Uric Acid and Risk of Cardiovascular Disease: A Question of Start and Finish
2021; Lippincott Williams & Wilkins; Volume: 78; Issue: 5 Linguagem: Inglês
10.1161/hypertensionaha.121.17631
ISSN1524-4563
AutoresClaudio Borghi, Federica Piani,
Tópico(s)Pharmacological Effects of Natural Compounds
ResumoHomeHypertensionVol. 78, No. 5Uric Acid and Risk of Cardiovascular Disease: A Question of Start and Finish Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBUric Acid and Risk of Cardiovascular Disease: A Question of Start and Finish Claudio Borghi and Federica Piani Claudio BorghiClaudio Borghi Correspondence to: Claudio Borghi, Department of Medical and Surgical Sciences, IRCCS S.Orsola, University of Bologna, Via Albertoni 15, 40139, Bologna, Italy. Email E-mail Address: [email protected] https://orcid.org/0000-0001-8039-8781 Department of Medical and Surgical Sciences., IRCCS S.Orsola, University of Bologna, Bologna, Italy. Search for more papers by this author and Federica PianiFederica Piani Department of Medical and Surgical Sciences., IRCCS S.Orsola, University of Bologna, Bologna, Italy. Search for more papers by this author Originally published13 Oct 2021https://doi.org/10.1161/HYPERTENSIONAHA.121.17631Hypertension. 2021;78:1219–1221This article is a commentary on the followingSerum Urate Trajectory in Young Adulthood and Incident Cardiovascular Disease Events by Middle Age: CARDIA StudySee related article, pp 1211–1218Uric acid (UA) is the final product of purine metabolism and its increase in the circulating blood defines the presence of hyperuricemia commonly considered as a concentration of UA in serum above the threshold level of 7 mg/dL (416 μmol/L) in men and >6 mg/dL in women.1 The typical consequence of elevated UA levels is the development of gout, a condition affecting 2% to 3% of the general population with a higher prevalence in patients with cardiac and metabolic diseases.1 Beside the effects on gout, the elevated levels of UA have been associated with a significant increase in the risk of hypertension, metabolic syndrome, and cardiovascular disease (CVD) regardless of the presence of serum urate deposition.2 All this evidence clearly supports a primary cardiovascular role for elevated serum UA probably based on multiple and interactive mechanisms of action3 not necessarily involving the articular and tissue deposition. In particular, the mechanism of production of serum uric acid (SUA) directly involves the XOR (xanthine oxidoreductase) enzyme whose activation produces oxidative species leading to vascular endothelial dysfunction, LDL (low-density lipoprotein) oxidation, and activation of the inflammasome and atherogenic processes whose entity is largely proportional to the plasma levels of UA and more evident is SUA hyperproducers.3 As alternative hypothesis, the deposition of urate crystal could activate the inflammasome system at the vascular levels,3 but this mechanism is less supported according to the evidence from the URRAH (uric acid and cardiovascular risk of the Italian Society of Hypertension) study and many others4 suggesting a negative cardiovascular impact of UA for plasma levels well below those required for urate crystal precipitation (6.5 mg/dL).In the present issue of the Journal, Morikawa et al5 have investigated the relationship between SUA trajectories and the rate of CVD for over 20 years in a population of >3000 subjects enrolled in the CARDIA study (Coronary Artery Risk Development in Young Adults). They concluded that high-increasing serum UA pattern trajectory during adulthood is associated with incident CVD later in life with a major impact on blood pressure during the exposure period. The results remain significant after adjustment for the most relevant confounding risk factors including age, gender, blood pressure, body mass index, lipid profile, and glomerular filtration rate. Similar conclusions have been reached by 2 previous cohort studies assessing the relationship between different UA trajectories and the new onset of hypertension. Cicero et al6 have reported the results of different UA patterns in a cohort of about 3000 subjects of the Brisighella Heart Study. They demonstrated that the increase in serum UA over a 4-year follow-up is associated with an age-related increase of SBP and fasting serum glucose, whereas an opposite trend was observed in subjects showing to a decrease in urate levels. Ma et al,7 in a prospective cohort of about 6000 normotensive middle-aged subjects, identified 5 distinct trajectory groups of serum UA and reported an adjusted hazard ratio for new onset of hypertension that was higher in all subgroups showing an increase in serum UA (low-high, moderate-high, and stable high) regardless of concurrent changes in body weight. The study of Morikawa et al5 is the ideal extension of such earlier observations and confirms the negative impact of incremental UA trajectories on blood pressure and the risk of CVD over a longer period of follow-up. Cumulatively these 3 studies support the hypothesis of a sequential mechanism leading from increased serum UA, to changes in vascular tone, raised blood pressure values, and major CVD.3 Furthermore, the serial measurement of SUA levels may support the recent concept of exposure to risk factors that have already been applied to lipid profile8 by considering the role of time and age to quantify an area of risk that could be more discriminant in terms of cardiovascular outcome when compared with a single time point approach. In terms of clinical epidemiology, the study proposes an interesting evolution of the concept of UA as a risk factor for CVD by significantly reducing the confounding effect of individual fluctuations of serum UA levels particularly when tested against hard measures of cardiovascular outcome (target organ damage, overt cardiovascular disease).The main study limitation is the categorization of patients, that describes populations already identified at the baseline while the use of trajectories is just reflecting the time course of the disease. This problem could be solved by a different aggregation of patients (eg, distribution around reference or median serum urate levels), or by demonstrating the additive value of serum UA trajectories