Serum Uric Acid and Cardiometabolic Disease

HomeHypertensionVol. 69, No. 6Serum Uric Acid and Cardiometabolic Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSerum Uric Acid and Cardiometabolic DiseaseAnother Brick in the Wall? Claudio Borghi and Arrigo Francesco Giuseppe Cicero Claudio BorghiClaudio Borghi From the Department of Medical and Surgical Sciences, University of Bologna, Italy. and Arrigo Francesco Giuseppe CiceroArrigo Francesco Giuseppe Cicero From the Department of Medical and Surgical Sciences, University of Bologna, Italy. Originally published10 Apr 2017https://doi.org/10.1161/HYPERTENSIONAHA.117.09081Hypertension. 2017;69:1011–1013Other 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 1036–1044Several epidemiological and experimental studies have demonstrated a significant relationship between hyperuricemia and hypertension, metabolic syndrome, chronic kidney disease, and cardiovascular events.1,2 This is confirmed in patients with gout,3 as well as in those with asymptomatic hyperuricemia,4 and may significantly contribute to the overall cardiovascular risk beyond the role of traditional risk factors. However, most of the studies assessing the role of elevated serum uric acid (SUA) in cardiovascular disease have been performed in patients with ≥1 interfering comorbidities. In the present issue of Hypertension, Kuwabara et al5 have provided an interesting demonstration that hyperuricemia, per se, can be associated with an independent increase in the risk of cardiometabolic diseases in a large Japanese population. Specifically, after exclusion of all the patients with overt cardiometabolic disease at baseline, hyperuricemia was still associated with an increased incidence of hypertension, dyslipidemia, chronic kidney disease, and overweight/obesity. These results agree with those of the MRFIT (Multiple Risk Factor Intervention Trial)6 and the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni)7 studies, showing a significant increase in the new onset of hypertension and metabolic syndrome in healthy subjects with elevated SUA levels after the adjustment for confounding risk factors associated with hyperuricemia.The findings of Kuwabara et al5 partially overcome one of the main obstacles in the evaluation of the pathogenetic role of elevated SUA levels in cardiovascular disease, namely the possible interference of other risk factors currently associated with hyperuricemia. This problem has usually been resolved with the application of multiple statistical adjustments, leading to a better definition of the importance of the different causative factors by excluding spurious correlations. However, data adjustment engenders an artificial interpretation of evidence because it is based on a presumed reciprocal interaction among causative factors without considering the sequential mechanistic approach. A typical example is the adjustment for baseline blood pressure values that were used by the Framingham investigators to exclude a causative role of SUA as a risk factor for cardiovascular disease.8 At present, such adjustment seems difficult to justify in presence of many demonstrations of a significant effect of SUA over the new onset of hypertension.1 Furthermore, although data adjustment can reasonably exclude the independent causative role of covariates, it cannot rule out their contributing effect to the physiological cascade, leading to a clinical phenotype. This seems to be the case for elevated levels of SUA. Elevated levels of SUA have been the object of extensive adjustment procedures, reaching different conclusions about its independent role as a risk factor for cardiometabolic disease. However, a proper definition of the role of SUA can be achieved by a direct evaluation of an appropriate population of subjects where any possible concurrent risk factors for cardiovascular disease can be reasonably excluded at baseline.All these considerations support