Abstract
Studies on the association between serum uric acid levels and the risk of cardiovascular disease have yielded inconsistent results. We investigated the association of serum uric acid levels with cardiovascular disease mortality in a Japanese community. A total of 2633 community-dwelling Japanese people aged ≥40 years without a history of cardiovascular disease were followed up for 19 years. Serum uric acid levels were categorized into quintiles (Q1, lowest; Q5, highest). The hazard ratios for mortality from cardiovascular disease, stroke, and coronary heart disease were computed using a Cox proportional hazards model. During the follow-up, 235 subjects died from cardiovascular disease (including 84 from stroke and 53 from coronary heart disease). Risks for cardiovascular disease mortality were higher in both the Q1 and Q5 groups than in the Q3 group after adjustment for confounding factors (Q1, hazard ratio 1.50 [95% confidence interval 0.94–2.39]; Q2, 1.06 [0.66–1.72]; Q3, 1.00 [reference]; Q4, 1.44 [0.93–2.23]; and Q5, 1.89 [1.23–2.91]). A similar U-shaped association was observed for stroke mortality (Q1, 3.26 [1.29–8.25]; Q2, 2.21 [0.85–5.73]; Q3, 1.00 [reference]; Q4, 2.65 [1.07–6.58]; and Q5, 3.77 [1.54–9.24]), while coronary heart disease mortality was increased only in the Q5 group (Q1, 1.27 [0.46–3.50]; Q2, 0.85 [0.29–2.48]; Q3, 1.00 [reference]; Q4, 1.57 [0.63–3.92]; and Q5, 2.53 [1.03–6.18]). Elevated serum uric acid was suggested to be a significant risk factor for stroke or coronary heart disease mortality in a Japanese community. Conversely, the excess risk of stroke mortality in individuals with lower serum uric acid levels may indicate a possible cerebroprotective role of uric acid.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lee SW, Kim HC, Nam C, Lee HY, Ahn SV, Oh YA, et al. Age-differential association between serum uric acid and incident hypertension. Hypertens Res. 2019;42:428–37.
Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:1811–21.
Nakamura K, Sakurai M, Miura K, Morikawa Y, Yoshita K, Ishizaki M, et al. Alcohol intake and the risk of hyperuricaemia: a 6-year prospective study in Japanese men. Nutr Metab Cardiovasc Dis. 2012;22:989–96.
Borghi C, Rosei EA, Bardin T, Dawson J, Dominiczak A, Kielstein JT, et al. Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens. 2015;33:1729–41.
Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005;16:3553–62.
Yu MA, Sánchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the renin–angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens. 2010;28:1234–42.
Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. JAMA. 2000;283:2404–10.
Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam Study. Stroke. 2006;37:1503–7.
Stack AG, Hanley A, Casserly LF, Cronin CJ, Abdalla AA, Kiernan TJ, et al. Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality. QJM. 2013;106:647–58.
Bombelli M, Ronchi I, Volpe M, Facchetti R, Carugo S, Dell’oro R, et al. Prognostic value of serum uric acid: new-onset in and out-of-office hypertension and long-term mortality. J Hypertens. 2014;32:1237–44.
Chen JH, Chuang SY, Chen HJ, Yeh WT, Pan WH. Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a Chinese cohort study. Arthritis Rheum. 2009;61:225–32.
Zhang W, Iso H, Murakami Y, Miura K, Nagai M, Sugiyama D, et al. Serum uric acid and mortality form cardiovascular disease: EPOCH-JAPAN Study. J Atheroscler Thromb. 2016;23:692–703.
Gerber Y, Tanne D, Medalie JH, Goldbourt U. Serum uric acid and long-term mortality from stroke, coronary heart disease and all causes. Eur J Cardiovasc Prev Rehabil. 2006;13:193–8.
Kuo CF, See LC, Yu KH, Chou IJ, Chiou MJ, Luo SF. Significance of serum uric acid levels on the risk of all-cause and cardiovascular mortality. Rheumatology. 2013;52:127–34.
Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci. 1981;78:6858–62.
Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis. 2000;148:131–9.
Li R, Huang C, Chen J, Guo Y, Tan S. The role of uric acid as a potential neuroprotectant in acute ischemic stroke: a review of literature. Neurol Sci. 2015;36:1097–103.
Hata J, Ninomiya T, Hirakawa Y, Nagata M, Mukai N, Gotoh S, et al. Secular trends in cardiovascular disease and its risk factors in Japanese: half-century data from the Hisayama Study (1961–2009). Circulation. 2013;128:1198–205.
Ninomiya T. Japanese legacy cohort studies: the Hisayama Study. J Epidemiol. 2018;28:444–51.
Fujishima M, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, et al. Diabetes and cardiovascular disease in a prospective population survey in Japan: the Hisayama Study. Diabetes. 1996;45:S14–16.
