Ambulatory Blood Pressure Phenotypes, Arterial Stiffness And Cardiac Remodelling.

BACKGROUND: Evidence on the association of arterial stiffness and left ventricular (LV) concentric remodelling/ LVH assessed by echocardiography, with abnormal blood pressure (BP) phenotypes, defined by office and ambulatory BP monitoring (ABPM) in the community is scanty. We investigated this issue in the participants to the Pressioni Monitorate E Loro Associazioni (PAMELA) study. METHODS: The study included 491 participants who attended the second and third survey of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, blood examinations, office, ABPM, echocardiographic and Cardio-Ankle Vascular Index (CAVI) measurements. RESULTS: In the whole study sample (age 66 + 10 years, 50% males), the prevalence rates of sustained normotension (NT), white coat hypertension (WCH), masked hypertension (MH), sustained hypertension (SH) and non-dipping (ND) were 31.2, 10.0, 24.2, 34.6, and 35.8% and respectively. The likelihood of having SH, the BP phenotype carrying the greatest CV risk, was four times higher (OR= 4.31, CI:2.39-7.76, p<0.0001) in participants with increased CAVI and LV remodelling/LVH compared to their counterparts without organ damage. This association showed an incremental value in discriminating SH compared to both isolated markers of organ damage (OR=1.92,p=0.03 for increased CAVI and OR= 2.02, p=0.02 for LV remodelling/LVH). The presence of isolated but also combined organ damage was unrelated to ND. CONCLUSIONS: Our study provides new evidence of the incremental value of looking for both vascular and cardiac organ damage to optimize the identification and clinical management of SH in the general population.

Cardio-Ankle Vascular Index and left ventricular mass as markers of nocturnal blood pressure fall in the general population.

BACKGROUND: Findings regarding the association between Cardio-Ankle Vascular Index (CAVI) and the extent of nocturnal blood pressure (BP) fall in the general population are scanty. We sought to investigate this issue in the participants enrolled in the Pressioni Monitorate E Loro Associazioni (PAMELA) study. METHODS: The study included 491 participants who attended the second and third surveys of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, office, home, ambulatory blood pressure BP monitoring (ABPM), blood examinations, echocardiography, and CAVI measurements. RESULTS: In the whole study, both CAVI and left ventricular mass index (LVMI) were inversely correlated with nocturnal SBP fall, expressed as day-night percent change (r = - 0.152, p = 0.0007, and r = - 0.213, p < 0.0001, respectively). However, after adjustment for sex and age, the correlation remained significant only for LVMI (r = - 0.124, p = 0.006). Non-dipper participants exhibited significantly higher sex-age adjusted LVMI (91 ± 22 vs 82 ± 18 g/m2 (p < 0.0001)), but not of CAVI (9.07 ± 2.0 and 9.57 ± 2.2 m/s, p = ns). Similar results were found when classifying participants into quartiles of nocturnal SBP drop. Finally, both sex-age adjusted CAVI and LVMI were positively correlated with mean nocturnal SBP (r = 0.181, p < 0.001, and r = 0.240, p < 0.0001). CONCLUSIONS: Although arterial stiffness assessed by CAVI, unlike LVMI, is unrelated with the degree of nocturnal BP drop, this marker is useful in identifying nocturnal hypertension and optimizing cardiovascular risk stratification in the community.

Reliability of heart rate in reflecting cardiac sympathetic overdrive in type 2 diabetes mellitus.

PURPOSE: Clinical trials have shown that in type 2 diabetes mellitus (T2D) resting office heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk, a worse prognosis and an unfavorable outcome. The present study was aimed at investigating whether the above mentioned treshold HR values reflect a sympathetic overdrive of marked degree. METHODS: In 58 T2D patients (age range: 39-57 years) without signs of autonomic neuropathy and in 52 age-matched healthy controls, we assessed muscle sympathetic nerve activity (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC), subdividing the study population in different subgroups according to their clinic and 24-h HR values. RESULTS: In T2D progressively greater clinic and 24-h HR values were accompanied by progressive increases in MSNA and NE. HR cutoff values indicated by clinical trials as associated with an increased cardiovascular risk (> 70 beats/minute) were accompanied by MSNA values significantly higher than those detected in patients with lower HR, this being the case also for NE. In T2D both MSNA and NE were significantly related to clinic (r = 0.93, P < 0.0001 and r = 0.87, P < 0.0001, respectively) and 24-h (r = 0.92, P < 0.0001 and r = 0.84, P < 0.0001, respectively) HR. The MSNA and NE behaviour observed in T2D was not detected in healthy controls. CONCLUSIONS: In T2D clinic HR values allow to detect patients with a greater sympathetic overactivity. Considering the adverse clinical impact of the sympathetic overdrive on prognosis, our data emphasize the need of future studies investigating the potential usefulness of lifestyle and pharmacological interventions exerting sympathomodulatory effects.