the notion that a correct interpretation of the pathogenetic role of SUA, in subjects at risk of cardiometabolic disease, cannot only consider the impact of hyperuricemia but should also take into account the heterogeneity of subjects apparently bearing the same levels of SUA (phenotypic profile).A large body of evidence has demonstrated that a comparable level of SUA can be observed either as a consequence of an increased urate reabsorption or in response to an overproduction of the same compound. The second option may result from an excessive introduction/degradation of purine precursors or as a consequence of enhanced activation of xanthine oxidoreductase system.9 This dual mechanism identifies 2 different types of patients but also 2 different approaches to the interpretation of data on SUA with respect to cardiovascular risk (Figure). The renal (entero-renal according with the distribution of URAT-1 [urate transporter-1]) predominance is more typical of patients with gout and might be associated with metabolic disorders, including obesity and insulin resistance, largely involved in the secondary increase in plasma levels of uric acid. In this subtype of patients, the adjustment of data for the possible confounding factors is more than justified and may provide a reliable estimate of the residual impact of hyperuricemia beyond that of the established cardiovascular risk factor. Conversely, the productive pathway is probably associated to the increased oxidative stress that accompanies the activation of xanthine oxidoreductase; this may cause a functional and structural change of the vascular system and neurohormonal control.9 A hypothesis of a 2-component system controlling for the increased plasma levels of SUA has already been proposed in the literature10 and could represent a reliable explanation for the clinical differences among subjects with comparable serum urate levels. The predominant role of a mechanism linking the production of uric acid to oxidative stress can reasonably explain the evidence of an increased risk of death and major cardiovascular disease in subjects with SUA levels falling within the so-called normal range (usually <6.8 mg/dL).11,12 Increased uric acid production and, perhaps xanthine oxidase activity, might explain the results reported in this issue of Hypertension by Kuwabara et al5 because this enzyme can generate reactive oxygen species as a side production. This interpretation, however, does not exclude a direct mechanism involving the intracellular transport of urate resulting from the activation of the same transport systems (eg, URAT-1) that are responsible for renal urate handling and gout.13 Increased intracellular urate levels can promote the activation of oxidative mechanisms, as well as mitochondrial dysfunction and renin–angiotensin system stimulation14 that may contribute to adverse cardiometabolic effects of hyperuricemia.Download figureDownload PowerPointFigure. Schematic summary of the main pathways involved in uric acid production, serum levels, and impact on cardiometabolic disease. CV indicates cardiovascular; LDL, low-density lipoprotein; NO, nitric oxide; RAAS, renin-angiotensin-aldosterone system; SUA, serum uric acid; XO, xanthine oxide; and XOR, xanthine oxidoreductase.Consequently, the reliability of SUA levels as a risk factor for future cardiometabolic disease might be considerably increased by identifying those patients with an increased production of uric acid. For this purpose, the measure of plasma levels of xanthine oxidase is probably not the solution unless integrated by a precise accountability of the corresponding purines load. On the other hand, the simple determination of urate excretion or the ratio of SUA/urate excretion are also inadequate estimates of overproduction because of the unpredictable contribution of intestinal urate absorption to the cumulative urate handling. Future research should probably