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Serum Uric Acid Predicts All-Cause and Cardiovascular Mortality Independently of Hypertriglyceridemia in Cardiometabolic Patients without Established CV Disease: A Sub-Analysis of the URic acid Right for heArt Health (URRAH) Study.

ABSTRACT: High serum uric acid (SUA) and triglyceride (TG) levels might promote high-cardiovascular risk phenotypes across the cardiometabolic spectrum. However, SUA predictive power in the presence of normal and high TG levels has never been investigated. We included 8124 patients from the URic acid Right for heArt Health (URRAH) study cohort who were followed for over 20 years and had no established cardiovascular disease or uncontrolled metabolic disease. All-cause mortality (ACM) and cardiovascular mortality (CVM) were explored by the Kaplan-Meier estimator and Cox multivariable regression, adopting recently defined SUA cut-offs for ACM (≥4.7 mg/dL) and CVM (≥5.6 mg/dL). Exploratory analysis across cardiometabolic subgroups and a sensitivity analysis using SUA/serum creatinine were performed as validation. SUA predicted ACM (HR 1.25 [1.12-1.40], p < 0.001) and CVM (1.31 [1.11-1.74], p < 0.001) in the whole study population, and according to TG strata: ACM in normotriglyceridemia (HR 1.26 [1.12-1.43], p < 0.001) and hypertriglyceridemia (1.31 [1.02-1.68], p = 0.033), and CVM in normotriglyceridemia (HR 1.46 [1.23-1.73], p < 0.001) and hypertriglyceridemia (HR 1.31 [0.99-1.64], p = 0.060). Exploratory and sensitivity analyses confirmed our findings, suggesting a substantial role of SUA in normotriglyceridemia and hypertriglyceridemia. In conclusion, we report that SUA can predict ACM and CVM in cardiometabolic patients without established cardiovascular disease, independent of TG levels.

SUBMITTER: Mengozzi A

PROVIDER: S-EPMC9959524 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Serum Uric Acid Predicts All-Cause and Cardiovascular Mortality Independently of Hypertriglyceridemia in Cardiometabolic Patients without Established CV Disease: A Sub-Analysis of the URic acid Right for heArt Health (URRAH) Study.

Mengozzi Alessandro A Pugliese Nicola Riccardo NR Desideri Giovambattista G Masi Stefano S Angeli Fabio F Barbagallo Carlo Maria CM Bombelli Michele M Cappelli Federica F Casiglia Edoardo E Cianci Rosario R Ciccarelli Michele M Cicero Arrigo F G AFG Cirillo Massimo M Cirillo Pietro P Dell'Oro Raffaella R D'Elia Lanfranco L Ferri Claudio C Galletti Ferruccio F Gesualdo Loreto L Giannattasio Cristina C Grassi Guido G Iaccarino Guido G Lippa Luciano L Mallamaci Francesca F Maloberti Alessandro A Masulli Maria M Mazza Alberto A Muiesan Maria Lorenza ML Nazzaro Pietro P Palatini Paolo P Parati Gianfranco G Pontremoli Roberto R Quarti-Trevano Fosca F Rattazzi Marcello M Reboldi Gianpaolo G Rivasi Giulia G Russo Elisa E Salvetti Massimo M Tikhonoff Valerie V Tocci Giuliano G Ungar Andrea A Verdecchia Paolo P Viazzi Francesca F Volpe Massimo M Borghi Claudio C Virdis Agostino A

Metabolites 20230207 2

High serum uric acid (SUA) and triglyceride (TG) levels might promote high-cardiovascular risk phenotypes across the cardiometabolic spectrum. However, SUA predictive power in the presence of normal and high TG levels has never been investigated. We included 8124 patients from the URic acid Right for heArt Health (URRAH) study cohort who were followed for over 20 years and had no established cardiovascular disease or uncontrolled metabolic disease. All-cause mortality (ACM) and cardiovascular mo ...[more]