Serum Uric Acid, Hypertriglyceridemia, and Carotid Plaques: A Sub-Analysis of the URic Acid Right for Heart Health (URRAH) Study.

High levels of serum uric acid (SUA) and triglycerides (TG) might promote high-cardiovascular-risk phenotypes, including subclinical atherosclerosis. An interaction between plaques xanthine oxidase (XO) expression, SUA, and HDL-C has been recently postulated. Subjects from the URic acid Right for heArt Health (URRAH) study with carotid ultrasound and without previous cardiovascular diseases (CVD) (n = 6209), followed over 20 years, were included in the analysis. Hypertriglyceridemia (hTG) was defined as TG ≥ 150 mg/dL. Higher levels of SUA (hSUA) were defined as ≥5.6 mg/dL in men and 5.1 mg/dL in women. A carotid plaque was identified in 1742 subjects (28%). SUA and TG predicted carotid plaque (HR 1.09 [1.04-1.27], p < 0.001 and HR 1.25 [1.09-1.45], p < 0.001) in the whole population, independently of age, sex, diabetes, systolic blood pressure, HDL and LDL cholesterol and treatment. Four different groups were identified (normal SUA and TG, hSUA and normal TG, normal SUA and hTG, hSUA and hTG). The prevalence of plaque was progressively greater in subjects with normal SUA and TG (23%), hSUA and normal TG (31%), normal SUA and hTG (34%), and hSUA and hTG (38%) (Chi-square, 0.0001). Logistic regression analysis showed that hSUA and normal TG [HR 1.159 (1.002 to 1.341); p = 0.001], normal SUA and hTG [HR 1.305 (1.057 to 1.611); p = 0.001], and the combination of hUA and hTG [HR 1.539 (1.274 to 1.859); p = 0.001] were associated with a higher risk of plaque. Our findings demonstrate that SUA is independently associated with the presence of carotid plaque and suggest that the combination of hyperuricemia and hypertriglyceridemia is a stronger determinant of carotid plaque than hSUA or hTG taken as single risk factors. The association between SUA and CVD events may be explained in part by a direct association of UA with carotid plaques.

Habitual Regular Coffee Consumption and Arterial Stiffness: Data From the 3rd Pamela Survey.

BACKGROUND: We evaluated whether chronic coffee consumption affects arterial stiffness, assessed by cardio-ankle vascular index (CAVI). METHODS: In 514 subjects, aged 66.6 ±â€…9.9 years (mean ±â€…SD), recruited in the 3rd follow-up of the PAMELA study, subdivided into 3 groups according to the daily intake of regular coffee (0, 1-2, and ≥3 cups/day), we measured CAVI and clinic, ambulatory blood pressure (BP), and other variables. RESULTS: The 3 groups displayed similar age, gender, metabolic, and renal profile. Clinic and ambulatory BPs were similar in the 3 groups, this being the case for CAVI (0 cup: 9.1 ±â€…1.8, 1-2 cups: 9.5 ±â€…2.3, and ≥3 cups: 9.2 ±â€…2.1 m/s, P = NS). No significant gender difference in CAVI and in participants under antihypertensive treatment was detected. CONCLUSIONS: Our data show that chronic coffee consumption leaves unaffected arterial stiffness in the general population, this being the case in subgroups. The neutral vascular impact of coffee may favor the absence of any significant BP effect of habitual coffee intake.

Effects of acute carotid baroreceptor stimulation on sympathetic nerve traffic in resistant and uncontrolled hypertension: a systematic review and meta-analysis.

In resistant hypertensive patients acute carotid baroreflex stimulation is associated with a blood pressure (BP) reduction, believed to be mediated by a central sympathoinhbition.The evidence for this sympathomodulatory effect is limited, however. This meta-analysis is the first to examine the sympathomodulatory effects of acute carotid baroreflex stimulation in drug-resistant and uncontrolled hypertension, based on the results of microneurographic studies. The analysis included 3 studies assessing muscle sympathetic nerve activity (MSNA) and examining 41 resistant uncontrolled hypertensives. The evaluation included assessment of the relationships between MSNA and clinic heart rate and BP changes associated with the procedure. Carotid baroreflex stimulation induced an acute reduction in clinic systolic and diastolic BP which achieved statistical significance for the former variable only [systolic BP: -19.98 mmHg (90% CI, -30.52, -9.43), P < 0.002], [diastolic BP: -5.49 mmHg (90% CI, -11.38, 0.39), P = NS]. These BP changes were accompanied by a significant MSNA reduction [-4.28 bursts/min (90% CI, -8.62, 0.06), P < 0.07], and by a significant heart rate decrease [-3.65 beats/min (90% CI, -5.49, -1.81), P < 0.001]. No significant relationship was detected beween the MSNA, systolic and diastolic BP changes induced by the procedure, this being the case also for heart rate. Our data show that the acute BP lowering responses to carotid baroreflex stimulation, although associated with a significant MSNA reduction, are not quantitatively related to the sympathomoderating effects of the procedure. This may suggest that these BP effects depend only in part on central sympathoinhibition, at least in the acute phase following the intervention.

