Serum Uric Acid/Serum Creatinine Ratio and Cardiovascular Mortality in Diabetic Individuals-The Uric Acid Right for Heart Health (URRAH) Project.

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.

Triglyceride-glucose Index and Mortality in a Large Regional-based Italian Database (Urrah Project).

PURPOSE: Recently, a novel index (triglyceride-glucose index-TyG) was considered a surrogate marker of insulin resistance (IR); in addition, it was estimated to be a better expression of IR than widely used tools. Few and heterogeneous data are available on the relationship between this index and mortality risk in non-Asian populations. Therefore, we estimated the predictive role of baseline TyG on the incidence of all-cause and cardiovascular (CV) mortality in a large sample of the general population. Moreover, in consideration of the well-recognized role of serum uric acid (SUA) on CV risk and the close correlation between SUA and IR, we also evaluated the combined effect of TyG and SUA on mortality risk. METHODS: The analysis included 16,649 participants from the URRAH cohort. The risk of all-cause and CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. RESULTS: During a median follow-up of 144 months, 2569 deaths occurred. We stratified the sample by the optimal cut-off point for all-cause (4.62) and CV mortality (4.53). In the multivariate Cox regression analyses, participants with TyG above cut-off had a significantly higher risk of all-cause and CV mortality, than those with TyG below the cut-off. Moreover, the simultaneous presence of high levels of TyG and SUA was associated with a higher mortality risk than none or only one of the two factors. CONCLUSIONS: The results of this study indicate that these TyG (a low-cost and simple non-invasive marker) thresholds are predictive of an increased risk of mortality in a large and homogeneous general population. In addition, these results show a synergic effect of TyG and SUA on the risk of mortality.

Prognostic Value and Relative Cutoffs of Triglycerides Predicting Cardiovascular Outcome in a Large Regional-Based Italian Database.

BACKGROUND: Despite longstanding epidemiologic data on the association between increased serum triglycerides and cardiovascular events, the exact level at which risk begins to rise is unclear. The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension has conceived a protocol aimed at searching for the prognostic cutoff value of triglycerides in predicting cardiovascular events in a large regional-based Italian cohort. METHODS AND RESULTS: Among 14 189 subjects aged 18 to 95 years followed-up for 11.2 (5.3-13.2) years, the prognostic cutoff value of triglycerides, able to discriminate combined cardiovascular events, was identified by means of receiver operating characteristic curve. The conventional (150 mg/dL) and the prognostic cutoff values of triglycerides were used as independent predictors in separate multivariable Cox regression models adjusted for age, sex, body mass index, total and high-density lipoprotein cholesterol, serum uric acid, arterial hypertension, diabetes, chronic renal disease, smoking habit, and use of antihypertensive and lipid-lowering drugs. During 139 375 person-years of follow-up, 1601 participants experienced cardiovascular events. Receiver operating characteristic curve showed that 89 mg/dL (95% CI, 75.8-103.3, sensitivity 76.6, specificity 34.1, P<0.0001) was the prognostic cutoff value for cardiovascular events. Both cutoff values of triglycerides, the conventional and the newly identified, were accepted as multivariate predictors in separate Cox analyses, the hazard ratios being 1.211 (95% CI, 1.063-1.378, P=0.004) and 1.150 (95% CI, 1.021-1.295, P=0.02), respectively. CONCLUSIONS: Lower (89 mg/dL) than conventional (150 mg/dL) prognostic cutoff value of triglycerides for cardiovascular events does exist and is associated with increased cardiovascular risk in an Italian cohort.

The Results of the URRAH (Uric Acid Right for Heart Health) Project: A Focus on Hyperuricemia in Relation to Cardiovascular and Kidney Disease and its Role in Metabolic Dysregulation.