consider development of a simple and reproducible estimate of xanthine oxidase levels that integrate the measurement of serum urate levels. A similar approach has already been developed in patients with primary hyperaldosteronism by measuring the levels of plasma renin activity as an estimate of the renin–angiotensin system activation behind the aldosterone plasma levels. This dual approach could allow a clinical interpretation of SUA levels not simply as absolute values, but as an indirect estimate of the level of generated oxidative stress.In the study of Kuwabara et al,5 there is a possibility that in most uncomplicated patients reaching the primary study end point, the activation of the productive pathway of SUA can play a predominant role in addition to that of serum urate levels. This is supported by the fact that during the period of observation, there was apparently no report of incident gout, and the impact of hyperuricemia on hypertension, diabetes mellitus, and CKD was more evident in women where the contribution of renal mechanisms is minimal because of the uricosuria effect of estrogens (mean age of the population from 46.6 to 48.4 years).In conclusion, the results of the study by Kuwabara et al5 must be considered as another brick in the wall that supports the role of SUA as a risk factor for cardiometabolic diseases. Specifically, we suggest that a correct interpretation of serum levels of uric acid can offer a practical, informative, and cheap approach to the identification of those patients where high residual cardiovascular risk may still be responsible for a considerable rate of cardiovascular disease, despite the recommendations of the golden guidelines.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Claudio Borghi, Unità Operative di Medicina Interna, Policlinico S.Orsola-Malpighi, 40139 Bologna, Italy. E-mail [email protected]References1. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk.N Engl J Med. 2008; 359:1811–1821. doi: 10.1056/NEJMra0800885.CrossrefMedlineGoogle Scholar2. Borghi C, Rosei EA, Bardin T, Dawson J, Dominiczak A, Kielstein JT, Manolis AJ, Perez-Ruiz F, Mancia G. Serum uric acid and the risk of cardiovascular and renal disease.J Hypertens. 2015; 33:1729–41; discussion 1741. doi: 10.1097/HJH.0000000000000701.CrossrefMedlineGoogle Scholar3. Bhole V, Krishnan E. Gout and the heart.Rheum Dis Clin North Am. 2014; 40:125–143. doi: 10.1016/j.rdc.2013.10.004.CrossrefMedlineGoogle Scholar4. Cicero AF, Salvi P, D'Addato S, Rosticci M, Borghi C; Brisighella Heart Study group. Association between serum uric acid, hypertension, vascular stiffness and subclinical atherosclerosis: data from the Brisighella Heart Study.J Hypertens. 2014; 32:57–64. doi: 10.1097/HJH.0b013e328365b916.CrossrefMedlineGoogle Scholar5. Kuwabara M, Niwa K, Hisatome I, Nakagawa T, Roncal-Jimenez C, Andres-Hernando A, Bjornstad P, Jensen T, Sato Y, Milagres T, Garcia G, Ohno M, Lanaspa MA, Johnson RJ. Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: five-year Japanese cohort study.Hypertension. 2017; 69:1036–1044. doi: 10.1161/HYPERTENSIONAHA.116.08998LinkGoogle Scholar6. Krishnan E, Kwoh CK, Schumacher HR, Kuller L. Hyperuricemia and incidence of hypertension among men without metabolic syndrome.Hypertension. 2007; 49:298–303. doi: 10.1161/01.HYP.0000254480.64564.b6.LinkGoogle Scholar7. Bombelli M, Ronchi I, Volpe M, Facchetti R, Carugo S, Dell'oro R, Cuspidi C, Grassi G, Mancia G. Prognostic value of serum uric acid: new-onset in and out-of-office hypertension and long-term mortality.J Hypertens. 2014; 32:1237–1244. doi: 10.1097/HJH.0000000000000161.CrossrefMedlineGoogle Scholar8. 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.CrossrefMedlineGoogle Scholar9. Landmesser U, Spiekermann S, Preuss C, Sorrentino S, Fischer D, Manes C, Mueller M, Drexler H. Angiotensin II induces endothelial xanthine oxidase activation: role for endothelial dysfunction in patients with coronary disease.Arterioscler Thromb Vasc Biol. 2007; 27:943–948. doi: 10.1161/01.ATV.0000258415.32883.bf.LinkGoogle Scholar10. Ichida K, Matsuo H, Takada T, et al. Decreased extra-renal urate excretion is a common cause of hyperuricemia.Nat Commun. 