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Objective: In the frame of the Uric Acid Right for Heart Health (URRAH) study, a nationwide multicenter study involving adult participants recruited on a regional community basis from all the territory of Italy under the patronage of the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension, we searched for the cut-off values of the ratio between serum uric acid (SUA) and serum creatinine (sCr) able to predict cardiovascular (CV) events., Methods: Among 20 724 participants followed-up for 126 ± 64 months, after detecting cut-off by the receiver operating characteristic curves, we calculated by Cox models adjusted for confounders having CV events as dependent variable the hazard ratio (HR) of SUA/sCr > cut-off. We also verified if the role of cut-off varied with increasing SUA/sCr., Results: A plausible prognostic cut-off of SUA/sCr was found and was the same in the whole database, in men and in women (>5.35). The HR of SUA/sCr > cut-off was 1.159 (95% confidence interval [CI] 1.092-1.131, P < 0.03) in all, 1.161 (95% CI 1.021-1.335, P < 0.02) in men, and 1.444 (95% CI 1.012-1.113, P < 0.03) in women. In increasing quintiles of SUA/sCr the cut-offs were >3.08, >4.87, >5.35, >6.22 and >7.58, respectively. The HRs significantly increased from the 3rd to the 5th quintile (1.21, 95% CI 1.032-1.467, P = 0.018; 1.294, 95% CI 1.101-1.521, P = 0.002; and 1.642, 95% CI 1.405-1.919, P < 0.0001; respectively), that is, over 5.35, whereas the 2nd quintile was not significantly different from the 1st (reference)., Conclusion: Having SUA/sCr >5.35 is an independent CV risk indicator both in men and women. The cut-off is dynamic and significantly increases with increasing SUA/sCr., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: In older individuals, the role of serum uric acid (SUA) as risk factor for mortality is debated. This study investigated the association of SUA with all-cause and cardiovascular (CV) mortality in older adults participating in the large multicentre observational uric acid right for heart health (URRAH) study., Methods: Eight thousand URRAH participants aged 65+ were included in the analysis. The predictive role of SUA was assessed using Cox regression models stratified according to the cut-off age of 75. SUA was tested as continuous and categorical variable (age-specific quartiles). The prognostic threshold of SUA for mortality was analysed using receiver operating characteristic curves., Results: Among participants aged 65-74, multivariate Cox regression analysis adjusted for CV risk factors and comorbidities identified an independent association of SUA with both all-cause mortality (hazard ratio [HR] 1.169, 95% confidence interval [CI] 1.107-1.235) and CV mortality (HR 1.146, 95% CI 1.064-1.235). The cut-off value of 4.8 mg/dl discriminated mortality status. In participants aged 75+, we observed a J-shaped relationship of SUA with all-cause and CV mortality, with risk increasing at extreme SUA levels., Conclusions: These results confirmed the predictive role of SUA for all-cause and CV mortality in older adults, while revealing considerable age-related differences. Mortality risk increased at higher SUA levels in participants aged 65-74, with a prognostic threshold of 4.8 mg/dl. The relationship between SUA and mortality was J-shaped in oldest participants. Large interventional studies are needed to clarify the benefits and possible risks of urate-lowering treatments in older adults., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: A higher leptin (LPT) is associated with a greater cardiometabolic risk. Some studies also showed a positive association between LPT and cardiovascular organ damage but no consistent data are available about a predictive role of LPT on cardiac remodelling. Hence, the aim of this study was to evaluate the potential role of LPT on the incidence of left ventricular hypertrophy (LVH) in a sample of adult men., Methods: The study population was made up of 439 individuals (age: 51 years) without LVH at baseline, participating in The Olivetti Heart Study. The ECG criteria were adopted to exclude LVH at baseline and echocardiogram criteria for diagnosis of LVH at follow-up were considered., Results: At baseline, LPT was significantly and positively correlated with BMI, waist circumference, ECG indices, SBP and DBP but not with age and renal function. At the end of the 8-year follow-up period, there was an incidence of 23% in LVH by echocardiography. Individuals who developed LVH had higher baseline age, LPT, BMI, waist circumference, blood pressure and ECG indices (P < 0.05). Furthermore, those that had LPT above the median had greater risk to develop LVH (odds ratio: 1.7; P < 0.05). This association was also confirmed after adjustment for main confounders, among which changes in blood pressure and anthropometric indices., Conclusion: The results of this study suggest a predictive role of circulating LPT levels on cardiac remodelling expressed by echocardiographic LVH, independently of body weight and blood pressure changes over the years., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Although the relationship between hyperuricemia and cardiovascular events has been