The relationship between Serum Uric Acid (UA) and Cardiovascular (CV) diseases has already been extensively evaluated, and it was found to be an independent predictor of all-cause and cardiovascular mortality but also acute coronary syndrome, stroke and heart failure. Similarly, also many papers have been published on the association between UA and kidney function, while less is known on the role of UA in metabolic derangement and, particularly, in metabolic syndrome. Despite the substantial number of publications on the topic, there are still some elements of doubt: (1) the better cut-off to be used to refine CV risk (also called CV cut-off); (2) the needing for a correction of UA values for kidney function; and (3) the better definition of its role in metabolic syndrome: is UA simply a marker, a bystander or a key pathological element of metabolic dysregulation?. The Uric acid Right for heArt Health (URRAH) project was designed by the Working Group on uric acid and CV risk of the Italian Society of Hypertension to answer the first question. After the first papers that individuates specific cut-off for different CV disease, subsequent articles have been published responding to the other relevant questions. This review will summarise most of the results obtained so far from the URRAH research project.

Prognostic cardiovascular cut-off values of dietary caffeine in a cohort of unselected men and women from general population.

BACKGROUND AND AIMS: Among an unselected cohort of men and women from general population (n = 1.668), the prognostic effects of being over the cut-off of all-source dietary caffeine intake were studied. METHODS AND RESULTS: Prognostic cut-off values for coronary events, incident heart failure (HF), cerebrovascular events (CBV) and arrhythmic events (ARR) were found by means of the receiver-operating-characteristic curves method. Those for HF (>230 mg/day), for CBV (>280 mg/day) and for ARR (>280 mg/day) were confirmed in multivariate Cox analysis adjusted for age, body mass index, circulating thyroid hormone, diabetes mellitus, arterial hypertension, smoking, dietary intake of ethanol, basal heart rate, low-density-lipoprotein cholesterol, forced expiratory volume in 1 s and ß-blocking therapy. Being over these cut-off values was associated to a reduced hazard ratio during the follow-up in the whole cohort (HR 0.678, 95%CI 0.567-0.908, p = 0.009 for HF; 0.651, 95%CI 0.428-0.994, p = 0.018 for CBV; 0.395, 95%CI 0.395-0.933, p = 0.022 for ARR) and in men (0.652, 0.442-0.961, p = 0.029; 0.432, 0.201-0.927, p = 0.03; 0.553, 0.302-1.000, p = 0.05, respectively) but not in women. The caffeine-induced risk decrease observed in the whole cohort is therefore entirely attributable to men. In the case of HF, heart rate entered the risk equation in a positive manner without rejecting caffeine. The -163C>A polymorphism of the CYP1A2 gene, codifying for ability to metabolize caffeine, introduced in sensitivity analysis, did not alter the prognostic models. CONCLUSION: Men introducing >230 mg/day caffeine show a reduced risk of HF, and those introducing >280 mg/day a reduced risk of CBV and ARR independent of genetic pattern.

Derivation of an Outcome-Driven Threshold for Aortic Pulse Wave Velocity: An Individual-Participant Meta-Analysis.

BACKGROUND: Aortic pulse wave velocity (PWV) predicts cardiovascular events (CVEs) and total mortality (TM), but previous studies proposing actionable PWV thresholds have limited generalizability. This individual-participant meta-analysis is aimed at defining, testing calibration, and validating an outcome-driven threshold for PWV, using 2 populations studies, respectively, for derivation IDCARS (International Database of Central Arterial Properties for Risk Stratification) and replication MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease Health Survey - Copenhagen). METHODS: A risk-carrying PWV threshold for CVE and TM was defined by multivariable Cox regression, using stepwise increasing PWV thresholds and by determining the threshold yielding a 5-year risk equivalent with systolic blood pressure of 140 mm Hg. The predictive performance of the PWV threshold was assessed by computing the integrated discrimination improvement and the net reclassification improvement. RESULTS: In well-calibrated models in IDCARS, the risk-carrying PWV thresholds converged at 9 m/s (10 m/s considering the anatomic pulse wave travel distance). With full adjustments applied, the threshold predicted CVE (hazard ratio [CI]: 1.68 [1.15-2.45]) and TM (1.61 [1.01-2.55]) in IDCARS and in MONICA (1.40 [1.09-1.79] and 1.55 [1.23-1.95]). In IDCARS and MONICA, the predictive accuracy of the threshold for both end points was ≈0.75. Integrated discrimination improvement was significant for TM in IDCARS and for both TM and CVE in MONICA, whereas net reclassification improvement was not for any outcome. CONCLUSIONS: PWV integrates multiple risk factors into a single variable and might replace a large panel of traditional risk factors. Exceeding the outcome-driven PWV threshold should motivate clinicians to stringent management of risk factors, in particular hypertension, which over a person's lifetime causes stiffening of the elastic arteries as waypoint to CVE and death.

