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Background: The relationship between HyperUricemia (HU) and Metabolic Sindrome (MS) and if Uric Acid (UA) should be inserted into MS definitions is a matter of debate. Aim of our study was to evaluate the correlation between UA and HU with Insulin Resistance (IR) and MS in a population of hypertensive patients. HU was defined with two cut-offs (the classic one of ≥6 mg/dL for women and ≥ 7 for men; the newly proposed URRAH one with ≥5.6 mg/dL for both sexes)., Methods: We enrolled 473 Hypertensive patients followed by the Hypertension Unit of San Gerardo Hospital (Monza, Italy). IR was defined through TG/HDL ratio and NCEP-ATP-III criteria were used for MS diagnosis., Results: MS was found in 33.6 % while HU affected 14.8 % of subjects according to the traditional cut-off and 35.9 % with the URRAH cut-off. 9.7 % (traditional cut-off) and 17.3 % (URRAH's threshold) of the subjects had both HU and MS. UA level was significantly higher in MS group (5.7 vs 4.9 mg/dL, p < 0.0001) as well as for HU (29.0 vs 7.6 % and 51.6 vs 28.0 %, for classic and URRAH cut-off respectively, p < 0.0001 for both comparison). Logistic multivariable regression models showed that UA is related to MS diagnosis (OR = 1.608 for each 1 mg/dL), as well as HU with both cut-off (OR = 5.532 and OR = 3.379, p < 0.0001 for all comparison, for the classic cut-off and the URRAH one respectively)., Conclusions: The main finding of our study is that UA and HU significantly relate to IR and MS. The higher the values of UA and the higher the cut-off used, the higher the strength of the relationship., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Few certainties exist regarding optimal management of Blood Pressure (BP) in the very first hours after an ischemic stroke and many questions remain still unanswered. Our work aimed to evaluate the role of BP and its trend as possible determinants of in-hospital mortality (primary outcome), discharge disabilities and hospitalization length (secondary outcomes) in ischemic stroke patients presented with Hypertensive Emergencies (HE)., Methods: We retrospectively evaluated patients presented to Niguarda Hospital, Emergency Department (ED), from 2015 to 2017 with a neurological ischemic HE. BP at ED presentation (T0), its management in ED (T1) and its values at the stroke unit admission (T2) were evaluated., Results: 267 patients were included (0.13 % of all ED accesses and 17.9 % of all ischemic strokes). In the whole population, BP values were not associated with in-hospital mortality while T0 and T2 SBP result were associated to discharge disability and hospitalization length. In pre-specified subgroup analysis these associations were confirmed only in untreated subjects (not anti-hypertensive nor thrombolysis). In fact, no significant relationship can be found between BP values and any secondary outcome in thrombolysis and anti-hypertensive treated patients., Conclusions: BP values and its management can not be related to in-hospital mortality in stroke patients, presented with HE, while they are associated to discharge disability and hospitalization length. In subgroup analysis, results were confirmed only in untreated (not anti-hypertensive therapies nor thrombolytic)., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2024 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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.

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.