PMID: 36837863

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Project description:BackgroundHyperuricemia is commonly observed in patients with chronic kidney disease (CKD). However, a better understanding of the relationship among uric acid (UA) values, glomerular filtration rate (GFR) and albuminuria may shed light on the mechanisms underlying the excess of cardiovascular mortality associated with both chronic kidney disease and hyperuricemia and lead to better risk stratification. Our main goal was to study the relationships between serum uric acid and kidney disease measures (namely estimated GFR [eGFR] and albuminuria) in a large cohort of individuals at cardiovascular risk from the URic acid Right for heArt Health (URRAH) Project database.MethodsClinical data of 26,971 individuals were analyzed. Factors associated with the presence of hyperuricemia defined on the basis of previously determined URRAH cutoffs for cardiovascular and all-cause mortality were evaluated through multivariate analysis. Chronic kidney disease was defined as eGFR < 60 ml/min per 1.73 m2 and/or abnormal urinary albumin excretion diagnosed as: (i) microalbuminuria if urinary albumin concentration was > 30 and ≤ 300 mg/L, or if urinary albumin-to-creatinine ratio (ACR) was > 3.4 mg/mmol and ≤ 34 mg/mmol; (ii) macroalbuminuria if urinary albumin concentration was > 300 mg/L, or if ACR was > 34 mg/mmol.ResultsMean age was 58 ± 15 years (51% males, 62% with hypertension and 12% with diabetes), mean eGFR was 81 ml/min per 1.73m22with a prevalence of eGFR < 60 and micro- or macroalbuminuria of 16, 15 and 4%, respectively. Serum uric acid showed a trend towards higher values along with decreasing renal function. Both the prevalence of gout and the frequency of allopurinol use increased significantly with the reduction of eGFR and the increase in albuminuria. Hyperuricemia was independently related to male gender, eGFR strata, and signs of insulin resistance such as body mass index (BMI) and triglycerides.ConclusionsThe lower the eGFR the higher the prevalence of hyperuricemia and gout. In subjects with eGFR < 60 ml/min the occurrence of hyperuricemia is about 10 times higher than in those with eGFR > 90 ml/min. The percentage of individuals treated with allopurinol was below 2% when GFR was above 60 ml/min, it increased to 20% in the presence of CKD 3b and rose further to 35% in individuals with macroalbuminuria.

Project description:Several studies have detected a direct association between serum uric acid (SUA) and cardiovascular (CV) risk. In consideration that SUA largely depends on kidney function, some studies explored the role of the serum creatinine (sCr)-normalized SUA (SUA/sCr) ratio in different settings. Previously, the URRAH (URic acid Right for heArt Health) Study has identified a cut-off value of this index to predict CV mortality at 5.35 Units. Therefore, given that no SUA/sCr ratio threshold for CV risk has been identified for patients with diabetes, we aimed to assess the relationship between this index and CV mortality and to validate this threshold in the URRAH subpopulation with diabetes; the URRAH participants with diabetes were studied (n = 2230). The risk of CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. During a median follow-up of 9.2 years, 380 CV deaths occurred. A non-linear inverse association between baseline SUA/sCr ratio and risk of CV mortality was detected. In the whole sample, SUA/sCr ratio > 5.35 Units was not a significant predictor of CV mortality in diabetic patients. However, after stratification by kidney function, values > 5.35 Units were associated with a significantly higher mortality rate only in normal kidney function, while, in participants with overt kidney dysfunction, values of SUA/sCr ratio > 7.50 Units were associated with higher CV mortality. The SUA/sCr ratio threshold, previously proposed by the URRAH Study Group, is predictive of an increased risk of CV mortality in people with diabetes and preserved kidney function. While, in consideration of the strong association among kidney function, SUA, and CV mortality, a different cut-point was detected for diabetics with impaired kidney function. These data highlight the different predictive roles of SUA (and its interaction with kidney function) in CV risk, pointing out the difference in metabolic- and kidney-dependent SUA levels also in diabetic individuals.