Blood pressure and cardiovascular risk in relation to birth weight and urinary sodium: an individual-participant meta-analysis of European family-based population studies.

BACKGROUND: Although the relation of salt intake with blood pressure (BP) is linear, it is U-shaped for mortality and cardiovascular disease (CVD). This individual-participant meta-analysis explored whether the relation of hypertension, death or CVD with 24-h urinary sodium excretion (UVNA) or sodium-to-potassium (UNAK) ratio was modified by birth weight. METHODS: Families were randomly enrolled in the Flemish Study on Genes, Environment and Health Outcomes (1985-2004) and the European Project on Genes in Hypertension (1999-2001). Categories of birth weight, UVNA and UNAK (≤2500, >2500-4000, >4000 g; <2.3, 2.3-4.6 and >4.6 g; and <1, 1-2, >2, respectively) were coded using deviation-from-mean coding and analyzed by Kaplan-Meier survival functions and linear and Cox regression. RESULTS: The study population was subdivided into the Outcome ( n  = 1945), Hypertension ( n  = 1460) and Blood Pressure cohorts ( n  = 1039) to analyze the incidence of mortality and cardiovascular endpoints, hypertension and BP changes as function of UVNA changes. The prevalence of low/medium/high birth weight in the Outcome cohort was 5.8/84.5/9.7%. Over 16.7 years (median), rates were 4.9, 8 and 27.1% for mortality, CVD and hypertension, respectively, but were not associated with birth weight. Multivariable-adjusted hazard ratios were not significant for any endpoint in any of the birth weight, UVNA and UNAK strata. Adult body weight tracked with birth weight ( P  < 0.0001). The partial r in the low-birth-weight group associating changes from baseline to follow-up in UVNA and SBP was 0.68 ( P  = 0.023) but not significant in other birth weight groups. CONCLUSION: This study did not substantiate its prior hypothesis but showed tracking of adult with birth weight and suggest that low birth weight increases salt sensitivity.

Serum uric acid and left ventricular mass index independently predict cardiovascular mortality: The uric acid right for heart health (URRAH) project.

A relationship between serum uric acid (SUA) and cardiovascular (CV) events has been documented in the Uric Acid Right for Heart Health (URRAH) study. AIM: of this study was to investigate the association between SUA and left ventricular mass index (LVMI) and whether SUA and LVMI or their combination may predict the incidence of CV death. METHODS: Subjects with echocardiographic measurement of LVMI included in the URRAH study (n=10733) were part of this analysis. LV hypertrophy (LVH) was defined as LVMI > 95 g/m2 in women and 115 g/m2 in men. RESULTS: A significant association between SUA and LVMI was observed in multiple regression analysis in men: beta 0,095, F 5.47, P< 0.001 and women: beta 0,069, F 4.36, P<0.001. During follow-up 319 CV deaths occurred. Kaplan-Meier curves showed a significantly poorer survival rate in subjects with higher SUA (> 5.6 mg/dl in men and 5.1 mg/dl in women) and LVH (log-rank chi-square 298.105; P<0.0001). At multivariate Cox regression analysis in women LVH alone and the combination of higher SUA and LVH but not hyperuricemia alone, were associated with a higher risk of CV death, while in men hyperuricemia without LVH, LVH without hyperuricemia and their combination were all associated with a higher incidence of CV death. CONCLUSIONS: Our findings demonstrate that SUA is independently associated with LVMI and suggest that the combination of hyperuricemia with LVH is an independent and powerful predictor for CV death both in men and women.

