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      Uric acid is a risk factor for ischemic stroke and all-cause mortality in the general population: a gender specific analysis from The Tromsø Study

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          Abstract

          Background

          The role of serum uric acid as an independent predictor of cardiovascular disease and death is uncertain in the general population. Adjustments for additional cardiovascular risk factors have not been consistent. We examined the association of serum uric acid with all-cause mortality, ischemic stroke and myocardial infarction in a prospective population based study, with several traditional and non-traditional risk factors for cardiovascular disease included in the model.

          Methods

          A population-based prospective cohort study was performed among 2696 men and 3004 women. Endpoints were all-cause mortality after 15 years, and fatal or non-fatal myocardial infarction (MI) and ischemic stroke after 12 years.

          Results

          1433 deaths, 659 MIs and 430 ischemic strokes occurred during follow-up. Fully adjusted Cox regression analyses showed that per 1 SD (87 μmol/L) increase in serum uric acid level, the risk of all-cause mortality increased in both genders (hazard ratios, HR men; 1.11, 95% CI 1.02-1.20, women; 1.16, 1.05-1.29). HRs and 95% CI for stroke were 1.31, 1.14-1.50 in men, 1.13, 0.94-1.36 in women, and 1.22 (1.09, 1.35) in the overall population. No independent associations were observed with MI.

          Conclusion

          Serum uric acid was associated with all-cause mortality in men and women, even after adjustment for blood pressure, estimated GFR, urinary albumin/creatinine ratio, drug intake and traditional cardiovascular risk factors. After the same adjustments, serum uric acid was associated with 31% increased risk of stroke in men.

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          Most cited references25

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          Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells.

          Recent experimental and human studies have shown that hyperuricemia is associated with hypertension, systemic inflammation, and cardiovascular disease mediated by endothelial dysfunction and pathologic vascular remodeling. Elevated levels of C-reactive protein (CRP) have emerged as one of the most powerful independent predictors of cardiovascular disease. In addition to being a marker of inflammation, recent evidence suggests that CRP may participate directly in the development of atherosclerotic vascular disease. For investigating whether uric acid (UA)-induced inflammatory reaction and vascular remodeling is related to CRP, the UA-induced expression of CRP in human vascular smooth muscle cells (HVSMC) and human umbilical vein endothelial cells (HUVEC) was examined, as well as the pathogenetic role of CRP in vascular remodeling. It is interesting that HVSMC and HUVEC expressed CRP mRNA and protein constitutively, revealing that vascular cells are another source of CRP production. UA (6 to 12 mg/dl) upregulated CRP mRNA expression in HVSMC and HUVEC with a concomitant increase in CRP release into cell culture media. Inhibition of p38 or extracellular signal-regulated kinase 44/42 significantly suppressed UA-induced CRP expression, implicating these pathways in the response to UA. UA stimulated HVSMC proliferation whereas UA inhibited serum-induced proliferation of HUVEC assessed by 3H-thymidine uptake and cell counting, which was attenuated by co-incubation with probenecid, the organic anion transport inhibitor, suggesting that entry of UA into cells is responsible for CRP expression. UA also increased HVSMC migration and inhibited HUVEC migration. In HUVEC, UA reduced nitric oxide (NO) release. Treatment of vascular cells with anti-CRP antibody revealed a reversal of the effect of UA on cell proliferation and migration in HVSMC and NO release in HUVEC, which suggests that CRP expression may be responsible for UA-induced vascular remodeling. This is the first study to show that soluble UA, at physiologic concentrations, has profound effects on human vascular cells. The observation that UA alters the proliferation/migration and NO release of human vascular cells, mediated by the expression of CRP, calls for careful reconsideration of the role of UA in hypertension and vascular disease.
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            Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study.

            Hyperuricemia is associated with risk for cardiovascular disease and death. However, the role of uric acid independent of established risk factors is uncertain. To examine the relation of serum uric acid level to incident coronary heart disease, death from cardiovascular disease, and death from all causes. Community-based, prospective observational study. Framingham, Massachusetts. 6763 Framingham Heart Study participants (mean age, 47 years). Serum uricacid level at baseline (1971 to 1976); event rates per 1000 person-years by sex-specific uric acid quintile. During 117,376 person-years of follow-up, 617 coronary heart disease events, 429 cardiovascular disease deaths, and 1460 deaths from all causes occurred. In men, after adjustment for age, elevated serum uric acid level was not associated with increased risk for an adverse outcome. In women, after adjustment for age, uric acid level was predictive of coronary heart disease (P = 0.002), death from cardiovascular disease (P = 0.009), and death from all causes (P = 0.03). After additional adjustment for cardiovascular disease risk factors, uric acid level was no longer associated with coronary heart disease, death from cardiovascular disease, or death from all causes. In a stepwise Cox model, diuretic use was identified as the covariate responsible for rendering serum uric acid a statistically nonsignificant predictor of outcomes. These findings indicate that uric acid does not have a causal role in the development of coronary heart disease, death from cardiovascular disease, or death from all causes. Any apparent association with these outcomes is probably due to the association of uric acid level with other risk factors.
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              The World Health Organization MONICA Project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. WHO MONICA Project Principal Investigators.

              A World Health Organization Working Group has developed a major international collaborative study with the objective of measuring over 10 years, and in many different populations, the trends in, and determinants of, cardiovascular disease. Specifically the programme focuses on trends in event rates for validated fatal and non-fatal coronary heart attacks and strokes, and on trends in cardiovascular risk factors (blood pressure, cigarette smoking and serum cholesterol) in men and women aged 25-64 in the same defined communities. By this means it is hoped both to measure changes in cardiovascular mortality and to see how far they are explained; on the one hand by changes in incidence mediated by risk factor levels; and on the other by changes in case-fatality rates, related to medical care. Population centres need to be large and numerous; to reliably establish 10-year trends in event rates within a centre 200 or more fatal events in men per year are needed, while for the collaborative study a multiplicity of internally homogeneous centres showing differing trends will provide the best test of the hypotheses. Forty-one MONICA Collaborating Centres, using a standardized protocol, are studying 118 Reporting Units (subpopulations) with a total population aged 25-64 (both sexes) of about 15 million.
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                Author and article information

                Contributors
                Journal
                BMC Cardiovasc Disord
                BMC Cardiovasc Disord
                BMC Cardiovascular Disorders
                BioMed Central
                1471-2261
                2013
                11 December 2013
                : 13
                : 115
                Affiliations
                [1 ]Section of Haematology, University Hospital of North Norway, Tromsø, Norway
                [2 ]Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway
                [3 ]Section of Nephrology, University Hospital of North Norway, N-9038, Tromsø, Norway
                [4 ]Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway
                [5 ]Renal Division, The George Institute for International Health, University of Sydney, Sydney, Australia
                [6 ]Renal Medicine, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia
                [7 ]Department of Nephrology, Oslo University Hospital Rikshospitalet, Oslo, Norway
                Article
                1471-2261-13-115
                10.1186/1471-2261-13-115
                4029378
                24330812
                e04c8dc5-cc13-422c-a075-c6f6380e2e12
                Copyright © 2013 Storhaug et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 May 2013
                : 5 December 2013
                Categories
                Research Article

                Cardiovascular Medicine
                all-cause mortality,gender,myocardial infarction,stroke,uric acid
                Cardiovascular Medicine
                all-cause mortality, gender, myocardial infarction, stroke, uric acid

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