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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.

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 an-tihypertensive 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.

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.

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.

The objective of this study was to investigate the longitudinal association of metabolically healthy overweight/obese adults with major adverse cardiovascular events (MACE) and the effect of LDL-cholesterol levels on this association. This study was conducted with 15,904 participants from the URRAH study grouped according to BMI and metabolic status. Healthy metabolic status was identified with and without including LDL-cholesterol. The risk of MACE during 11.8 years of follow-up was evaluated with multivariable Cox regressions. Among the participants aged <70 years, high BMI was associated with an increased risk of MACE, whereas among the older subjects it was associated with lower risk. Compared to the group with normal weight/healthy metabolic status, the metabolically healthy participants aged <70 years who were overweight/obese had an increased risk of MACE with an adjusted hazard ratio of 3.81 (95% CI, 1.34-10.85, p = 0.012). However, when LDL-cholesterol < 130 mg/dL was included in the definition of healthy metabolic status, no increase in risk was found in the overweight/obese adults compared to the normal weight individuals (hazard ratio 0.70 (0.07-6.71, p = 0.75). The present data show that the risk of MACE is increased in metabolically healthy overweight/obese individuals identified according to standard criteria. However, when LDL-cholesterol is included in the definition, metabolically healthy individuals who are overweight/obese have no increase in risk.

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.

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.

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 ± 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 ± 2.8 vs. 9.2 ± 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.

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.

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

Unlabelled: 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.

Purpose of Review: To examine published and unpublished data documenting the role of sympathetic neural factors in the pathogenesis of different hypertensive phenotypes. These phenotypes relate to attended or unattended blood pressure measurements, to nighttime blood pressure profile alterations, and to resistant, pseudoresistant, and refractory hypertension. Results of original clinical studies as well as of recent meta-analyses based on the behavior of different sympathetic biomarkers in various hypertensive forms will be also discussed. Recent Findings: Studies performed in the past decade have shown that office blood pressure measurements, including in recent years those characterizing unattended or attended blood pressure assessment, are associated with profound changes in the behavior of different sympathetic biomarkers. This is the case for the clinical hypertensive phenotypes characterized by alterations in the nocturnal blood pressure profile and by sleep duration abnormalities. This is also the case for the clinical conditions defined as resistant, refractory, and pseudoresistant hypertension. Summary: Data reviewed in the present paper highlight the relevance of sympathetic neural factors in the development and progression of different clinical hypertensive phenotypes. This suggests that a common hallmark of the majority of the essential hypertensive states detectable in current clinical practice is represented by the alteration in the sympathetic blood pressure control.

Objective: SARS-CoV-2 infection could be complicated by serious autonomic imbalance caused directly by the virus or through secondary release of inflammatory cytokines. Some studies suggested that elevated resting heart rate (HR) and resting tachycardia, being markers of an increased adrenergic cardiac drive, are associated with poor prognosis in COVID-19 syndrome. Design and method: We performed a retrospective analysis in an inpatient cohort of 389 subjects diagnosed with SARS-CoV-2 infection to investigate the prognostic relevance of HR in predicting the maximum care intensity needed during hospitalization according to the following four severity outcome classes: I) no need for oxygen support/need for low flow oxygen therapy; II) need for high flow oxygen therapy/continuous positive airway pressure; III) transfer to the Intensive Care Unit; IV) death. HR assessments were recorded on admission and during the first 3 and 7 days of hospitalization. Results: For each class increase in maximum care intensity we observed a corresponding significant increase in HR, considering both data collected on admission (average HR value: 90.1 ± 17 beats/minute, p-value trend = 0.0397), and during the first 3 days (p-value trend < 0.0006) or 7 days (p-value trend < 0.0001) of hospitalization. The significant trend was maintained after adjustment for age, sex, comorbidities and fever and in the subpopulation of patients (n = 118) not receiving drugs potentially active on HR both before and during hospitalization. Kaplan-Meier curves for survival based on HR displayed a significant decreased survival in patients with higher HR. Conclusions: The assessment of HR during hospitalization provides information on the clinical outcome of patients affected by SARS-CoV-2 infection independently of other confounders. HR as an in-hospital prognostic marker can be obtained both through a first assessment at the admission or mean values over the course of hospitalization with an increase o

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.