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.

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.

Hyperuricemia increases the risk of cardiovascular mortality associated with very high HdL-cholesterol level.

BACKGROUND AND AIMS: Whether the association between very high HDL-cholesterol levels and cardiovascular mortality (CVM) is modulated by some facilitating factors is unclear. Aim of the study was to investigate whether the risk of CVM associated with very high HDL-cholesterol is increased in subjects with hyperuricemia. METHODS AND RESULTS: Multivariable Cox analyses were made in 18,072 participants from the multicentre URRAH study stratified by sex and HDL-cholesterol category. During a median follow-up of 11.4 years there were 1307 cases of CVM. In multivariable Cox models a J-shaped association was found in the whole population, with the highest risk being present in the high HDL-cholesterol group [>80 mg/dL, adjusted hazard ratio (HR), 1.28; 95%CI, 1.02-1.61; p = 0.031)]. However, a sex-specific analysis revealed that this association was present only in women (HR, 1.34; 95%CI, 1.02-1.77; p = 0.034) but not in men. The risk of CVM related to high HDL-cholesterol was much greater in the women with high uric acid (>0.30 mmol/L, HR 1.61; 95%CI, 1.08-2.39) than in those with low uric acid (HR, 1.17; 95%CI, 0.80-1.72, p for interaction = 0.016). In women older than 70 years with hyperuricemia the risk related to high HDL-cholesterol was 1.83 (95%CI, 1.19-2.80, p < 0.005). Inclusion of BMI in the models weakened the strength of the associations. CONCLUSION: Our data indicate that very high HDL-cholesterol levels in women are associated with CVM in a J-shaped fashion. The risk of CVM is increased by concomitant hyperuricemia suggesting that a proinflammatory/oxidative state can enhance the detrimental cardiovascular effects associated with high HDL-cholesterol.

Serum uric acid / serum creatinine ratio as a predictor of cardiovascular events. Detection of prognostic cardiovascular cut-off values.

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.

Predictive power of 24-h ambulatory pulse pressure and its components for mortality and cardiovascular outcomes in 11 848 participants recruited from 13 populations.

BACKGROUND: The role of pulse pressure (PP) 'widening' at older and younger age as a cardiovascular risk factor is still controversial. Mean PP, as determined from repeated blood pressure (BP) readings, can be expressed as a sum of two components: 'elastic PP' (elPP) and 'stiffening PP' (stPP) associated, respectively, with stiffness at the diastole and its relative change during the systole. We investigated the association of 24-h ambulatory PP, elPP, and stPP ('PP variables') with mortality and composite cardiovascular events in different age classes. METHOD: Longitudinal population-based cohort study of adults with baseline observations that included 24-h ambulatory BP. Age classes were age 40 or less, 40-50, 50-60, 60-70, and over 70 years. Co-primary endpoints were total mortality and composite cardiovascular events. The relative risk expressed by hazard ratio per 1SD increase for each of the PP variables was calculated from multivariable-adjusted Cox regression models. RESULTS: The 11 848 participants from 13 cohorts (age 53 ±â€Š16 years, 50% men) were followed for up for 13.7 ±â€Š6.7 years. A total of 2946 participants died (18.1 per 1000 person-years) and 2093 experienced a fatal or nonfatal cardiovascular event (12.9 per 1000 person-years). Mean PP, elPP, and stPP were, respectively, 49.7, 43.5, and 6.2 mmHg, and elPP and stPP were uncorrelated ( r  = -0.07). At age 50-60 years, all PP variables displayed association with risk for almost all outcomes. From age over 60 years to age over 70 years, hazard ratios of of PP and elPP were similar and decreased gradually but differently for pulse rate lower than or higher than 70 bpm, whereas stPP lacked predictive power in most cases. For age 40 years or less, elPP showed protective power for coronary events, whereas stPP and PP predicted stroke events. Adjusted and unadjusted hazard ratio variations were similar over the entire age range. CONCLUSION: This study provides a new basis for associating PP components with outcome and arterial properties in different age groups and at different pulse rates for both old and young age. The similarity between adjusted and unadjusted hazard ratios supports the clinical usefulness of PP components but further studies are needed to assess the prognostic significance of the PP components, especially at the young age.