Nagata M, Ninomiya T, Doi Y, Yonemoto K, Kubo M, Hata J, et al. Trends in the prevalence of chronic kidney disease and its risk factors in a general Japanese population: the Hisayama Study. Nephrol Dial Transpl. 2010;25:2557–64.
Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S. Modification of the CKD epidemiology collaboration (CKD-EPI) equation for Japanese: accuracy and use for population estimates. Am J Kidney Dis. 2010;56:32–8.
Braga F, Pasqualetti S, Ferraro S, Panteghini M. Hyperuricemia as risk factor for coronary heart disease incidence and mortality in the general population: a systematic review and meta-analysis. Clin Chem Lab Med. 2016;54:7–15.
Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum. 2009;61:885–92.
Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999;131:7–13.
Moriarity JT, Folsom AR, Iribarren C, Nieto FJ, Rosamond WD. Serum uric acid and risk of coronary heart disease: Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol. 2000;10:136–43.
Palmer TM, Nordestgaard BG, Benn M, Tybjærg-Hansen A, Davey Smith G, Lawlor DA, et al. Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts. BMJ. 2013;347:f4262.
Keenan T, Zhao W, Rasheed A, Ho WK, Malik R, Felix JF, et al. Causal assessment of serum urate levels in cardiometabolic diseases through a mendelian randomization study. J Am Coll Cardiol. 2016;67:407–16.
White J, Sofat R, Hemani G, Shah T, Engmann J, Dale C, et al. International Consortium for Blood Pressure (ICBP), Smith GD, Dudbridge F, Casas JP, Holmes MV, Hingorani AD; UCLEB (University College London-London School of Hygiene & Tropical Medicine-Edinburgh-Bristol Consortium. Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2016;4:327–36.
Li X, Meng X, Timofeeva M, Tzoulaki I, Tsilidis KK, Ioannidis JP, et al. Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies. BMJ. 2017;357:j2376.
George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006;114:2508–16.
Otani N, Toyoda S, Sakuma M, Hayashi K, Ouchi M, Fujita T, et al. Effects of uric acid on vascular endothelial function from bedside to bench. Hypertens Res. 2018;41:923–31.
Tan S, Radi R, Gaudier F, Evans RA, Rivera A, Kirk KA, et al. Physiologic levels of uric acid inhibit xanthine oxidase in human plasma. Pediatr Res. 1993;34:303–7.
Chamorro A, Obach V, Cervera A, Revilla M, Deulofeu R, Aponte JH. Prognostic significance of uric acid serum concentration in patients with acute ischemic stroke. Stroke. 2002;33:1048–52.
Acknowledgements
We would like to express our sincere gratitude to Professor Yoshinao Oda, Professor Toru Iwaki, and their colleagues in the Department of Anatomic Pathology and Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, who provided insight and expertize regarding the autopsy findings that greatly assisted our research. We also thank the staff of the Division of Health and Welfare of Hisayama for their cooperation in this study.
Funding
This study was supported in part by Grants-in-Aid for Scientific Research (A) (JP16H02692), (B) (JP16H05850, JP17H04126, and JP18H02737) and (C) (JP17K09114, JP17K09113, JP17K01853, JP18K07565, JP18K09412, and JP19K07890) and for Early-Career Scientists (JP18K17925 and JP18K17382) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by Health and Labour Sciences Research Grants of the Ministry of Health, Labour and Welfare of Japan (H29-Junkankitou-Ippan-003 and H30-Shokuhin-[Sitei]-005); and by the Japan Agency for Medical Research and Development (JP19dk0207025, JP19ek0210082, JP19ek0210083, JP19km0405202, JP19ek0210080, and JP19fk0108075). This study was sponsored by Teijin Pharma Limited (Tokyo, Japan). The sponsor of the study had no role in the study design, conduct of the study, data collection, data interpretation, or preparation of the report.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The study protocol was approved by the Kyushu University Institutional Review Board for Clinical Research, and the procedures followed were in accordance with national guidelines. Written informed consent was obtained from the study subjects.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Sakata, S., Hata, J., Honda, T. et al. Serum uric acid levels and cardiovascular mortality in a general Japanese population: the Hisayama Study. Hypertens Res 43, 560–568 (2020). https://doi.org/10.1038/s41440-019-0390-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41440-019-0390-8
Keywords
This article is cited by
-
Impact of hyperuricemia on chronic kidney disease and atherosclerotic cardiovascular disease
Hypertension Research (2022)
-
Annual reports on hypertension research 2020
Hypertension Research (2022)
-
Association of childhood anthropometric measurements and laboratory parameters with high blood pressure in young adults
Hypertension Research (2021)
-
J-shaped curve for the association between serum uric acid levels and the prevalence of blood pressure abnormalities
Hypertension Research (2021)