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Serum uric acid and fatal myocardial infarction: detection of prognostic cut-off values: The URRAH (Uric Acid Right for Heart Health) study.
Casiglia, E, Tikhonoff, V, Virdis, A, Masi, S, Barbagallo, CM, Bombelli, M, Bruno, B, Cicero, AFG, Cirillo, M, Cirillo, P, et al
Journal of hypertension. 2020;(3):412-419
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Abstract
OBJECTIVE The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension conceived and designed an ad-hoc study aimed at searching for prognostic cut-off values of serum uric acid (SUA) in predicting fatal myocardial infaction (MI) in women and men. METHODS The URic acid Right for heArt Health study is a nationwide, multicentre, observational cohort study involving data on individuals aged 18-95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 122.3 ± 66.9 months. RESULTS A total of 23 467 individuals were included in the analysis. Cut-off values of SUA able to discriminate MI status were identified by mean of receiver operating characteristic curves in the whole database (>5.70 mg/dl), in women (>5.26 mg/dl) and in men (>5.49 mg/dl). Multivariate Cox regression analyses adjusted for confounders (age, arterial hypertension, diabetes, chronic kidney disease, smoking habit, ethanol intake, BMI, haematocrit, LDL cholesterol and use of diuretics) identified an independent association between SUA and fatal MI in the whole database (hazard ratio 1.381, 95% confidence intervals, 1.096-1.758, P = 0.006) and in women (hazard ratio 1.514, confidence intervals 1.105-2.075, P < 0.01), but not in men. CONCLUSION The results of the current study confirm that SUA is an independent risk factor for fatal MI after adjusting for potential confounding variables, and demonstrate that a prognostic cut-off value associated to fatal MI can be identified at least in women.
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Hyperuricemia: a novel old disorder-relationship and potential mechanisms in heart failure.
Borghi, C, Palazzuoli, A, Landolfo, M, Cosentino, E
Heart failure reviews. 2020;(1):43-51
Abstract
Uric acid, the metabolic mediator of gout and urate renal stones, is associated with increased cardiovascular risk burden. Hyperuricemia is an old emerging metabolic disorder, and interaction among uric acid and cardiovascular diseases has been clearly described. Several illness including hypertension, myocardial infarction, metabolic syndrome, and heart failure, are related with uric acid levels increase. In this review, we will discuss the pathophysiology of hyperuricemia and describe the biological plausibility for this metabolite to participate in the pathogenesis of cardiovascular disorders. In particular, we will focus on the implications of hyperuricemia in the onset and progression of heart failure, paying special attention to the pathophysiology and the possible clinical implications. We will conclude by discussing the effects of lowering plasma uric acid concentration on the prognosis of heart failure by reviewing most of available data on the different classes of drugs directly or indirectly involved in the hyperuricemia management.
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The interaction between serum uric acid and triglycerides level on blood pressure in middle-aged and elderly individuals in China: result from a large national cohort study.
Zhang, L, Li, JL, Guo, LL, Li, H, Li, D, Xu, G
BMC cardiovascular disorders. 2020;(1):174
Abstract
BACKGROUND The purpose of the research was to explore the extent of interaction between triglycerides (TG) and serum uric acid (SUA) level with blood pressure (BP) in middle-aged and elderly individuals in China. METHODS Data were selected from the China Health and Retirement Longitudinal Study (CHARLS), a cross-sectional study. 3345(46.99%) men with average ages of 60.24 ± 9.24 years and 3774 (53.01%) women with average ages of 59.91 ± 9.95 years were included in the study. Differences between gender, or between categories of blood pressure levels were evaluated by t-test or chi-square test. The adjusted associations between various characteristics and BP status were first compared using linear regression models, as appropriate. Then, A general linear model adjusted for confounding factors (socio-demographic characteristics [age, educational levels, marital status, place of residence], health behaviors [cigarette smoking, alcohol drinking, eating habits, social and leisure activities, accidental injury, physical activities], medical history [history of cardiovascular diseases, hepatitis history, antidiabetic drugs, history of antilipidemic medication, anti-hypertensive therapy], metabolic measures [C-reactive protein (CRP), hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate (eGFR), body mass index (BMI)]) was used to examine the synergistic effect of SUA and TG level on BP in middle-aged and elderly individuals in China. RESULTS Age-adjusted partial Pearson's correlation coefficient showed that SUA and TG level positively correlated with both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in both men and women. Multiple linear regression analysis showed the TG level was significantly and positively associated with SBP and DBP in both men (SBP: β =0.068, P = 0.001; DBP: β =0.064, P = 0.002) and women (SBP: β =0.061, P = 0.002; DBP: β =0.084, P = 0.000), but SUA were significantly and positively associated with SBP in both men (SBP: β =0.047, P = 0.013) and women (SBP: β =0.040, P = 0.028), regardless of other confounding factors. After adjusting for related potential confounders, evidence of interaction between SUA and TG level on SBP (men: β = - 1.090, P = 0.726; women: β = - 0.692, P = 0.861) and DBP (men: β = - 1.026, P = 0.572; women: β = - 0.794, P = 0.842) was not observed. CONCLUSION The interaction effect of SUA and TG level on BP was not observed in our study. Moreover, high SUA level was significantly associated with SBP, while high TG level was strongly related to both DBP and SBP.