Serum uric acid levels threshold for mortality in diabetic individuals: The URic acid Right for heArt Health (URRAH) project.

BACKGROUND AND AIM: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes. METHODS AND RESULTS: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA <5.6 mg/dl. Increased all-cause mortality risk was shown in participants with SUA ≥4.7 mg/dl vs SUA below 4.7 mg/dl, but not statistically significant after adjustment for all confounders. CONCLUSIONS: SUA thresholds previously proposed by the URRAH study group are predictive of total and CV mortality also in people with diabetes. The threshold of 5.6 mg/dl can predict both total and CV mortality, and so is candidate to be a clinical cut-off for the definition of hyperuricemia in patients with diabetes.

Risk Stratification by Cross-Classification of Central and Brachial Systolic Blood Pressure.

BACKGROUND: Whether cardiovascular risk is more tightly associated with central (cSBP) than brachial (bSBP) systolic pressure remains debated, because of their close correlation and uncertain thresholds to differentiate cSBP into normotension versus hypertension. METHODS: In a person-level meta-analysis of the International Database of Central Arterial Properties for Risk Stratification (n=5576; 54.1% women; mean age 54.2 years), outcome-driven thresholds for cSBP were determined and whether the cross-classification of cSBP and bSBP improved risk stratification was explored. cSBP was tonometrically estimated from the radial pulse wave using SphygmoCor software. RESULTS: Over 4.1 years (median), 255 composite cardiovascular end points occurred. In multivariable bootstrapped analyses, cSBP thresholds (in mm Hg) of 110.5 (95% CI, 109.1-111.8), 120.2 (119.4-121.0), 130.0 (129.6-130.3), and 149.5 (148.4-150.5) generated 5-year cardiovascular risks equivalent to the American College of Cardiology/American Heart Association bSBP thresholds of 120, 130, 140, and 160. Applying 120/130 mm Hg as cSBP/bSBP thresholds delineated concordant central and brachial normotension (43.1%) and hypertension (48.2%) versus isolated brachial hypertension (5.0%) and isolated central hypertension (3.7%). With concordant normotension as reference, the multivariable hazard ratios for the cardiovascular end point were 1.30 (95% CI, 0.58-2.94) for isolated brachial hypertension, 2.28 (1.21-4.30) for isolated central hypertension, and 2.02 (1.41-2.91) for concordant hypertension. The increased cardiovascular risk associated with isolated central and concordant hypertension was paralleled by cerebrovascular end points with hazard ratios of 3.71 (1.37-10.06) and 2.60 (1.35-5.00), respectively. CONCLUSIONS: Irrespective of the brachial blood pressure status, central hypertension increased cardiovascular and cerebrovascular risk indicating the importance of controlling central hypertension.

The International Database of Central Arterial Properties for Risk Stratification: Research Objectives and Baseline Characteristics of Participants.