over the single time point estimate. The relative importance of reference levels has been estimated by comparing different pattern of serum UA changes defined according to serum urate levels above or below the normal value suggest by American College of Rheumatology guidelines (6.8 mg/dL).9 This approach has indirectly confirmed the relevance of trajectory pattern by showing a comparable hazard ratio for CVD in low-to-high (1.83 [95% CI, 1.18–2.85]) and high-to-low groups (1.73 [95% CI, 0.80–3.74]) that seem to exclude the possibility that a simple estimate of baseline serum UA levels can universally predict CVD. However, the selected threshold value applies to the risk of developing gout, whereas the results of several observations, including a couple of recent papers of our group, have shown that even levels of serum UA usually considered in the normal range (>5.0 mg/dL in men or 4.5 mg/dL in postmenopausal women) can be associated with an increased incidence and mortality for CVD and heart failure.4,10 The implications of this gap in the threshold level of serum UA is probably a misclassification of the expected cardiovascular risk with some subjects at high risk of CVD contributing to the event rate observed in the normal group. Conversely, the use of the individual changes of median value of serum UA that is closer to the cardiovascular threshold, allows a more correct categorization of patients at risk of CVD (low-to-high: hazard ratio, 1.88 [95% CI, 1.10–3.21] and high-to-low: 1.18 [95% CI, 0.63–2.23]), supporting the idea that future investigations on the cardiovascular impact of serum UA should be conducted according to a different range of normal values. This potential limitation in the estimate of the dangerous serum UA levels can be largely circumvented by considering the pattern of serum urate changes over time because this approach is largely independent of baseline values and reasonably includes a significant number of subjects whose SU levels are within the new cardiovascular range. However, the most reliable evidence of the superior consistency of the different patterns of trajectories in comparison to a single measure of serum urate was included in the sensitivity analysis in the Morikawa et al’s study5 that provided a value of Net Reclassification Improvement showing a better predictive value for serum urate trajectories for incident CVD when compared to single value of serum urate level (net reclassification improvement, 0.14 [95% CI, 0.050–24]). In particular, the estimate of SUA trajectories could reflect both the extent and the persistence of xanthine oxidase activation and their cardiovascular implication (Figure). This introduces the important concept of exposure to SUA-mediated oxidative stress and indirectly identifies those hyperproducer subjects where XOR activity is more probably under genetic control.Download figureDownload PowerPointFigure. Mechanism integrating the relevance of serum uric acid trajectory with XOR (xanthine oxidoreductase) activation in the development of hypertension and cardiovascular (CV) disease in patients with hyperuricemia. LDL-C, low-density lipoprotein cholesterol.In conclusion, the dynamic analysis of time-dependent trajectories of cardiovascular risk factors is a new approach to the interpretation and clinical management of cardiovascular disease. The overall representativity of a pattern of modification seems to better define the prognostic role of a single risk factor and could be probably improved by an integrated interpretation of the different patterns beyond the role of risk cards and algorithms. The main difference between risk cards, single value readings, and the interpretation of multiple trajectories is the time, that is the third-dimension additive to estimated probability of risk and event rate and that allow the identification of significant cardiovascular risk conditions where the practical approach based on the discipline of thresholds and targets is probably not enough.Sources of FundingNone.Disclosures C. Borghi has received personal fees from Servier, Novartis, Alfasigma, Alnylam, Merck Pharma, Sanofi, Menarini Corporate as a speaker or member of advisory board. The other author reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1221.Correspondence to: Claudio Borghi, Department of Medical and Surgical Sciences, IRCCS S.Orsola, University of Bologna, Via Albertoni 15, 40139, Bologna, Italy. Email claudio.[email protected]itReferences1. Bardin T, Richette P. Definition of hyperuricemia and gouty conditions.Curr Opin Rheumatol. 2014; 26:186–191. doi: 10.1097/BOR.0000000000000028CrossrefMedlineGoogle Scholar2. Borghi C, Agabiti-Rosei E, Johnson RJ, Kielstein JT, Lurbe E, Mancia G, Redon J, Stack AG, Tsioufis KP. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease.Eur J Intern Med. 2020; 80:1–11. doi: 10.1016/j.ejim.2020.07.006CrossrefMedlineGoogle Scholar3. Ndrepepa G. Uric acid and cardiovascular disease.Clin Chim Acta. 2018; 484:150–163. doi: 10.1016/j.cca.2018.05.046CrossrefMedlineGoogle Scholar4. Virdis A, Masi S, Casiglia E, Tikhonoff V, Cicero AFG, Ungar A, Rivasi G, Salvetti M, Barbagallo CM, Bombelli M, et al.; from the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension. 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Muiesan ML, Salvetti M, Virdis A, Masi S, Casiglia E, Tikhonoff V, Barbagallo CM, Bombelli M, Cicero AFG, Cirillo M, et al.; from the Working Group on Uric Acid, Cardiovascular Risk of the Italian Society of Hypertension. Serum uric acid, predicts heart failure in a large Italian cohort: search for a cut-off value the URic acid right for heart health study.J Hypertens. 2021; 39:62–69. doi: 10.1097/HJH.0000000000002589CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesSerum Urate Trajectory in Young Adulthood and Incident Cardiovascular Disease Events by Middle Age: CARDIA StudyNagisa Morikawa, et al. Hypertension. 2021;78:1211-1218 November 2021Vol 78, Issue 5Article InformationMetrics Download: 251 © 2021 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.121.17631PMID: 34644173 Originally publishedOctober 13, 2021 PDF download Advertisement SubjectsCardiovascular DiseaseHypertension
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