Aim:We sought to assess the long-term changes in aortic root diameter in a population-based sample, focusing on new-onset aortic root dilatation, as well as on the demographic and clinical variables independently related to this dynamic process.Methods:A total of 1122 participants with measurable echocardiographic parameters at baseline and after a 10-year follow-up were included in the analysis. Sex-specific upper limits of normality for absolute aortic root diameter, aortic root diameter indexed to body surface area (BSA) and to height were derived from 712 healthy normotensive PAMELA participants.Results:Over the 10-year follow-up, new aortic root dilatation occurred in 3.4% (aortic root /BSA), 4.4% (aortic root /height) and 7.3% (absolute aortic root), respectively. No substantial relationship was observed between baseline office and ambulatory blood pressure (BP) or their changes over time and incident aortic root /BSA and aortic root /height dilatation. Baseline aortic root diameter and left ventricular mass index (LVMI) emerged as important predictors of aortic root dilation, regardless of the diagnostic criteria used. This was also the case for the 10-year change in LVMI. The strength of association between nonhemodynamic variables and new-onset aortic root dilatation was variable, depending on the definition of the aortic phenotype.Conclusion:The incidence of aortic root dilatation in a general middle-aged population is a relatively infrequent but not so rare event and scarcely influenced by both office and out-office BP. On the contrary, it is strongly related to LVMI (and its variations over time). From a clinical perspective, this underlines that LVH prevention and regression can reduce the risk of aortic root dilatation in the community.

The present study was designed to provide information on the ability of several different anthropometric markers to reflect the renal impairment associated with body weight increase and to predict the development of renal alterations linked to overweight and obesity. In 574 subjects representative of the general population of the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study, with an age range between 57 and 73 years, we investigated the association between different anthropometric markers of body fat, as alternative to body mass index, and renal failure, to obtain information useful for determining their potential predictive value. Renal dysfunction was significantly associated with almost all anthropometric markers of adiposity related to body weight and body shape. After adjustment for confounders, such as age, sex, office blood pressure, serum glucose, antihypertensive drugs and smoking habit, association remained significant only for waist-to-hip ratio (WHR), lipid accumulation product (LAP) and visceral adiposity index (VAI). These 3 markers also displayed at the receiver operating curves (ROC) analysis the best ability to detect subjects with or without kidney dysfunction. The results of the present study provide evidence that WHR, LAP and VAI represent the best markers of renal dysfunction associated with visceral body fat accumulation.

Microcirculation is pervasive and orchestrates a profound regulatory cross-talk with the surrounding tissue and organs. Similarly, it is one of the earliest biological systems targeted by environmental stressors and consequently involved in the development and progression of ageing and age-related disease. Microvascular dysfunction, if not targeted, leads to a steady derangement of the phenotype, which cumulates comorbidities and eventually results in a nonrescuable, very high-cardiovascular risk. Along the broad spectrum of pathologies, both shared and distinct molecular pathways and pathophysiological alteration are involved in the disruption of microvascular homeostasis, all pointing to microvascular inflammation as the putative primary culprit. This position paper explores the presence and the detrimental contribution of microvascular inflammation across the whole spectrum of chronic age-related diseases, which characterise the 21st-century healthcare landscape. The manuscript aims to strongly affirm the centrality of microvascular inflammation by recapitulating the current evidence and providing a clear synoptic view of the whole cardiometabolic derangement. Indeed, there is an urgent need for further mechanistic exploration to identify clear, very early or disease-specific molecular targets to provide an effective therapeutic strategy against the otherwise unstoppable rising prevalence of age-related diseases.

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.

Epidemiological studies have unequivocally shown that elevated heart rate values measured at rest have an adverse prognostic impact in the hypertensive patient, being associated with an increased risk of cardiovascular events and complications. In recent years new data have been collected on this issue, strengthening the clinical relevance of elevated heart rate as a specific hypertensive phenotype. The present paper will review old and new data on the prognostic importance of resting tachycardia in the hypertensive patient. It will also examine the role of the sympathetic nervous system in the development of this alteration as well as its therapeutic implications. The different approaches to dynamically assess heart rate values in the clinical setting will be finally discussed.