extensively examined, data on the role of diuretic-related hyperuricemia are still scanty. The present study was designed to collect information on the relationship between diuretic-related hyperuricemia and cardiovascular events., Methods: The URic acid Right for heArt Health (URRAH) study is a nationwide, multicentre, observational cohort study involving data on individuals recruited from all the Italy territory under the patronage of the Italian Society of Hypertension with an average follow-up period of 122.3 ± 66.9 months. Patients were classified into four groups according to the diuretic use (yes vs. no) and serum uric acid (SUA) levels (higher vs. lower than the median value of 4.8 mg/dl). All-cause death, cardiovascular deaths and first cardiovascular event were considered as outcomes., Results: Seventeen thousand, seven hundred and forty-seven individuals were included in the analysis. Mean age was 57.1 ± 15.2 years, men were 45.3% and SBP and DBP amounted to 144.1 ± 24.6 and 85.2 ± 13.2 mmHg. 17.2% of individuals take diuretics of whom 58% had SUA higher than median value. Patients with hyperuricemia without diuretic use served as reference group. In multivariate adjusted analysis (sex, age, SBP, BMI, glucose, total cholesterol, and glomerular filtration rate) individuals with hyperuricemia and diuretic use exhibit a similar risk for the three outcomes as compared with the reference group., Conclusion: Our study showed that diuretic-related hyperuricemia carry a similar risk of cardiovascular events and all-cause mortality when compared with individuals that present hyperuricemia in absence of diuretic therapy., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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.

Objective: Arterial stiffness is an independent cardiovascular risk factor and sodium intake could be a determinant of arterial stiffness. Nevertheless, the studies that investigated the effect of reducing dietary sodium intake on arterial stiffness in humans provided inconsistent results. Therefore, we performed a systematic review and a meta-analysis of the available randomized controlled trials of salt restriction and arterial stiffness to try and achieve more definitive conclusions., Methods: A systematic search of the online databases available (from 1996 through July 2017) was conducted including randomized controlled trials that reported arterial stiffness, expressed by carotid-femoral pulse wave velocity (PWV), as difference between the effects of two different sodium intake regimens. For each study, the mean difference and 95% confidence intervals were pooled using a random effect model. Sensitivity, heterogeneity, publication bias, subgroup and meta-regression analyses were performed., Results: Eleven studies met the predefined inclusion criteria and provided 14 cohorts with 431 participants and 1-6 weeks intervention time. In the pooled analysis, an average reduction in sodium intake of 89.3 mmol/day was associated with a 2.84% (95% CI: 0.51-5.08) reduction in PWV. There was no significant heterogeneity among studies and no evidence of publication bias was detected. No single feature of the studies analyzed seemed to impact on the effect of salt restriction on PWV., Conclusion: The results of this meta-analysis indicate that restriction of dietary sodium intake reduces arterial stiffness. This effect seems be at least in part independent of the changes in blood pressure.

Objective: The mechanisms underlying high blood pressure in the framework of metabolic syndrome (MS) are not clarified: we thus analyzed the relationship of MS and its components to renal tubular sodium handling among participants of the Olivetti Heart Study, an epidemiological investigation of a representative sample of adult white male population in southern Italy., Methods: Proximal (FPRNa) and distal (FDRNa) fractional sodium reabsorption were estimated by the clearance of exogenous lithium in 702 participants aged 25-75 years examined in 1994-1995. Blood pressure and relevant anthropometric and biochemical variables were also measured. The diagnosis of MS was based on modified National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) criteria., Results: FPRNa, but not FDRNa, was directly associated with body mass index (BMI), waist circumference, diastolic pressure, serum triglyceride and uric acid, independently of age and of antihypertensive treatment. After adjustment for age, FPRNa, but not FDRNa, was significantly greater in individuals with MS, as compared to those without [77.6% (95% confidence interval = 76.7-80.1) versus 74.4% (73.7-75.1), P < 0.001]. A similar difference was observed after the exclusion of participants on current antihypertensive treatment (P = 0.018). In untreated individuals, a significant interaction was observed between obesity and insulin resistance as related to FPRNa (P = 0.002): the highest age-adjusted levels of FPRNa were detected in obese hypertensive and obese insulin-resistant participants., Conclusion: In this sample of an adult male population, MS was associated with an increased rate of FPRNa. This finding is relevant to the pathophysiology of MS and possibly to the prevention of its cardiovascular and renal consequences.