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Lack of effect of tart cherry concentrate dose on serum urate in people with gout.
Stamp, LK, Chapman, P, Frampton, C, Duffull, SB, Drake, J, Zhang, Y, Neogi, T
Rheumatology (Oxford, England). 2020;(9):2374-2380
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Abstract
OBJECTIVES Cherry concentrate has been suggested to reduce serum urate (SU) and gout flares. The aims of this study were to determine the magnitude of the effect of tart cherry concentrate on SU in people with gout, the most effective dose of tart cherry concentrate for lowering SU, and adverse effects. METHODS Fifty people with gout and SU > 0.36 mmol/l were recruited. Half were on allopurinol and half were on no urate-lowering therapy. Participants were randomized to receive tart cherry juice concentrate: placebo, 7.5 ml, 15 ml, 22.5 ml or 30 ml twice daily for 28 days. Blood samples were taken at baseline, then at 1, 3 and 5 h post cherry and then on days 1, 3, 7, 14, 21 and 28. The area under the curve for SU was calculated over the 28-day study period. RESULTS Cherry concentrate dose had no significant effect on reduction in SU area under the curve, urine urate excretion, change in urinary anthocyanin between day 0 and day 28, or frequency of gout flares over the 28-day study period (P = 0.76). There were 24 reported adverse events, with only one (hyperglycaemia) considered possibly to be related to cherry concentrate. Allopurinol use did not modify the effect of cherry on SU or urine urate excretion. CONCLUSION Tart cherry concentrate had no effect on SU or urine urate excretion. If there is an effect of cherry concentrate on gout flares over a longer time period, it is not likely to be mediated by reduction in SU. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR), https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368887, ANZCTR 12615000741583).
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A novel mutation in gene of PRPS1 in a young Chinese woman with X-linked gout: a case report and review of the literature.
Yang, BY, Yu, HX, Min, J, Song, XX
Clinical rheumatology. 2020;(3):949-956
Abstract
Pyrophosphate synthetase-1(PRS-1) is a crucial enzyme that catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) with substrate: adenosine triphosphate (ATP) and ribose-5-phophate(R5P) in the de novo pathways of purine and pyrimidine nucleotide synthesis. Mutation in PRPS1 can result in a series of diseases of purine metabolism, which includes PRS-1 superactivity. The common clinical phenotypes are hyperuricemia and hyperuricosuria. We identified a novel missense mutation in X-chromosomal gene PRPS1 in a young Chinese woman while her mother has heterogeneous genotype and phenotype. A 24-year-old Chinese female patient suffered hyperuricemia, gout, and recurrent hyperpyrexia for more than 6 years, and then was diagnosed with hyperandrogenism, insulin resistance (IR), and polycystic ovary syndrome (PCOS). A novel missense mutation, c.521(exon)G>T, p.(Gly174Val) was detected by next-generation sequencing (NGS) and confirmed by Sanger sequencing in the patient and her parents. Interestingly, her mother has the same heterozygous missense mutation but without uric acid overproduction which can be explained by the phenomenon of the skewed X-chromosome inactivation. The substituted amino acid Val for Gly174 is positioned in the pyrophosphate (PPi) binding loop, and this mutation impacts the binding rate of Mg2+-ATP complex to PRS-1, thus the assembling of homodimer is affected by changed Val174 leading to the instability of the allosteric site. Our report highlights the X-linked inheritance of gout in females caused by mutation in PRPS1 accompanied with severe metabolic disorders and recurrent hyperpyrexia.