2012; 3:764. doi: 10.1038/ncomms1756.CrossrefMedlineGoogle Scholar11. Niskanen LK, Laaksonen DE, Nyyssönen K, Alfthan G, Lakka HM, Lakka TA, Salonen JT. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study.Arch Intern Med. 2004; 164:1546–1551. doi: 10.1001/archinte.164.14.1546.CrossrefMedlineGoogle Scholar12. Loeffler LF, Navas-Acien A, Brady TM, Miller ER, Fadrowski JJ. Uric acid level and elevated blood pressure in US adolescents: National Health and Nutrition Examination Survey, 1999-2006.Hypertension. 2012; 59:811–817. doi: 10.1161/HYPERTENSIONAHA.111.183244.LinkGoogle Scholar13. Price KL, Sautin YY, Long DA, Zhang L, Miyazaki H, Mu W, Endou H, Johnson RJ. Human vascular smooth muscle cells express a urate transporter.J Am Soc Nephrol. 2006; 17:1791–1795. doi: 10.1681/ASN.2006030264.CrossrefMedlineGoogle Scholar14. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, Ishimoto T, Sautin YY, Lanaspa MA. Sugar, uric acid, and the etiology of diabetes and obesity.Diabetes. 2013; 62:3307–3315. doi: 10.2337/db12-1814.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByNardi V, Franchi F, Prasad M, Fatica E, Alexander M, Bois M, Lam J, Singh R, Meyer F, Lanzino G, Xiong Y, Lutgens E, Lerman L and Lerman A (2022) Uric Acid Expression in Carotid Atherosclerotic Plaque and Serum Uric Acid Are Associated With Cerebrovascular Events, Hypertension, 79:8, (1814-1823), Online publication date: 1-Aug-2022. Yu X, Gu M, Zhu Y, Zhang L, Kong W and Zou Y (2022) Efficacy of Urate–Lowering Therapy in Patients With Chronic Kidney Disease: A Network Meta-Analysis of Randomized Controlled Trials, Clinical Therapeutics, 10.1016/j.clinthera.2022.03.014, 44:5, (723-735.e6), Online publication date: 1-May-2022. Bao R, Chen Q, Li Z, Wang D, Wu Y, Liu M, Zhang Y and Wang T (2022) Eurycomanol alleviates hyperuricemia by promoting uric acid excretion and reducing purine synthesis, Phytomedicine, 10.1016/j.phymed.2021.153850, 96, (153850), Online publication date: 1-Feb-2022. Yazdi F, Baghaei M, Baniasad A, Naghibzadeh‐Tahami A, Najafipour H and Gozashti M (2021) Investigating the relationship between serum uric acid to high‐density lipoprotein ratio and metabolic syndrome, Endocrinology, Diabetes & Metabolism, 10.1002/edm2.311, 5:1, Online publication date: 1-Jan-2022. Chen S, Wu N, Yu C, Xu Y, Xu C, Huang Y, Zhao J, Li N and Pan X (2021) Association between baseline and changes in serum uric acid and incident metabolic syndrome: a nation-wide cohort study and updated meta-analysis, Nutrition & Metabolism, 10.1186/s12986-021-00584-x, 18:1, Online publication date: 1-Dec-2021. Liu L, Lei J, Zhang L, Ma N, Xu Z, Peng L, Nie C, Zhong J, Zhang X and Hong F (2021) A multiethnic association analysis of hyperuricaemia with cardiovascular risk in rural and urban areas in Chinese adults, Scientific Reports, 10.1038/s41598-021-02740-y, 11:1, Online publication date: 1-Dec-2021. Tan Y, Qing J, Wu G, Li X, Guo F, Wang Y, Wang L and Li M (2021) Correlation between serum uric acid levels and carotid plaque neovascularisation assessed by contrast-enhanced ultrasound, Clinical Radiology, 10.1016/j.crad.2021.08.003, 76:12, (942.e1-942.e6), Online publication date: 1-Dec-2021. Ganji M, Nardi V, Prasad M, Jordan K, Bois M, Franchi F, Zhu X, Tang H, Young M, Lerman L and Lerman A (2021) Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression, Stroke, 52:9, (2792-2801), Online publication date: 1-Sep-2021. Alghamdi A, Althumali J, Almalki M, Almasoudi A, Almuntashiri A, Almuntashiri A, Mohammed A, Alkinani A, Almahdawi M and Mahzari M An Overview on the Role of Xanthine Oxidase Inhibitors in Gout Management, Archives Of Pharmacy Practice, 10.51847/RkCPaycprc, 12:3, (94-99) F.G. Cicero