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.

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.

Mechanisms of Vascular Inflammation and Potential Therapeutic Targets: A Position Paper From the ESH Working Group on Small Arteries.

Inflammatory responses in small vessels play an important role in the development of cardiovascular diseases, including hypertension, stroke, and small vessel disease. This involves various complex molecular processes including oxidative stress, inflammasome activation, immune-mediated responses, and protein misfolding, which together contribute to microvascular damage. In addition, epigenetic factors, including DNA methylation, histone modifications, and microRNAs influence vascular inflammation and injury. These phenomena may be acquired during the aging process or due to environmental factors. Activation of proinflammatory signaling pathways and molecular events induce low-grade and chronic inflammation with consequent cardiovascular damage. Identifying mechanism-specific targets might provide opportunities in the development of novel therapeutic approaches. Monoclonal antibodies targeting inflammatory cytokines and epigenetic drugs, show promise in reducing microvascular inflammation and associated cardiovascular diseases. In this article, we provide a comprehensive discussion of the complex mechanisms underlying microvascular inflammation and offer insights into innovative therapeutic strategies that may ameliorate vascular injury in cardiovascular disease.

Cardio-Ankle Vascular Index as a Marker of Left Ventricular Hypertrophy in Treated Hypertensives: Findings From the Pamela Study.

BACKGROUND: Findings regarding the association between Cardio-Ankle Vascular Index (CAVI) and cardiac hypertension-mediated organ damage (HMOD), such as left ventricular hypertrophy (LVH) assessed by echocardiography, in elderly hypertensive patients are scanty. We sought to investigate this issue in the hypertensive fraction of the general population treated with anti-hypertensive drugs enrolled in the Pressioni Monitorate E Loro Associazioni (PAMELA) study. METHODS: The study included 239 out of 562 participants who attended the second and third surveys of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, office, home, ambulatory blood pressure (BP), blood examinations, echocardiography, and CAVI measurements. RESULTS: In the whole study sample (age 69 ±â€…9 years, 54% males), CAVI was positively correlated with age, office, home, ambulatory systolic BP, LV mass (LVM) index, and negatively associated with body mass index (BMI). In multivariate analysis, CAVI was associated with the LVM index (P < 0.05) independently of major confounders. The participants with LVH exhibited significantly higher CAVI (10.6 ±â€…2.8 vs. 9.2 ±â€…1.8 m/s P < 0.001), larger left atrial diameter, and lower LV ejection fraction values than their counterparts without it. The CAVI value of 9.4 m/s was the best cut-off for prediction of LVH in the whole sample. CONCLUSIONS: Our study provides new evidence of an independent association between CAVI and LVH in treated elderly hypertensive patients and suggests that the use of this metric of arterial stiffness could not only be used to evaluate vascular damage but also to stratify the risk of LVH.

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.

Renal Denervation in End-Stage Renal Disease: Current Evidence and Perspectives.

In patients with end-stage renal disease (ESRD) undergoing haemodialysis, hypertension is of common detection and frequently inadequately controlled. Multiple pathophysiological mechanisms are involved in the development and progression of the ESRD-related high blood pressure state, which has been implicated in the increased cardiovascular risk reported in this hypertensive clinical phenotype. Renal sympathetic efferent and afferent nerves play a relevant role in the development and progression of elevated blood pressure values in patients with ESRD, often leading to resistant hypertension. Catheter-based bilateral renal nerves ablation has been shown to exert blood pressure lowering effects in resistant hypertensive patients with normal kidney function. Promising data on the procedure in ESRD patients with resistant hypertension have been reported in small scale pilot studies. Denervation of the native non-functioning kidney's neural excitatory influences on central sympathetic drive could reduce the elevated cardiovascular morbidity and mortality seen in ESRD patients. The present review article will focus on the promising results obtained with renal denervation in patients with ESRD, its mechanisms of action and future perspectives in these high risk patients.

Regional and temporal differences in the associations between cardiovascular disease and its classic risk factors: an analysis of 49 cohorts from 11 European countries.