Objective: To study the interaction between the C(-344)T polymorphism and known determinants (age, body mass and dietary sodium) of blood pressure and plasma aldosterone., Design: Cross-sectional and longitudinal (1980-1995) survey of male workers in southern Italy., Setting: Medical centre of the Olivetti factories., Participants: In 1995, the C(-344)T polymorphism was characterized in 811 untreated men. A subgroup of 280 participants already seen in 1980 was the object of longitudinal analysis., Main Outcome Measures: Blood pressure, demographic, anthropometric and biochemical variables (serum and urinary electrolytes and plasma aldosterone) and frequency of the C(-344)T polymorphism., Results: In the whole population, there was no difference among genotypes for any of the variables examined. However, multiple regression showed a significant interaction between age (but not body mass or sodium intake) and genotype with regard to systolic (P = 0.03) and diastolic ( P= 0.02) pressure variability independently of covariates. Diastolic pressure increased linearly with age in carriers of the T allele (TT, P<0.001 and TC, P= 0.005), but not in CC homozygotes ( P= 0.848). In T carriers - but not in CC homozygotes - blood pressure and serum potassium increased and plasma aldosterone and serum sodium decreased across quintiles of age (P< 0.001 for all trends). In the longitudinal study, diastolic pressure increased significantly over time only in T carriers (TC+TT: +2.6 +/- 0.6, versus CC: -0.4 +/- 1.5 mmHg, P= 0.04)., Conclusion: Inter-individual variation of blood pressure and plasma aldosterone is affected by the interaction of C(-344)T polymorphism and ageing, thus supporting a role for this variant in mechanisms affecting blood pressure regulation.

Methods: The association of the Trp64Arg polymorphism of the beta3-adrenoceptor (beta3-AR) gene with high blood pressure, central adiposity and other features of the metabolic syndrome was investigated in a large unselected sample of a white male working population in Southern Italy (n = 979)., Results: In the whole population, subjects heterozygous for the Trp64Arg mutation (11.2%) were not different from the homozygous Trp64Trp for any of the variables investigated. However, upon stratification for age, among men in the upper tertile of age (> 53 years), the Trp64Arg genotype was associated with higher waist: hip ratio (0.992 +/- 0.021 versus 0.982 +/- 0.037, P< 0.05), serum uric acid (6.34 +/- 1.50 versus 5.75 +/- 1.30 micromol/l, P < 0.05) and systolic blood pressure (144.3 +/- 19.4 versus 136.9 +/- 18.9 mmHg, P< 0.05) compared with the wild-type homozygotes. Accordingly, in the same age group, the carriers of Trp64Arg genotype were more often in the upper tertile of abdominal adiposity (69.7 versus 43.7%, P< 0.02) and serum uric acid (56.3 versus 34.8%, P < 0.02) and were more often hypertensive (68.6 versus 57.6%, P< 0.058) than the Trp64Trp homozygotes. No such differences were observed in younger age groups. No association was found with fasting serum insulin and the homeostasis model assessment (HOMA) index of insulin resistance. Furthermore, in a subgroup of 457 men for whom retrospective 20-year follow-up data were available, the variant genotype was associated with a higher probability of developing overweight (44.7 versus 27.0%, P < 0.05) and a trend to higher blood pressure (52.6 versus 38.4%, P = 0.09) over 20 years., Conclusion: We conclude that the Trp64Arg variant of the beta3-AR receptor predicts a greater tendency to develop abdominal adiposity and high blood pressure with advancing age.