrp (mg/dl) 0.13±0.006 Alcohol intake (g ethanol/day) 12.8±0.3 Data given as mean ± SEM. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; AST, aspartate transaminase; ALT, alanine transaminase; γ-gtp, γ-glutamyl transpeptidase; LDL, low-density lipoprotein; HDL, high-density lipoprotein; hscrp, high-sensitivity C-reactive protein. from the present study because they constituted only a small proportion of the group. All employees completed the physical, blood, and electrocardiography examinations performed in The examination included completion of medical questionnaires including questions regarding alcohol consumption. Among these subjects, 352 (9%) and 88 (2%) were receiving anti-hypertensive and/or uric acid-lowering drugs, respectively. The study protocol was approved by the ethics committee of Kyushu University. Data Collection Blood pressure was measured in the right arm in the sitting position. Measurements were repeated and the steady value of blood pressure was used for analysis. Serum aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyl transpeptidase (γ-gtp), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, serum creatinine, and serum uric acid were measured, and body mass index (BMI) was calculated as a marker for obesity. BMI was defined as weight (in kg) divided by height (in m 2 ). The alcohol consumption was calculated as g/day of ethanol. Data Analysis The subjects were divided into 6 groups according to blood pressure levels based on the Japanese Society of Hypertension Guideline for the Management of Hypertension (JSH 2009): 15 optimal blood pressure (systolic blood pressure [SBP] <120 mmhg and diastolic blood pressure [DBP] <80 mmhg); normal blood pressure (SBP mmhg or DBP mmhg); high-normal blood pressure (SBP mmhg or DBP mmhg); grade I hypertension (SBP mmhg or DBP mmhg); grade II hypertension (SBP mmhg or DBP mmhg); or grade III hypertension (SBP 180 mmhg or DBP 110 mmhg). In order to analyze the effects of serum uric acid on blood pressure level, 1-way ANOVA followed by Duncan s test for multiple comparisons was performed. In addition, we performed multiple regression analyses to determine the association of serum uric acid with blood pressure. Statistical analysis was carried using SAS for Windows, version 9.2 (SAS Institute, Cary, NC, USA). P<0.05 was considered statistically significant. Results Subject characteristics are listed in Table 1. On univariate analysis, SBP and DBP were positively correlated with age, serum uric acid, BMI, AST, ALT, γ-gtp, LDL-cholesterol, triglyceride, and hemoglobin (Hb) A1c, creatinine, high-sensitivity C-reactive protein (hscrp), and alcohol intake (Table 2). DBP was also significantly related to HDL-cholesterol. On multiple regression analysis, SBP was positively associated with age, serum uric acid, BMI, HDL-cholesterol, triglyceride, hematocrit, HbA1c, and alcohol intake, independently of other confounding factors. In addition, DBP was also significantly Table 2. Blood Pressure: Univariate Analysis SBP DBP r P value r P value Age (years) < < Serum uric acid (mg/dl) < < BMI (kg/m 2 ) < < AST (IU/L) < < ALT (IU/L) < < γ-gtp (IU/L) < < LDL-cholesterol (mg/dl) < < HDL-cholesterol (mg/dl) Triglyceride (mg/dl) < < Hemoglobin (g/dl) < < Hematocrit (%) < < Hemoglobin A1c (%) < < Creatinine (mg/dl) hscrp (mg/dl) Alcohol intake (g ethanol/day) < < Abbreviations see in Table 1.