Background and aims: Chronic coffee consuption has been reported to be associated with a modest but significant increase in blood pressure (BP), although some recent studies have shown the opposite. These data, however, largely refer to clinic BP and virtually no study evaluated cross-sectionally the association between chronic coffee consuption, out-of-office BP and BP variability. Methods and results: In 2045 subjects belonging to the population of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, we analyzed cross-sectionally the association between clinic, 24-hour, home BP and BP variability and level of chronic coffee consumption. Results show that when adjusted for confounders (age, gender, body mass index, cigarette smoking, physical activity and alcohol drinking) chronic coffee consumption does not appear to have any major lowering effect on BP values, particulary when they are assessed via 24-hour ambulatory (0 Cup/day: 118.5 ± 0.7/72.8 ± 0.4 mmHg vs 3 cups/day: 120.2 ± 0.4/74.8 ± 0.3 mmHg, PNS) or home BP monitoring (0 cup/day: 124.1 ± 1.2/75.4 ± 0.7 mmHg vs 3 cups/day: 123.3 ± 0.6/76.4 ± 0.36 mmHg, PNS). However, daytime BP was significantly higher in coffee consumers (about 2 mmHg), suggesting some pressor effects of coffee which vanish during nighttime. Both BP and HR 24-hour HR variability were unaffected. Conclusion: Thus chronic coffee consumption does not appear to have any major lowering effect either on absolute BP values, particulary when they are assessed via 24-hour ambulatory or home BP monitoring, or on 24-hour BP variability.

Purpose: Renal denervation (RDN) exerts sympathoinhibitory effects. No information is available, however, on whether these effects have a regional or a more generalized behavior. Methods: In 14 patients with resistant hypertension (RHT, age 58.3 ± 2.2 years, mean ± SEM), we recorded muscle and skin sympathetic nerve traffic (MSNA and SSNA, respectively) using the microneurographic technique, before, 1 month, and 3 months after RDN. Measurements included clinic blood pressure (BP), heart rate (HR), 24-h BP and HR, as well as routine laboratory and echocardiographic variables. Ten age-matched RHT patients who did not undergo RDN served as controls. Results: MSNA, but not SSNA, was markedly higher in RHT. RDN caused a significant reduction in MSNA 1 month after RDN, with this reduction increasing after 3 months (from 68.1 ± 2.5 to 64.8 ± 2.4 and 63.1 ± 2.6 bursts/100 heartbeats, P < 0.05). This effect was not accompanied by any significant change in SSNA (from 13.1 ± 0.5 to 13.4 ± 0.6 and 13.3 ± 0.4 bursts/min, P = NS). No quantitative or, in some cases, qualitative relationship was found between BP and the MSNA reduction induced by RDN. No significant changes in various sympathetic markers were detected in the control group who did not undergo RDN and were followed for 3-months observation. Conclusions: These data provide the first evidence that RDN exerts heterogeneous effects on sympathetic cardiovascular drive, inducing a marked reduction in MSNA but not in SSNA, which appears to be within the normal range in this condition.These effects may depend on the different reflex modulation regulating neuroadrenergic drive in these cardiovascular districts.

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.

Background: Whether and to what extent the reported blood pressure (BP) lowering effects of renal denervation (RDN) are associated with a central sympathoinhibition is controversial. We examined this issue by performing a meta-analysis of the microneurographic studies evaluating the BP and muscle sympathetic nerve activity (MSNA) responses to RDN in drug-resistant or uncontrolled hypertension (RHT). Methods: This analysis comprised 11 studies including a total of >400 RHT patients undergoing RDN and were followed up for 6 months. Evaluation was extended to the relationships of MSNA with clinic heart rate and BP changes associated with RDN. Results: MSNA showed a significant reduction after RDN (-4.78 bursts/100 heart beats; P<0.04), which was also accompanied by a significant systolic (-11.45 mm Hg; P<0.002) and diastolic (-5.24 mm Hg; P=0.0001) BP decrease. No significant quantitative relationship was found between MSNA and systolic (r=-0.96, P=0.19) or diastolic BP (r=-0.97, P=0.23) responses to RDN. This was also the case for clinic heart rate (r=0.53, P=0.78, respectively), whose post RDN values were not significant different from the pre-RDN ones. More than 10 renal nerves ablations were found to be needed for obtaining a significant sympathoinhibition. Conclusions: This meta-analysis, the first ever done on the MSNA responses to RDN, shows that in a consistent number of RHT patients RDN is associated with a significant, although modest, central sympathoinhibition, which appears to be unrelated to the BP lowering effects of the procedure. Thus factors other than the central sympathetic outflow inhibition may concur at the BP lowering effects of RDN.