OBJECTIVE: To address to what extent central hemodynamic measurements, improve risk stratification, and determine outcome-based diagnostic thresholds, we constructed the International Database of Central Arterial Properties for Risk Stratification (IDCARS), allowing a participant-level meta-analysis. The purpose of this article was to describe the characteristics of IDCARS participants and to highlight research perspectives. METHODS: Longitudinal or cross-sectional cohort studies with central blood pressure measured with the SphygmoCor devices and software were included. RESULTS: The database included 10,930 subjects (54.8% women; median age 46.0 years) from 13 studies in Europe, Africa, Asia, and South America. The prevalence of office hypertension was 4,446 (40.1%), of which 2,713 (61.0%) were treated, and of diabetes mellitus was 629 (5.8%). The peripheral and central systolic/diastolic blood pressure averaged 129.5/78.7 mm Hg and 118.2/79.7 mm Hg, respectively. Mean aortic pulse wave velocity was 7.3 m per seconds. Among 6,871 participants enrolled in 9 longitudinal studies, the median follow-up was 4.2 years (5th-95th percentile interval, 1.3-12.2 years). During 38,957 person-years of follow-up, 339 participants experienced a composite cardiovascular event and 212 died, 67 of cardiovascular disease. CONCLUSIONS: IDCARS will provide a unique opportunity to investigate hypotheses on central hemodynamic measurements that could not reliably be studied in individual studies. The results of these analyses might inform guidelines and be of help to clinicians involved in the management of patients with suspected or established hypertension.

Identification of a plausible serum uric acid cut-off value as prognostic marker of stroke: the Uric Acid Right for Heart Health (URRAH) study.

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 combined (fatal and non-fatal) cerebrovascular (CBV) events in the whole database. The URic acid Right for heArt Health study is a nationwide, multicenter, observational cohort study involving data on subjects 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 120.7 ± 61.8 months. A total of 14,588 subjects were included in the analysis. A prognostic cut-off value of SUA able to discriminate combined CBV events (>4.79 mg/dL or >284.91 µmol/L) was identified by means of receiver operating characteristic curve in the whole database. Multivariate Cox regression analysis adjusted for confounders (age, sex, arterial hypertension, diabetes, chronic kidney disease, smoking habit, ethanol intake, body mass index, low-density lipoprotein cholesterol, and use of diuretics) identified an independent association between SUA and combined CBV events in the whole database (HR 1.249, 95% confidence interval, 1.041-1.497, p = 0.016). The results of the present study confirm that SUA is an independent risk marker for CBV events after adjusting for potential confounding variables, including arterial hypertension, and demonstrate that >4.79 mg/dL is a valid prognostic cut-off value.

Association of uric acid with kidney function and albuminuria: the Uric Acid Right for heArt Health (URRAH) Project.

BACKGROUND: Hyperuricemia 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. METHODS: Clinical 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. RESULTS: Mean 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. CONCLUSIONS: The 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.

The association of uric acid with mortality modifies at old age: data from the uric acid right for heart health (URRAH) study.

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.

Serum Uric Acid and Kidney Disease Measures Independently Predict Cardiovascular and Total Mortality: The Uric Acid Right for Heart Health (URRAH) Project.

Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence of chronic kidney disease (CKD). Our goal was to study the independent impact of uric acid and CKD on mortality. Methods: We retrospectively investigated 21,963 patients from the URRAH study database. Hyperuricemia was defined on the basis of outcome specific cut-offs separately identified by ROC curves according to eGFR strata. The primary endpoints were cardiovascular and all-cause mortality. Results: After a mean follow-up of 9.8 year, there were 1,582 (7.20%) cardiovascular events and 3,130 (14.25%) deaths for all causes. The incidence of cardiovascular and all-cause mortality increased in parallel with reduction of eGFR strata and with progressively higher uric acid quartiles. During 215,618 person-years of follow-up, the incidence rate for cardiovascular mortality, stratified based on eGFR (>90, between 60 and 90 and <60 ml/min) was significantly higher in patients with hyperuricemia and albuminuria (3.8, 22.1 and 19.1, respectively) as compared to those with only one risk factor or none (0.4, 2.8 and 3.1, respectively). Serum uric acid and eGFR significantly interact in determining cardiovascular and all-cause mortality. For each SUA increase of 1 mg/dl the risk for mortality increased by 10% even after adjustment for potential confounding factors included eGFR and the presence of albuminuria. Conclusions: hyperuricemia is a risk factor for cardiovascular and all-cause mortality additively to eGFR strata and albuminuria, in patients at cardiovascular risk.