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Association between serum vitamin D and uric acid in the eastern Chinese population: a population-based cross-sectional study.
Chen, Y, Cheng, J, Chen, Y, Wang, N, Xia, F, Chen, C, Han, B, Lu, Y
BMC endocrine disorders. 2020;(1):79
Abstract
BACKGROUND Uric acid (UA) is the end product of purine metabolism, which is thought to be related to many human diseases, such as nephrolithiasis, gout, cardiovascular disease (CVD), type 2 diabetes mellitus, metabolic syndrome. However, the relationship between serum UA (SUA) and 25(OH) D is still unclear in the eastern Chinese population. METHODS We did a population-based observational investigation, which included 12,770 residents living in eastern China. Ultimately, data from 9220 subjects were analyzed. Serum 25(OH) D, SUA, fasting plasma glucose (FPG), fasting insulin, HbA1c and other metabolic parameters were tested. Waist circumference (WC), weight and height were also measured. Questionnaires were collected from these subjects for information on smoking and drinking status. RESULTS We enrolled 9220 Chinese adults, including 3681 males (age 55.57 ± 13.23 years) and 5539 females (age 54.31 ± 12.83 years). The levels of SUA were 352.07 ± 79.25 nmol/L and 269.29 ± 64.68 nmol/L in males and females, respectively. The proportion of adults with hyperuricemia (HUA) was 12.26% in the total population. Levels of SUA were positively associated with 25(OH) D, and the incidence of HUA increased 9.4% for every 10 nmol/L increase in 25(OH) D (P < 0.001). CONCLUSIONS SUA was positively associated with 25(OH) D in the eastern Chinese population. Higher levels of serum 25(OH) D may be a potential predictor of HUA.
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Mendelian randomization study of serum uric acid levels and diabetes risk: evidence from the Dongfeng-Tongji cohort.
Keerman, M, Yang, F, Hu, H, Wang, J, Wang, F, Li, Z, Yuan, J, Yao, P, Zhang, X, Guo, H, et al
BMJ open diabetes research & care. 2020;(1)
Abstract
OBJECTIVE Limited Mendelian randomization (MR) studies have assessed the causal relationship between serum uric acid levels and diabetes risk. Here we investigated causality between the serum uric acid concentration and diabetes risk in Chinese population. RESEARCH DESIGN AND METHODS The observational analysis, based on the Dongfeng-Tongji prospective cohort (n=15 195) we tested the association of serum uric acid levels with incident diabetes risk. In the instrumental variable analysis, we examined the association of the genetic risk score (GRS) of serum uric acid with diabetes risk in case-control design (2539 cases and 4595 controls) via MR analysis. RESULTS During a mean (SD) follow-up of 4.5 (0.5) years, 1156 incident diabetes cases were identified. Compared with those in the lowest quintile of serum uric acid levels, the HRs of incident diabetes were 1.19 (95% CI 0.96 to 1.48), 1.12 (95% CI 0.90 to 1.40), 1.38 (95% CI 1.12 to 1.70), and 1.51 (95% CI 1.23 to 1.87) for Q2, Q3, Q4 and Q5, respectively (P-trend <0.001). The GRS was strongly associated with serum uric acid levels (β=0.17, 95% CI 0.15 to 0.19; P=2.81×10-67). However, no significant association was observed between the GRS and diabetes risk (OR=1.01, 95 CI 0.95 to 1.06; P=0.75). CONCLUSIONS Even though serum uric acid levels were significantly associated with increased incident diabetes risk, the results did not provide evidence for a causal relationship between them.
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The biology of urate.