Vascular and sympathetic abnormalities characterize chronic heart failure (CHF). Alterations include (1) a reduction in arterial distensibility, (2) endothelial dysfunction, (3) a decrease in arterial compliance and a parallel increase in arterial stiffness, and (4) sympathetic cardiovascular activation. Altogether, these alterations represent important targets in therapeutic interventions, because they display an independent negative impact on the disease prognosis, favouring disease progression and the development of cardiovascular complications with direct and indirect mechanisms. The present review will examine the effects of the different therapeutic interventions targeting the vascular/sympathetic alterations detected in CHF. Non-pharmacological, pharmacological and device-based treatments will be discussed in detail, highlighting the possible mechanisms responsible for the vascular/sympathetic effects of each intervention. Finally, the unmet goals in treatment in relation to endothelial and adrenergic targets will be also discussed.

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.

We assessed the value of 3 electrocardiographic (EKG) voltage criteria in detecting variations of left ventricular mass (LVM) over time, taking echocardiographic (ECHO) LVM as reference, in the Pressioni Arteriose Monitorate E Loro Associazioni study. In 927 subjects (age 47 +/- 13 years on entry, 49.9% men) an ECHO evaluation of LVM and EKG suitable for measurement of EKG-LVH criteria (Sokolow-Lyon voltage, Cornell voltage and R-wave voltage in aVL) were available at baseline and at a 2(nd) evaluation performed 10 years later. Delta (delta) LVM, Delta LVMI, and Delta EKG parameters values were calculated from 2(nd) evaluation to baseline. The sensitivity of the EKG criteria in the diagnosis of LVH, poor at baseline, becomes even worse after 10 years, reaching very low values. Only the sensitivity of R-wave amplitude exhibited slight increase over time but with unsatisfactory absolute values. Despite the prevalence of ECHO-LVH at the 2(nd) evaluation was threefold increased compared to baseline (29.3% and 33.7% for LVM indexed to BSA and height(2.7), respectively), the prevalence of EKG-LVH was unchanged when evaluated by Sokolow-Lyon criteria, significantly reduced when assessed by Cornell voltage index, while significantly increased using R-wave voltage in aVL criteria. Despite an ECHO-LVM increase over the time, mean EKG changes were of opposite sign, except for R-wave amplitude in aVL. Our study highlights the discrepancy between ECHO and EKG in monitoring LVM changes over the time, especially for Sokolow-Lyon and Cornell voltage. Thus, EKG is an unsuitable method for the longitudinal evaluation of LVM variations.

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.

Whether blood pressure (BP) values differ when BP is measured with or without the presence of a doctor (attended and unattended BP measurements) is controversial, and no information exists on whether and to what extent neurogenic mechanisms participate at the possible BP differences between these measurements. In this study, we assessed continuous beat-to-beat finger systolic BP and diastolic BP, heart rate, muscle, and skin sympathetic nerve traffic (microneurography) before and during BP measurement by an automatic device in the presence or absence of a doctor. This was done in 18 untreated mild-to-moderate essential hypertensive patients (age, 40.2±2.8 years, mean±SEM). During attended BP measurement, there was an increase in systolic BP, diastolic BP, heart rate, and skin sympathetic nerve traffic and a muscle sympathetic nerve traffic decrease, the peak changes being +5.3%,+8.4%,+9.4%,+30.9%, and -15.2%, respectively (P<0.05 for all). In contrast, during unattended BP measurement, systolic BP, diastolic BP, heart rate, and skin sympathetic nerve traffic were modestly, albeit in most instances significantly, reduced, whereas muscle sympathetic nerve traffic remained almost unchanged. During unattended BP measurement, peak systolic BP was 14.1 mm Hg lower, peak heart rate was 10.6 bpm lower, and peak skin sympathetic nerve traffic was 8.5 bursts/min lower than the peak values detected during attended BP measurement. Thus the cardiovascular and neural sympathetic responses to the alerting reaction elicited by BP measurement in the presence of a doctor are almost absent during unattended BP measurement, during which, if anything, a modest cardiovascular sympathoinhibition occurs. This has important implications for comparison of studies using these different BP measurement approaches as well as for decision concerning threshold and target BP values for treatment.