A, Bove M, I. Cincione R, Fogacci F and Veronesi M (2021) Effect of combined lipid-lowering and antioxidant nutraceutical on plasma lipids, endothelial function, and estimated cardiovascular disease risk in moderately hypercholesterolemic patients: a double-blind, placebo-controlled randomized clinical trial, Archives of Medical Science – Atherosclerotic Diseases, 10.5114/amsad.2021.107843, 6:1, (145-151) Cicero A, Fogacci F and Borghi C (2020) Uric acid and thrombotic risk: an emerging link, Internal and Emergency Medicine, 10.1007/s11739-020-02322-2, 15:7, (1167-1168), Online publication date: 1-Oct-2020. Li R, Tian Z, Wang Y, Liu X, Tu R, Wang Y, Dong X, Wang Y, Wei D, Tian H, Mao Z, Li L, Huo W, Wang C and Bie R (2020) The Association of Body Fat Percentage With Hypertension in a Chinese Rural Population: The Henan Rural Cohort Study, Frontiers in Public Health, 10.3389/fpubh.2020.00070, 8 Mazidi M, Katsiki N, Mikhailidis D and Banach M (2020) Associations of serum uric acid with total and cause-specific mortality: Findings from individuals and pooling prospective studies, Atherosclerosis, 10.1016/j.atherosclerosis.2019.07.019, 296, (49-58), Online publication date: 1-Mar-2020. Zeng X, Lodge C, Dharmage S, Bloom M, Yu Y, Yang M, Chu C, Li Q, Hu L, Liu K, Yang B and Dong G (2019) Isomers of per- and polyfluoroalkyl substances and uric acid in adults: Isomers of C8 Health Project in China, Environment International, 10.1016/j.envint.2019.105160, 133, (105160), Online publication date: 1-Dec-2019. Nasi M, Patrizi G, Pizzi C, Landolfo M, Boriani G, Dei Cas A, Cicero A, Fogacci F, Rapezzi C, Sisca G, Capucci A, Vitolo M, Galiè N, Borghi C, Berrettini U, Piepoli M and Mattioli A (2019) The role of physical activity in individuals with cardiovascular risk factors, Journal of Cardiovascular Medicine, 10.2459/JCM.0000000000000855, 20:10, (631-639), Online publication date: 1-Oct-2019. Cicero A, Cosentino E, Kuwabara M, Degli Esposti D and Borghi C (2019) Effects of allopurinol and febuxostat on cardiovascular mortality in elderly heart failure patients, Internal and Emergency Medicine, 10.1007/s11739-019-02070-y, 14:6, (949-956), Online publication date: 1-Sep-2019. Song M, Li N, Yao Y, Wang K, Yang J, Cui Q, Geng B, Chen J, Wang Y, Cheng W and Zhou Y (2019) Longitudinal association between serum uric acid levels and multiterritorial atherosclerosis, Journal of Cellular and Molecular Medicine, 10.1111/jcmm.14337, 23:8, (4970-4979), Online publication date: 1-Aug-2019. Strilchuk L, Fogacci F and Cicero A (2019) Safety and tolerability of available urate-lowering drugs: a critical review, Expert Opinion on Drug Safety, 10.1080/14740338.2019.1594771, 18:4, (261-271), Online publication date: 3-Apr-2019. Cicero A, Fogacci F, Giovannini M, Grandi E, D'Addato S and Borghi C (2019) Interaction between low-density lipoprotein-cholesterolaemia, serum uric level and incident hypertension, Journal of Hypertension, 10.1097/HJH.0000000000001927, 37:4, (728-731), Online publication date: 1-Apr-2019. Kuwabara M, Chintaluru Y, Kanbay M, Niwa K, Hisatome I, Andres-Hernando A, Roncal-Jimenez C, Ohno M, Johnson R and Lanaspa M (2019) Fasting blood glucose is predictive of hypertension in a general Japanese population, Journal of Hypertension, 10.1097/HJH.0000000000001895, 37:1, (167-174), Online publication date: 1-Jan-2019. Bian M, Lin Z, Wang Y, Zhang B, Li G and Wang H (2018) Bioinformatic and Metabolomic Analysis Reveal Intervention Effects of Chicory in a Quail Model of Hyperuricemia, Evidence-Based Complementary and Alternative Medicine, 10.1155/2018/5730385, 2018, (1-13), Online publication date: 3-Dec-2018. Saxena T, Ali A and Saxena M (2018) Pathophysiology of essential hypertension: an update, Expert Review of Cardiovascular Therapy, 10.1080/14779072.2018.1540301, 16:12, (879-887), Online publication date: 2-Dec-2018. Cicero A, Fogacci F, Giovannini M, Grandi E, Rosticci M, D'Addato S and