J Korean Med Sci.  2023 Sep;38(38):e302. 10.3346/jkms.2023.38.e302.

Uric Acid and Risk of Cardiovascular Disease and Mortality: A Longitudinal Cohort Study

• Kim JY
• Seo C
• Pak H
• Lim H
• Chang TI

• KMID: 2546222
• DOI: http://doi.org/10.3346/jkms.2023.38.e302

Abstract

Background
This study aimed to examine the association of serum uric acid levels with incident cardiovascular disease and mortality in Korean adults without gout.
Methods
This large longitudinal cohort study included adults aged > 19 years who had serum uric acid levels measured at least once at the National Health Insurance Service Ilsan Hospital from January 1, 2006 to December 31, 2015. Longitudinal data on person-level cardiovascular disease and cardiovascular mortality were linked to the National Health Insurance Service claims database and National Death Index.
Results
Among a total of 92,454 study participants with a median follow-up of 4.7 years, 7,670 (8.3%) composite events of cardiovascular disease or cardiovascular mortality were observed. Multivariable Cox proportional-hazards models revealed that each 1 mg/dL increment in uric acid level was associated with a 6% higher risk of composite outcomes. Compared with that for the uric acid level category of 4.0 to < 5.0 mg/dL, adjusted hazard ratios (95% confidence interval) for uric acid level categories of 5.0 to < 6.0, 6.0 to < 7.0, and ≥ 7.0 mg/dL were 1.10 (1.04–1.18), 1.20 (1.11–1.30), and 1.36 (1.25–1.47), respectively. In the secondary analyses for cardiovascular disease or cardiovascular mortality examined separately, a higher uric acid level was similarly associated with a higher risk of each adverse outcome. These associations were generally consistent across clinically relevant subgroups.
Conclusion
A graded association was noted between serum uric acid levels and cardiovascular risk, suggesting that higher uric acid levels may adversely affect cardiovascular health and survival in individuals without gout.

Keyword

Uric Acid; Cardiovascular Disease; Mortality

Figure

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  Fig. 1 Associations between serum uric acid levels and the risk of composite cardiovascular outcomes. Adjustments in 1) Model 1: unadjusted; 2) Model 2: age, sex, comorbidities, and use of medications; 3) Model 3: all covariables in Model 2 plus serum albumin level, total cholesterol level, and estimated glomerular filtration rate.

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  Fig. 2 Associations between serum uric acid levels and cardiovascular outcomes using adjusted restricted cubic spline analyses. All models were adjusted for age, sex, comorbidities, use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, use of diuretics, and use of uric acid-lowering drugs. A histogram of observed serum uric acid levels and a hazard reference ratio of 1 (solid line) is overlaid.

Reference

1. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019; 139(10):e56–528. PMID: 30700139.

2. Heron M. Deaths: leading causes for 2017. Natl Vital Stat Rep. 2019; 68(6):1–77.

3. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2019; 74(10):e177–e232. PMID: 30894318.

4. Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016; 388(10055):2039–2052. PMID: 27112094.

5. 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(9):1729–1741. PMID: 26136207.

6. Borghi C, Cicero AF. Serum uric acid and cardiometabolic disease: another brick in the wall? Hypertension. 2017; 69(6):1011–1013. PMID: 28396532.

7. 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(1):7–13. PMID: 10391820.

8. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004; 351(13):1296–1305. PMID: 15385656.

9. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007; 116(1):85–97. PMID: 17606856.

10. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008; 359(17):1811–1821. PMID: 18946066.

11. Tangri N, Weiner DE. Uric acid, CKD, and cardiovascular disease: confounders, culprits, and circles. Am J Kidney Dis. 2010; 56(2):247–250. PMID: 20659624.

12. Wheeler JG, Juzwishin KD, Eiriksdottir G, Gudnason V, Danesh J. Serum uric acid and coronary heart disease in 9,458 incident cases and 155,084 controls: prospective study and meta-analysis. PLoS Med. 2005; 2(3):e76. PMID: 15783260.

13. Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2010; 62(2):170–180. PMID: 20191515.

14. Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003; 41(6):1183–1190. PMID: 12707287.

15. Song SO, Jung CH, Song YD, Park CY, Kwon HS, Cha BS, et al. Background and data configuration process of a nationwide population-based study using the Korean National Health Insurance System. Diabetes Metab J. 2014; 38(5):395–403. PMID: 25349827.

16. Kwon S. Thirty years of national health insurance in South Korea: lessons for achieving universal health care coverage. Health Policy Plan. 2009; 24(1):63–71. PMID: 19004861.

17. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150(9):604–612. PMID: 19414839.

18. Writing Group Members. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016; 133(4):e38–360. PMID: 26673558.

19. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005; 67(5):1739–1742. PMID: 15840020.

20. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001; 38(5):1101–1106. PMID: 11711505.

21. Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, et al. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J. 1997; 18(5):858–865. PMID: 9152657.

22. 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(6):1234–1242. PMID: 20486275.

23. Nakagawa T, Mazzali M, Kang DH, Sánchez-Lozada LG, Herrera-Acosta J, Johnson RJ. Uric acid--a uremic toxin? Blood Purif. 2006; 24(1):67–70. PMID: 16361844.

24. Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of major coronary heart disease events. Heart. 1997; 78(2):147–153. PMID: 9326988.

25. Odden MC, Amadu AR, Smit E, Lo L, Peralta CA. Uric acid levels, kidney function, and cardiovascular mortality in US adults: National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 1999-2002. Am J Kidney Dis. 2014; 64(4):550–557. PMID: 24906981.

26. Johnson RJ, Bakris GL, Borghi C, Chonchol MB, Feldman D, Lanaspa MA, et al. Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: report of a scientific workshop organized by the National Kidney Foundation. Am J Kidney Dis. 2018; 71(6):851–865. PMID: 29496260.