In the present study, an ethylene glycol-based electrolyte is used to electrodeposit copper onto zinc for the synthesis of the Zn/Cu/Sn stack, precursor of Cu2ZnSnS4. The employed solution contains diethanolamine (DEA) which supports the formation of amine-complexes, whose features are studied by UV–vis absorption, ESI-MS, and FTIR measurements, providing insight on the optimal concentration of DEA for copper complexation. Cyclic voltammetries (CVs) are carried out at increasing [DEA]/[Cu2+] ratios, highlighting the amine effect on the reduction potential of the copper species. The displacement reaction between copper and zinc is investigated by immersion potential measurements, showing a direct correlation to the voltammetric data. The optimized copper solution resulted in a negligible displacement contribution, allowing the electrochemical synthesis of Mo(sub)/Zn/Cu/Sn stack on a relatively large area (4 cm2). The metallic precursor is analyzed by SEM/EDS, AFM, XRD, and GDOES techniques. Finally, the kesterite CZTS phase is obtained through reactive annealing with elemental sulfur and it is characterized by SEM/EDS, XRD, and Raman spectroscopy. Photoelectrochemical water splitting on CZTS/CdS/Pt heterostructure is carried out in an aqueous solution at pH 6.85, showing a photocurrent of -5.05 mA/cm2 at 0 V vs RHE. A maximum applied bias photon-to-current efficiency (ABPE) value of 2.15% was found at 0.84 V bias.

Introduction: Serum uric acid (SUA) has been depicted as a contributory causal factor in metabolic syndrome (MS), which in turn, portends unfavourable prognosis. Aim: We assessed the prognostic role of SUA in patients with and without MS. Methods: We used data from the multicentre Uric Acid Right for Heart Health study and considered cardiovascular mortality (CVM) as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure. Results: A total of 9589 subjects (median age 58.5 years, 45% males) were included in the analysis, and 5100 (53%) patients had a final diagnosis of MS. After a median follow-up of 142 months, we observed 558 events. Using a previously validated cardiovascular SUA cut-off to predict CVM (> 5.1 mg/dL in women and 5.6 mg/dL in men), elevated SUA levels were significantly associated to a worse outcome in patients with and without MS (all p < 0.0001) and provided a significant net reclassification improvement of 7.1% over the diagnosis of MS for CVM (p = 0.004). Cox regression analyses identified an independent association between SUA and CVM (Hazard Ratio: 1.79 [95% CI, 1.15–2.79]; p < 0.0001) after the adjustment for MS, its single components and renal function. Three specific combinations of the MS components were associated with higher CVM when increasing SUA levels were reported, and systemic hypertension was the only individual component ever-present (all p < 0.0001). Conclusion: Increasing SUA levels are associated with a higher CVM risk irrespective of the presence of MS: a cardiovascular SUA threshold may improve risk stratification. Graphic abstract: [Figure not available: see fulltext.]

Among the observational studies performed in the area of blood pressure measurements in the population the “Pressioni Arteriose Monitorate E Loro Associazioni” (PAMELA) investigation represents a unique research for several reasons. The PAMELA study combines clinic, home and 24-hour blood pressure measurements in all participants, which were representative of the general population. Examination included metabolic variables, allowing us to determine the interrelationships between blood pressure and metabolic profile. The protocol also included evaluation of organ damage, such as left ventricular hypertrophy, left ventricular diastolic dysfunction, left atrial dimensions and aortic root diameters. Finally, PAMELA represents one of the few studies with a prolonged follow-up, the last survey being completed three years ago, and data collected are under analysis. This will allow to update the information related to cardiovascular morbidity and mortality in the study cohort. The present paper provided an overview of the various scientific contributions of the PAMELA study to the epidemiology, pathophysiology and clinical aspects of hypertension and hypertension related cardiovascular risk.

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 fortyseven 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.