3 Serum Uric Acid and Blood Pressure Table 3. Blood Pressure: Multivariate Analysis Independent variables SBP DBP β t value P value β t value P value Age (years) < < Serum uric acid (mg/dl) < BMI (kg/m 2 ) < < LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) < < Triglyceride (mg/dl) Hematocrit (%) < < Hemoglobin A1c (%) Creatinine (mg/dl) hscrp (mg/dl) Alcohol intake (g ethanol/day) < < Abbreviations see in Table 1. Table 4. Clinical Characteristics vs. Blood Pressure Blood pressure Optimal Normal High-normal Grade I HT Grade II HT Grade III HT n 1,306 1, Age (years) 38.1± ± ± ± ± ±1.6 Serum uric acid (mg/dl) 5.84± ± ± ± ± ±0.30 BMI (kg/m 2 ) 22.6± ± ± ± ± ±0.85 SBP (mmhg) 108.7± ± ± ± ± ±2.7 DBP (mmhg) 68.1± ± ± ± ± ±2.2 AST (IU/L) 20.9± ± ± ± ± ±1.6 ALT (IU/L) 25.5± ± ± ± ± ±5.3 γ-gtp (IU/L) 37.9± ± ± ± ± ±8.1 LDL-cholesterol (mg/dl) 117.4± ± ± ± ± ±8.4 HDL-cholesterol (mg/dl) 57.1± ± ± ± ± ±3.0 Triglyceride (mg/dl) 134.4± ± ± ± ± ±35.1 Hemoglobin (g/dl) 14.8± ± ± ± ± ±0.22 Hematocrit (%) 45.4± ± ± ± ± ±0.59 Hemoglobin A1c (%) 5.08± ± ± ± ± ±0.16 Creatinine (mg/dl) 0.80± ± ± ± ± ±0.03 hscrp (mg/dl) 0.12± ± ± ± ± ±0.08 Alcohol intake (g ethanol/day) 9.8± ± ± ± ± ±4.5 Medications (%) Hypertension Hyperuricemia Dyslipidemia Data given as mean ± SEM. HT, hypertension. Other abbreviations see in Table 1. related to age, serum uric acid, BMI, LDL-cholesterol, HDLcholesterol, triglyceride, hematocrit, hscrp, and alcohol intake (Table 3). To elucidate the association of serum uric acid with blood pressure, the subjects were divided into 6 groups according to the classification of blood pressure in adults based on JSH 2009: 15 optimal blood pressure, normal blood pressure, high-normal blood pressure, grade I hypertension, grade II hypertension, and grade III hypertension (Table 4). As shown in Table 4 and Figure 1a, serum uric acid was significantly elevated in a linear fashion as blood pressure increased, and serum uric acid in subjects with grade II and III hypertension was significantly higher than that in subjects with optimal blood pressure. Even after exclusion of the subjects who received anti-hypertensive or uric acid-lowering drugs, the level of serum uric acid significantly remained higher in subjects with grade II or grade III hypertension (serum uric acid: optimal blood pressure, 5.84±0.03 mg/dl; normal blood pressure, 6.00±0.04 mg/dl; highnormal blood pressure, 6.18±0.05 mg/dl; grade I hypertension, 6.25±0.07 mg/dl; grade II hypertension, 6.56±0.17 mg/dl; grade III hypertension, 6.58±0.31 mg/dl; Figure 1b). When the subjects with anti-hypertensive drugs, but without uric acidlowering drugs, were studied, the association of serum uric acid with the level of blood pressure was not found (serum uric acid: optimal blood pressure, 6.37±0.39 mg/dl; normal blood pressure, 6.13±0.18 mg/dl; high-normal blood pressure, 6.29± 0.11 mg/dl; grade I hypertension, 6.07±0.10 mg/dl; grade II

4 KANSUI Y et al. (a) * * (b) * * Serum uric acid (mg/dl) Serum uric acid (mg/dl) n O N HN I II III O N HN I II III n Figure 1. Box plots of serum uric acid vs. blood pressure in (a) the study subjects and (b) subjects treated with neither anti-hypertensive drugs nor uric acid-lowering drugs. HN, high-normal blood pressure; N, normal blood pressure; O, optimal blood pressure; I, grade I hypertension; II, grade II hypertension; III, grade III hypertension. *P<0.05 (vs. optimal blood pressure), Duncan s multiple range test. Serum uric acid (mg/dl) n O N HN I II III Figure 2. Box plot of serum uric acid vs. blood pressure in subjects treated with anti-hypertensive, but not with uric acidlowering, drugs. HN, high-normal blood pressure; N, normal blood pressure; O, optimal blood pressure; I, grade I hypertension; II, grade II hypertension; III, grade III hypertension. hypertension, 5.55±0.25 mg/dl; grade III hypertension, 7.00± 1.00 mg/dl; Figure 2). Discussion The present study has demonstrated that serum uric acid was positively correlated with blood pressure level in male Japanese subjects in a work-site group. Multiple regression analysis showed that blood pressure was closely related to serum uric acid independently of age, BMI, LDL-cholesterol, HDL-cholesterol, triglyceride, hematocrit, HbA1c, creatinine, hscrp, and alcohol consumption. When subjects were divided into 6 groups according to blood pressure levels based on JSH 2009, serum uric acid was increased according to the increase in blood pressure. These findings suggest that higher uric acid is associated with increased blood pressure independently of cardiovascular risk factors. Anti-hypertensive treatment affects serum uric acid levels. It has been shown that diuretics increase serum uric acid, 16 and that certain calcium channel blockers reduce serum uric acid Losartan, an angiotensin II receptor antagonist, has been shown to reduce serum uric acid through the inhibition of urate transporter 1 in renal tubules. 20,21 In the present study, even after the exclusion of the subjects with anti-hypertensive or uric acid-lowering treatment, higher blood pressure groups remained associated with higher serum uric acid levels. Although these findings further support the idea that blood pressure is associated with serum uric acid, this association was not found in the subjects taking anti-hypertensive medicine. These findings imply that higher uric acid by itself might con-