Project description:BackgroundAccumulating evidence suggests that elevated serum uric acid (SUA) may be a risk factor for hypertriglyceridemia (HTG). However, the epidemiological evidence for the association between SUA and HTG is limited. This article aimed to use the data from National Health and Nutrition Examination Survey (NHANES) (2007-2018) database to bridge the research gap.MethodsThis cross-sectional study used data from 10027 adults involved in NHANES from 2007-2018. We designed the exposure variable as SUA and the outcome variable as HTG. The covariates included demographics, questionnaires, laboratory, and examination information. Weighted logistic regression and subgroup analysis were used to explore the independent association between SUA and HTG. Furthermore, interaction tests were also carried out to evaluate the strata differences. Generalized additive models (GAM), smooth curve fittings, and threshold effect analysis were applied to examine the non-linear relationship.ResultsA total of 10027 participants were included, of which 3864 were HTG participants and 6163 were non-HTG participants. After fully adjusting for confounders, weighted multiple logistic regression models revealed a 77% increase in the risk of HTG when each unit of log2-SUA increased. There was also a positive association between elevated log2-SUA and developed risk of HTG in the quartile (Q) groups (Q1 OR: 1.00; Q2 OR: 1.17 [95%CI: 0.95,1.45]; Q3 OR: 1.43 [95%CI: 1.16,1.78]; Q4 OR: 1.68 [95%CI: 1.36,2.08]. The subgroup analysis results remained consistent across strata, with a strong positive correlation between SUA and HTG. Interaction tests showed no dependence on physical activity (PA), gender, BMI, smoking status, alcohol intake, hypertension, and diabetes for this positive association between log2-SUA and HTG (all p for interaction >0.05). The participants' age may impact the strength of the association between SUA and HTG (p for interaction <0.05).ConclusionThere is a positive association between SUA and HTG in US adults. Considering that SUA may be a risk factor for HTG, individuals diagnosed with HTG should prioritize the daily management of SUA as part of their comprehensive care.

Project description:BackgroundA protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies.MethodsUsing a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1.ResultsWe identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents.ConclusionsIn six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).

Project description:ObjectiveThe effects of coffee consumption on serum uric acid (SUA) levels and gout risk are controversial. There have hitherto been no reports based on Mendelian randomization (MR) analysis of its effects that consider pleiotropy. Here, we evaluated the effects of coffee consumption across ancestry populations, taking pleiotropy into account.MethodsWe performed the first MR analyses for coffee consumption on SUA levels and gout, considering pleiotropy. We used the following summary statistics of genome-wide association studies from a Japanese population: habitual coffee consumption (152,634 subjects), gout (3053 cases and 4554 controls), and SUA levels (121,745 subjects). In addition to fixed-effect inverse variance weighted (IVW) meta-analysis, we performed a robust evaluation of heterogeneity and removed several instruments for reasons of possible pleiotropy. Previous European datasets were also reevaluated while heterogeneity was considered.ResultsHabitual coffee consumption was significantly and inversely associated with gout (odds ratio [OR] = 0.29, 95% confidence interval [95% CI]: 0.16-0.51, P = 1.9 × 10-5 ) in random-effect IVW (Phet = 5.5 × 10-19 ). Excluding pleiotropic instruments, the protective effect on gout was confirmed in fixed-effect IVW analysis (OR = 0.75, 95% CI: 0.58-0.97, P = 0.026) without heterogeneity (Phet = 0.39). However, we observed no significance in the previous European datasets when heterogeneity was considered. Associations were not observed between coffee consumption and SUA levels in either ancestry in MR analyses that considered pleiotropy. Multivariable MR analysis showed that increased coffee consumption significantly reduced gout risk, even after adjusting for SUA levels (OR = 0.50, 95% CI: 0.31-0.81, P = 0.0046).ConclusionWith pleiotropy taken into account, our MR analyses revealed that coffee consumption can causally reduce gout risk, and that it may reduce gout risk independently of SUA levels.

Dataset Information

Serum Uric Acid Predicts All-Cause and Cardiovascular Mortality Independently of Hypertriglyceridemia in Cardiometabolic Patients without Established CV Disease: A Sub-Analysis of the URic acid Right for heArt Health (URRAH) Study.

Publications

Serum Uric Acid Predicts All-Cause and Cardiovascular Mortality Independently of Hypertriglyceridemia in Cardiometabolic Patients without Established CV Disease: A Sub-Analysis of the URic acid Right for heArt Health (URRAH) Study.

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