Hyperuricemia

HomeHypertensionVol. 71, No. 1Hyperuricemia Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHyperuricemiaDoes It Matter for the Progression From Prehypertension to Hypertension? Yi-Bang Cheng and Yan Li Yi-Bang ChengYi-Bang Cheng From the Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China. and Yan LiYan Li From the Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China. Originally published4 Dec 2017https://doi.org/10.1161/HYPERTENSIONAHA.117.10443Hypertension. 2018;71:66–67Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 See related article, pp 78–86Uric acid, the end product of purine oxidation, is engendered from nucleotides and adenosine triphosphate metabolism. Unlike most mammals, serum uric acid concentration is relatively high in humans, partly because of mutations in the uricase gene occurred nearly 15 million years ago.1 Although serum uric acid excess is generally considered as a risk factor for gout and renal calculus, the hypothesis that hyperuricemia mediates cardiovascular disease has emerged only since late 19th century.1 In 1879, it was noticed that some hypertensive patients were from gouty families and that uric acid was involved in the development of hypertension.1Most of subsequent cross-sectional and longitudinal studies demonstrated that serum uric acid was an independent predictor of hypertension. A meta-analysis2 of 18 prospective studies including 55 607 subjects revealed that hyperuricemia predicted incident hypertension, with a 13% higher risk per 1 mg/dL increment in serum uric acid. However, the association might vary according to age and sex, being more significant in younger and female subjects.2 Most recently, Liu et al3 found that the prediction of hyperuricemia was also true for incident prehypertension. In 15 143 subjects with optimal office blood pressure at baseline, subjects with a serum uric acid concentration belonging to the fourth and fifth quintiles, compared with those in the bottom quintile, had a 9% and 17% higher risk of incident prehypertension, respectively.In this issue of Hypertension, Kuwabara et al4 extended our knowledge by showing that hyperuricemia played a significant role in the progression from prehypertension to hypertension. In this retrospective cohort study,4 they found that the cumulative incidence rate of hypertension was significantly higher in subjects with hyperuricemia than those without in normotensive (5.6% versus 2.6%) and prehypertensive subjects (30.7% versus 24.0%). The difference in the incidence of hypertension from prehypertension between hyperuricemia and normouricemia seemed larger in women (38.4% versus 22.8%) than in men (28.7% versus 24.5%). These findings were striking. Over the five-year study period, approximately one fourth of the prehypertensive subjects developed hypertension. Hyperuricemia increased the risk of hypertension by ≈35%. The findings indicated that hyperuricemia might be a therapeutic target for the prevention of hypertension and provided rationale for the design of future interventional studies. Although the study was large in the sample size, the findings should be interpreted in the context of their limitations. For instance, it was a single-center study and lacked time-to-event data. The definition of prehypertension and hypertension might not be accurate enough because blood pressure in this study was measured in the office on one occasion. According to previous investigations, only half prehypertension on casual blood pressure measurement was confirmed at a second clinic visit.Although hyperuricemia predicted incident hypertension and prehypertension in most cohort studies, the causal relationship between hyperuricemia and hypertension had not been fully established. Genetic studies that applied Mendelian randomization approach did not support a causal role of serum uric acid in the development of hypertension. In a meta-analysis5 of genome-wide association studies involving 28 283 individuals, the genetic urate score estimated from 8 genetic loci was strongly associated with serum urate and gout, but not with incident hypertension nor blood pressure. However, recent gene knockout studies in mice showed that the loss of uricase6 or intestinal uric acid transporter SLC2A9 resulted in hypertension and metabolic disorders.7 Experimental studies in rats and cells further suggested that the pathophysiologic process of hyperuricemia-induced hypertension might include 2 phases1: an initial phase that was driven by uric acid per se and mediated by oxidative stress, inflammation, endothelial dysfunction, and activation of the renin–angiotensin–aldosterone system, and a later phase that was driven by arterial wall hypertrophy and renal microvascular changes and interstitial inflammation but no longer dependent on serum uric acid level (Figure). These possible mechanisms may explain why the association between hyperuricemia and hypertension is more evident in the young, and the benefit of uric acid lowering in hypertension has only been seen in adolescents.Download figureDownload PowerPointFigure. A diagram illustrating the putative mechanisms how uric acid might contribute to blood pressure increase. The pathophysiologic process for hyperuricemia-induced hypertension might include 2 phases: an initial acute phase that was driven by uric acid per se and mediated by oxidative stress, inflammation, endothelial dysfunction, and activation of the renin–angiotensin–aldosterone system, and a later chronic phase that was driven by arterial wall hypertrophy and renal microvascular changes and interstitial inflammation.Feig et al8 conducted a double-blind, placebo-controlled, crossover trial in 30 adolescents, who had newly diagnosed and treatment-naive stage I hypertension and a serum uric acid level ≥6 mg/dL. The