5 Serum Uric Acid and Blood Pressure tribute to higher blood pressure levels. In experimental studies, rats with moderate hyperuricemia developed hypertension, and hypertension related to hyperuricemia was reversible by reduction of serum uric acid. 22,23 Epidemiological studies also demonstrated that serum uric acid was an independent predictor of incident hypertension. 24,25 In the Framingham Heart Study, 3,329 participants free of hypertension were investigated to determine the relationship of serum uric acid to hypertension incidence. 24 In that study, hypertension incidence increased progressively from 9.8% for the lowest quartile to 15.6% for the top quartile of serum uric acid during 4 years of follow-up. Furthermore, a recent cross-over randomized trial has demonstrated that treatment with allopurinol reduced blood pressure over 4 weeks in hypertensive patients with hyperuricemia. 26 The present study has shown that serum uric acid was significantly associated with blood pressure levels even in men. In previous studies, however, the association between serum uric acid and hypertension was not clear in men. Grayson et al reported that the association between serum uric acid and incidence of hypertension was more obvious in women. 5 The NHANES I study also showed that the greater relationship between serum uric acid and cardiovascular mortality was found in women. 12 In an average follow-up of 24.9 years in Japan, Hakoda et al showed that increased serum uric acid level was a significant risk factor for cardiovascular mortality only in women. 6 In addition, our previous study also found that serum uric acid was associated with left ventricular hypertrophy in women, but not in men. 27 A possible explanation for the stronger effect of serum uric acid on blood pressure and cardiovascular mortality among women than men might be the lower serum uric acid levels. Therefore, the relative influence of having higher serum uric acid might be stronger among women. The present study possibly supports the idea that serum uric acid is associated with blood pressure even in male subjects. The reason for the different effect of serum uric acid on men between the present study and the previous Japanese study conducted by Hakoda et al 6 remains unclear, but the younger age of the present study subjects is likely to have played a role in the significant correlation between serum uric acid and blood pressure. It has been suggested, in previous studies with children and an experimental animal model, that the impact of serum uric acid levels on blood pressure is stronger in the early stage of hypertension, and that the correlation of uric acid levels with blood pressure is attenuated with aging. 32,33 In addition, it has been shown that hyperuricemia causes hypertension followed by preglomerular arteriolopathy. 30,31 Once preglomerular vascular disease develops, hypertension is driven by the kidney, and lowering uric acid is no longer protective. 29 Thus, the younger age of the present subjects might have contributed to the significant relationship of uric acid with blood pressure. At concentrations of serum uric acid >7 mg/dl, undissociated uric acid crystallizes in joint tissues or kidney. In the present study, serum uric acid concentration was <7 mg/dl in the majority of the study subjects. The serum uric acid level, however, appeared to exhibit continuous and linear association with blood pressure without an apparent threshold level, suggesting that serum uric acid level even within the normal range may play a role in an increase in blood pressure. It has been shown that serum uric acid is associated with incident hypertension without a specific cut-off or threshold. 5 In addition, in the present study, this close association was found in young and middle-aged subjects. The effects of serum uric acid in children aged 5 17 years on blood pressure level in adulthood were determined in the Bogalusa Heart Study. 34 After an average of 12 years follow-up, elevation of serum uric acid levels in childhood predicted blood pressure in adulthood. These findings suggest that maintaining an adequate serum uric acid level in the young population may be important to prevent the subsequent incidence of hypertension as well as cardiovascular disease. Potential mechanisms of uric acid in the development of hypertension have been investigated in experimental studies. Hyperuricemia causes hypertension and renal vascular injuries through the activation of the renin angiotensin system. 30,31 Addition of uric acid to cultured cells causes proliferation of vascular smooth muscle cells and endothelial dysfunction. 23,35 Uric acid also affects cell proliferation and inhibits nitric oxide production. 23,35 It has been shown that uric acid causes renal afferent arteriopathy and tubulointerstitial disease, leading to hypertension in a rodent model of hyperuricemia. 31 These previous findings might account for the present results. Further clinical and experimental studies are necessary to elucidate the effects of uric acid on hypertension and cardiovascular disease. The present study had several limitations. First, we included mainly middle-aged male subjects. It remains to be determined whether the present findings are applicable to older female subjects. Second, the study design was cross-sectional, and thus may not necessarily represent the role of uric acid as a cause of hypertension, although a lack of association of blood pressure and serum uric acid was found in the subjects treated with anti-hypertensive drugs. Third, data on potential confounding factors such as sodium, potassium, calcium, and protein intake, which might affect blood pressure, were not included in the present study. Further studies are needed to determine the role of uric acid in hypertension. In conclusion, in the present cross-sectional study, serum uric acid was closely associated with blood pressure level in young and middle-aged Japanese men in a work-site group. 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