AIMS: The regional and temporal differences in the associations between cardiovascular disease (CVD) and its classic risk factors are unknown. The current study examined these associations in different European regions over a 30-year period. METHODS AND RESULTS: The study sample comprised 553 818 individuals from 49 cohorts in 11 European countries (baseline: 1982-2012) who were followed up for a maximum of 10 years. Risk factors [sex, smoking, diabetes, non-HDL cholesterol, systolic blood pressure (BP), and body mass index (BMI)] and CVD events (coronary heart disease or stroke) were harmonized across cohorts. Risk factor-outcome associations were analysed using multivariable-adjusted Cox regression models, and differences in associations were assessed using meta-regression. The differences in the risk factor-CVD associations between central Europe, northern Europe, southern Europe, and the UK were generally small. Men had a slightly higher hazard ratio (HR) in southern Europe (P = 0.043 for overall difference), and those with diabetes had a slightly lower HR in central Europe (P = 0.022 for overall difference) compared with the other regions. Of the six CVD risk factors, minor HR decreases per decade were observed for non-HDL cholesterol [7% per mmol/L; 95% confidence interval (CI), 3-10%] and systolic BP (4% per 20 mmHg; 95% CI, 1-8%), while a minor HR increase per decade was observed for BMI (7% per 10 kg/m2; 95% CI, 1-13%). CONCLUSION: The results demonstrate that all classic CVD risk factors are still relevant in Europe, irrespective of regional area. Preventive strategies should focus on risk factors with the greatest population attributable risk.

All classic cardiovascular disease (CVD) risk factors are still relevant in Europe, irrespective of regional area. The differences in the associations of CVD risk factors with overt CVD between regions of Europe are generally small. Minor temporal hazard decreases were observed for non-HDL cholesterol and systolic blood pressure, while a minor hazard increase was observed for body mass index.

Long-term increase in serum uric acid and its predictors over a 25 year follow-up: Results of the PAMELA study.

BACKGROUND AND AIMS: Hyperuricemia (HU) has been shown to be associated with an adverse impact on cardiovascular and metabolic risk. Scanty data are available in the general population on the longitudinal changes in serum uric acid (SUA), the occurrence of HU and their potential predictors. We examined during a 25-year follow-up the SUA changes and the factors associated with HU development in the Pressioni Arteriose Monitorate E loro Associazioni (PAMELA) study. METHODS AND RESULTS: We analyzed data collected in 561 subjects of the PAMELA study evaluated during an average follow-up time amounting to 25.4 ± 1.0 years (mean ± SD). HU was defined by the Uric Acid Right for Heart Health (URRAh) cutoff (5.1 for females and 5.6 mg/dl for males). Mean SUA values during follow-up increased from 4.7 ± 1.1 to 5.0 ± 1.2 mg/dl (P<0.001), the average SUA elevation amounting to of 0.3 ± 1.1 mg/dl 26.7 % of the subjects displayed HU at the follow-up. This was associated at the multivariable analysis with female gender, office, home and 24-h blood pressure, diuretic treatment, serum triglycerides and baseline SUA, as well as the increase in waist circumference and the reduction in renal function. CONCLUSION: The present study provides longitudinal evidence that in the general population during a 25 year follow-up there is a progressive increase in SUA and HU development. Baseline SUA represents the most important factor associated with these modifications. Gender, renal dysfunction, triglycerides, obesity, diuretic treatment and blood pressure represent other variables capable to predict future occurrence of HU.

Comparison between visit-to-visit office and 24-h blood pressure variability in treated hypertensive patients.

OBJECTIVES: In any treated hypertensive patient office blood pressure (BP) values may differ between visits and this variability (V) has an adverse prognostic impact. However, little information is available on visit-to-visit 24-h BPV. METHODS: In 1114 hypertensives of the ELSA and PHYLLIS trials we compared visit-to-visit office and 24-h mean BPV by coefficient of variation (CV) of the mean systolic (S) and diastolic (D) BP obtained from yearly measurements during a 3-4 year treatment period. Visit-to-visit BPV during daytime and night-time were also compared. RESULTS: Twenty-four-hour SBP-CV was about 20% less than office SBP-CV ( P  < 0.0001). SBP-CV was considerably greater for the night-time than for the daytime period (20%, P  < 0.0001). Results were similar for DBP and in males and females, older and younger patients, patients under different antihypertensive drugs or with different baseline or achieved BP values. In the group as a whole and in subgroups there was significant correlations between office and 24-h BP-CV but the correlation coefficients was weak, indicating that office SBP or DBP CV accounted for only about 1-4% of 24-h SBP or DBP-CV values. CONCLUSION: Twenty-four-hour mean BP across visits is more stable than across visit office BP. Visit-to-visit office and 24-h BPV are significantly related to each other, but correlation coefficients are low, making visit-to-visit office BP variations poorly predictive of the concomitant 24-h BP variations and thus of on-treatment ambulatory BP stability.

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.