study participants received allopurinol 200 mg or placebo twice daily for 4 weeks in a randomized order, with a 2-week washout period in between. Allopurinol, compared with placebo, reduced office and ambulatory systolic/diastolic blood pressure by −4.9/−2.7 and −7.1/−4.3 mm Hg, respectively. The same group then performed a parallel-group comparison trial in 60 prehypertensive obese adolescents.9 The study participants were randomized to allopurinol, probenecid, or placebo for 8 weeks. Compared with placebo, allopurinol and probenecid reduced clinic systolic/diastolic blood pressure by ≈11 and 10 mm Hg, respectively, and ambulatory blood pressure by 11 and 8 mm Hg, respectively. However, the impressive blood pressure–lowering effect observed in these 2 single-center trials was not confirmed in a subsequent multicenter trial in 121 American adults with hyperuricemia. The negative results had not been published but could be seen online (https://clinicaltrials.gov/ct2/show/NCT01496469). A meta-analysis10 of these 3 trials showed that urate-lowering treatment had a marginally significant effect on office systolic blood pressure, but not on ambulatory blood pressure, which made the strategy of hypertension prevention by urate-lowering treatment still illusive. Definitely, we need more and larger trials to prove that treatment of hyperuricemia may reduce blood pressure and prevent hypertension. In this regard, study by Kuwabara et al4 provided important information that approximately a third prehypertensive, and hyperuricemia subjects would develop hypertension in 5 years and suggested a potential target population for future trials.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Yan Li, Shanghai Institute of Hypertension, Ruijin Second Rd 197, Shanghai 200025, China. E-mail [email protected]References1. Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ. The role of uric acid in the pathogenesis of human cardiovascular disease.Heart. 2013; 99:759–766. doi: 10.1136/heartjnl-2012-302535.CrossrefMedlineGoogle Scholar2. Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis.Arthritis Care Res (Hoboken). 2011; 63:102–110. doi: 10.1002/acr.20344.CrossrefMedlineGoogle Scholar3. Liu L, Gu Y, Li C, et al. Serum uric acid is an independent predictor for developing prehypertension: a population-based prospective cohort study.J Hum Hypertens. 2017; 31:116–120. doi: 10.1038/jhh.2016.48.CrossrefMedlineGoogle Scholar4. Kuwabara M, Hisatome I, Niwa K, Hara S, Roncal-Jimenez CA, Bjornstad P, Nakagawa T, Andres-Hernando A, Sato Y, Jensen T, Garcia G, Rodriguez-Iturbe B, Ohno M, Lanaspa MA, Johnson RJ. Uric acid is a strong risk marker for developing hypertension from prehypertension: a 5-year Japanese cohort study.Hypertension. 2018; 71:78–86. doi: 10.1161/HYPERTENSIONAHA.117.10370.LinkGoogle Scholar5. Yang Q, Köttgen A, Dehghan A, et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.Circ Cardiovasc Genet. 2010; 3:523–530. doi: 10.1161/CIRCGENETICS.109.934455.LinkGoogle Scholar6. Lu J, Hou X, Yuan X, et al. Knockout of the urate oxidase gene provides a stable mouse model of hyperuricemia associated with metabolic disorders [published online ahead of print July 17, 2017].Kidney Int. doi: 10.1016/j.kint.2017.04.031. http://www.sciencedirect.com/science/article/pii/S0085253817303319?via%3Dihub.Google Scholar7. DeBosch BJ, Kluth O, Fujiwara H, Schürmann A, Moley K. Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9.Nat Commun. 2014; 5:4642. doi: 10.1038/ncomms5642.CrossrefMedlineGoogle Scholar8. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial.JAMA. 2008; 300:924–932. doi: 10.1001/jama.300.8.924.CrossrefMedlineGoogle Scholar9. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents.Hypertension. 2012; 60:1148–1156. doi: 10.1161/HYPERTENSIONAHA.112.196980.LinkGoogle Scholar10. Gois PHF, Souza ERM. Pharmacotherapy for hyperuricemia in hypertensive patients.Cochrane Database Syst Rev. 2017; 4:CD008652. doi: 10.1002/14651858.CD008652.pub3.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Liu L, Zhang X, Li Q, Qie R, Han M, Zhan S, Zhang J, Zhang L, Zhang C and Hong F (2021) Serum uric acid and risk of prehypertension: a dose–response meta-analysis of 17 observational studies of approximately 79 thousand participants, Acta Cardiologica, 10.1080/00015385.2021.1878422, 77:2, (136-145), Online publication date: 7-Feb-2022. Ghosh A, Pal D, Debbarma S and Chakraborty P (2020) Study of Serum Uric Acid Level in Patients with SystemicEssential Hypertension in the Context of New 2017 ACC/AHA High Blood Pressure Clinical Practice Guideline, Journal of Evolution of Medical and Dental Sciences, 10.14260/jemds/2020/82, 9:06, (363-367), Online publication date: 10-Feb-2020. Valsaraj R, Singh A, Gangopadhyay K, Ghoshdastidar B, Goyal G, Batin M, Mukherjee D, Sengupta U, Chatterjee S and Sengupta N (2020) Management of asymptomatic hyperuricemia: Integrated Diabetes & Endocrine Academy (IDEA) consensus statement, Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 10.1016/j.dsx.2020.01.007, 14:2, (93-100), Online publication date: 1-Mar-2020. Rosas G, Gaffo A, Rahn E and Saag K (2020) Cardiovascular safety risks associated with gout treatments, Expert Opinion on Drug Safety, 10.1080/14740338.2020.1804551, 19:9, (1143-1154), Online publication date: 1-Sep-2020. Liu X, Chen D, Di F, Shi C, Li H, Wang J and Ji Y (2020) Association between cardiovascular risk factors and stage 1 hypertension defined by the 2017 ACC/AHA guidelines, Clinical and Experimental Hypertension, 10.1080/10641963.2020.1714639, 42:6, (483-489), Online publication date: 17-Aug-2020. January 2018Vol 71, Issue 1 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.117.10443PMID: 29203631 Originally publishedDecember 4, 2017 PDF download Advertisement SubjectsHigh Blood PressureRisk Factors