Borghi C (2018) Serum uric acid predicts incident metabolic syndrome in the elderly in an analysis of the Brisighella Heart Study, Scientific Reports, 10.1038/s41598-018-29955-w, 8:1, Online publication date: 1-Dec-2018. Katsiki N and Borghi C (2018) The future of febuxostat after the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial: who CARES?, Expert Opinion on Pharmacotherapy, 10.1080/14656566.2018.1532503, 19:17, (1853-1856), Online publication date: 22-Nov-2018. Johnson R, Bakris G, Borghi C, Chonchol M, Feldman D, Lanaspa M, Merriman T, Moe O, Mount D, Sanchez Lozada L, Stahl E, Weiner D and Chertow G (2018) Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation, American Journal of Kidney Diseases, 10.1053/j.ajkd.2017.12.009, 71:6, (851-865), Online publication date: 1-Jun-2018. Kuwabara M, Borghi C, Cicero A, Hisatome I, Niwa K, Ohno M, Johnson R and Lanaspa M (2018) Elevated serum uric acid increases risks for developing high LDL cholesterol and hypertriglyceridemia: A five-year cohort study in Japan, International Journal of Cardiology, 10.1016/j.ijcard.2018.03.045, 261, (183-188), Online publication date: 1-Jun-2018. Borghi C and Cicero A (2018) Letter by Borghi and Cicero Regarding Article, "Modifiable Risk Factors and Atrial Fibrillation", Circulation, 137:14, (1532-1533), Online publication date: 3-Apr-2018. Mazidi M, Katsiki N, Mikhailidis D and Banach M (2018) The link between insulin resistance parameters and serum uric acid is mediated by adiposity, Atherosclerosis, 10.1016/j.atherosclerosis.2017.12.033, 270, (180-186), Online publication date: 1-Mar-2018. Kuwabara M, Hisatome I, Niwa K, Hara S, Roncal-Jimenez C, Bjornstad P, Nakagawa T, Andres-Hernando A, Sato Y, Jensen T, Garcia G, Rodriguez-Iturbe B, Ohno M, Lanaspa M and Johnson R (2017) Uric Acid Is a Strong Risk Marker for Developing Hypertension From Prehypertension, Hypertension, 71:1, (78-86), Online publication date: 1-Jan-2018. Cicero A, Pirro M, Watts G, Mikhailidis D, Banach M and Sahebkar A (2017) Effects of Allopurinol on Endothelial Function: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials, Drugs, 10.1007/s40265-017-0839-5, 78:1, (99-109), Online publication date: 1-Jan-2018. Bove M, Cicero A and Borghi C (2017) The Effect of Xanthine Oxidase Inhibitors on Blood Pressure and Renal Function, Current Hypertension Reports, 10.1007/s11906-017-0793-3, 19:12, Online publication date: 1-Dec-2017. Borghi C (2017) The management of hyperuricemia: back to the pathophysiology of uric acid, Current Medical Research and Opinion, 10.1080/03007995.2017.1378502, 33:sup3, (1-4), Online publication date: 17-Nov-2017. Matsukuma Y, Masutani K, Tanaka S, Tsuchimoto A, Haruyama N, Okabe Y, Nakamura M, Tsuruya K and Kitazono T (2017) Association between serum uric acid level and renal arteriolar hyalinization in individuals without chronic kidney disease, Atherosclerosis, 10.1016/j.atherosclerosis.2017.09.017, 266, (121-127), Online publication date: 1-Nov-2017. Seravalle G and Grassi G (2017) Obesity and hypertension, Pharmacological Research, 10.1016/j.phrs.2017.05.013, 122, (1-7), Online publication date: 1-Aug-2017. Cicero A, Fogacci F, Bove M, Veronesi M, Rizzo M, Giovannini M and Borghi C (2017) Short-Term Effects of a Combined Nutraceutical on Lipid Level, Fatty Liver Biomarkers, Hemodynamic Parameters, and Estimated Cardiovascular Disease Risk: A Double-Blind, Placebo-Controlled Randomized Clinical Trial, Advances in Therapy, 10.1007/s12325-017-0580-1, 34:8, (1966-1975), Online publication date: 1-Aug-2017. Caliceti C, Calabria D, Roda A and Cicero A (2017) Fructose Intake, Serum Uric Acid, and Cardiometabolic Disorders: A Critical Review, Nutrients, 10.3390/nu9040395, 9:4, (395) June 2017Vol 69, Issue 6 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.117.09081PMID: 28396532 Originally publishedApril 10, 2017 PDF download Advertisement SubjectsCardiovascular DiseaseEpidemiologyRisk Factors