Keenan, RT
Seminars in arthritis and rheumatism. 2020;(3S):S2-S10
Abstract
Urate is the end-product of the purine metabolism in humans. The dominant source of urate is endogenous purines and the remainder comes through diet. Approximately two thirds of urate is eliminated via the kidney with the rest excreted in the feces. While the transporter BCRP, encoded by ABCG2, has been found to play a role in both the gut and kidney, SLC22A12 and SLC2A9 encoding URAT1 and GLUT9, respectively, are the two transporters best characterized. Only 8-12% of the filtered urate is excreted by the kidney. Renal elimination of urate depends substantially on specific transporters, including URAT1, GLUT9 and BCRP. Studies that have assessed the biologic effects of urate have produced highly variable results. Although there is a suggestion that urate may have anti-oxidant properties in some circumstances, the majority of evidence indicates that urate is pro-inflammatory. Hyperuricemia can result in the formation of monosodium urate (MSU) crystals that may be recognized as danger signals by the immune system. This immune response results in the activation of the NLRP3 inflammasome and ultimately in the production and release of interleukin-1β, and IL-18, that mediate both inflammation, pyroptotic cell death, and necroinflammation. It has also been demonstrated that soluble urate mediates effects on the kidney to induce hypertension and can induce long term epigenetic reprogramming in myeloid cells to induce "trained immunity." Together, these sequelae of urate are thought to mediate most of the physiological effects of hyperuricemia and gout, illustrating this biologically active molecule is more than just an "end-product" of purine metabolism.
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Uric Acid Elevation by Favipiravir, an Antiviral Drug.
Mishima, E, Anzai, N, Miyazaki, M, Abe, T
The Tohoku journal of experimental medicine. 2020;(2):87-90
Abstract
In light of the recent pandemic, favipiravir (Avigan®), a purine nucleic acid analog and antiviral agent approved for use in influenza in Japan, is being studied for the treatment of coronavirus disease 2019 (COVID-19). Increase in blood uric acid level is a frequent side effect of favipiravir. Here, we discussed the mechanism of blood uric acid elevation during favipiravir treatment. Favipiravir is metabolized to an inactive metabolite M1 by aldehyde oxidase and xanthine oxidase, and excreted into urine. In the kidney, uric acid handling is regulated by the balance of reabsorption and tubular secretion in the proximal tubules. Favipiravir and M1 act as moderate inhibitors of organic anion transporter 1 and 3 (OAT1 and OAT3), which are involved in uric acid excretion in the kidney. In addition, M1 enhances uric acid reuptake via urate transporter 1 (URAT1) in the renal proximal tubules. Thus, favipiravir is thought to decrease uric acid excretion into urine, resulting in elevation of uric acid levels in blood. Elevated uric acid levels were returned to normal after discontinuation of favipiravir, and favipiravir is not used for long periods of time for the treatment of viral infection. Thus, the effect on blood uric acid levels was subclinical in most studies. Nevertheless, the adverse effect of favipiravir might be clinically important in patients with a history of gout, hyperuricemia, kidney function impairment (in which blood concentration of M1 increases), and where there is concomitant use of other drugs affecting blood uric acid elevation.
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Circulating leptin is associated with serum uric acid level and its tubular reabsorption in a sample of adult middle-aged men.
D'Elia, L, Giaquinto, A, Cappuccio, FP, Iacone, R, Russo, O, Strazzullo, P, Galletti, F
Journal of endocrinological investigation. 2020;(5):587-593
Abstract
PURPOSE Leptin is associated with cardiovascular risk factors (e.g. hypertension, insulin resistance, kidney disease and excess body weight). Experimental studies showed that leptin might affect serum uric acid, by modulation of the uric acid excretion. However, there are few observational data on the relationship between leptin and uric acid in the general population. Therefore, the aim of the present study was to evaluate the relationship between leptin and uric acid and its excretion in a large middle-aged male general population. METHODS A sample of 930 adult male individuals (mean age: 52 years) without therapy for high uric acid was included in the analysis (the Olivetti Heart Study). RESULTS Uric acid was significantly and positively associated with blood pressure, BMI, waist circumference, insulin resistance, C-reactive protein and leptin (p < 0.01), while inversely with renal function (p = 0.01). The multivariate analysis confirmed the association between leptin and uric acid after adjustment for potential confounders (p < 0.01). After division for adiposity, this trend was confirmed separately for normal weight and excess body weight participants. Moreover, leptin was inversely associated with excretion of uric acid (p < 0.01), also in multivariate analysis (p = 0.03). CONCLUSION The results of this study indicate a positive association between circulating leptin levels and uric acid, independently of potential confounders, both in normal and excess body weight men. Furthermore, an inverse association between leptin and uric acid excretion was detected.