Background and Aim: Heterogeneous results have been obtained in the relationship between Uric Acid (UA) and Target Organ Damage (TOD). In the present study we sought to assess the prevalence of hyperuricemia in healthy subjects as well as the role of UA in determining TOD. We evaluated vascular, cardiac and renal TODs in the whole population as well as sub-grouped by gender., Methods and Results: As many as 379 blood donors participated at the present analysis. TOD was evaluated as Pulse Wave Velocity (PWV), Left Ventricular Mass Index (LVMI) and carotid Intima-Media Thickness (IMT). Hyperuricemia was defined with the classic cut-off (>7.0 in men and >6.0 mg/dL in women) but also with a most recently defined one (5.6 mg/dL for both sex). Hyperuricemia was present in 6.3% of the whole population (7.3% males, 2.8% females) considering the classic cut-off, while, with the recently identified one, it was present in 28.2% of the whole population (37.3% males, 4.7% females). Despite all the evaluated TODs significantly correlated with UA, linear multivariate regression analysis showed that none of them, except for GFR, displayed UA as a significant covariate. Similar figures were found also when both correlation and linear regression analyses were repeated in the two genders separately., Conclusions: Hyperuricemia is an important problem also in healthy subjects and its prevalence could further increase if lower cut-off will be used. In this specific population UA is significantly associated with renal impairment while this was not the case for cardiac and vascular damage., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the prognostic cut-off values of serum uric acid (SUA) in predicting fatal and morbid heart failure in a large Italian cohort in the frame of the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension., Methods: The URic acid Right for heArt Health (URRAH) study is a nationwide, multicentre, cohort study involving data on individuals aged 18-95 years, recruited on a community basis from all regions of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 128 ± 65 months. Incident heart failure was defined on the basis of International Classification of Diseases Tenth Revision codes and double-checked with general practitioners and hospital files. Multivariate Cox regression models having fatal and morbid heart failure as dependent variables, adjusted for sex, age, SBP, diabetes, estimated glomerular filtration rate, smoking habit, ethanol intake, BMI, haematocrit, LDL cholesterol, previous diagnosis of heart failure and use of diuretics as possible confounders, were used to search for an association between SUA as a continuous variable and heart failure. By means of receiver operating characteristic curves, two prognostic cut-off values (one for all heart failure and one for fatal heart failure) were identified as able to discriminate between individuals doomed to develop the event. These cut-off values were used as independent predictors to divide individuals according to prognostic cut-off values in a multivariate Cox models, adjusted for confounders., Results: A total of 21 386 individuals were included in the analysis. In Cox analyses, SUA as a continuous variable was a significant predictor of all [hazard ratio 1.29 (1.23-1.359), P < 0.0001] and fatal [hazard ratio 1.268 (1.121-1.35), P < 0.0001] incident heart failure. Cut-off values of SUA able to discriminate all and fatal heart failure status were identified by mean of receiver operating characteristic curves in the whole database: SUA more than 5.34 mg/dl (confidence interval 4.37-5.6, sensitivity 52.32, specificity 63.96, P < 0.0001) was the univariate prognostic cut-off value for all heart failure, whereas SUA more than 4.89 mg/dl (confidence interval 4.78-5.78, sensitivity 68.29, specificity 49.11, P < 0.0001) for fatal heart failure. The cut-off for all heart failure and the cut-off value for fatal heart failure were accepted as independent predictors in the Cox analysis models, the hazard ratios being 1.645 (1.284-2.109, P < 0.0001) for all heart failure and 1.645 (1.284-2.109, P < 0.0001) for fatal heart failure, respectively., Conclusion: The results of the current study confirm that SUA is an independent risk factor for all heart failure and fatal heart failure, after adjusting for potential confounding variables and demonstrate that a prognostic cut-off value can be identified for all heart failure (>5.34 mg/dl) and for fatal heart failure (>4.89 mg/dl).

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Objective: The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension conceived and designed an ad-hoc study aimed at searching for prognostic cut-off values of serum uric acid (SUA) in predicting fatal myocardial infaction (MI) in women and men., Methods: The URic acid Right for heArt Health study is a nationwide, multicentre, observational cohort study involving data on individuals aged 18-95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 122.3 ± 66.9 months., Results: A total of 23 467 individuals were included in the analysis. Cut-off values of SUA able to discriminate MI status were identified by mean of receiver operating characteristic curves in the whole database (>5.70 mg/dl), in women (>5.26 mg/dl) and in men (>5.49 mg/dl). Multivariate Cox regression analyses adjusted for confounders (age, arterial hypertension, diabetes, chronic kidney disease, smoking habit, ethanol intake, BMI, haematocrit, LDL cholesterol and use of diuretics) identified an independent association between SUA and fatal MI in the whole database (hazard ratio 1.381, 95% confidence intervals, 1.096-1.758, P = 0.006) and in women (hazard ratio 1.514, confidence intervals 1.105-2.075, P < 0.01), but not in men., Conclusion: The results of the current study confirm that SUA is an independent risk factor for fatal MI after adjusting for potential confounding variables, and demonstrate that a prognostic cut-off value associated to fatal MI can be identified at least in women.

Serum uric acid (SUA) levels discriminating across the different strata of cardiovascular risk is still unknown. By utilizing a large population-based database, we assessed the threshold of SUA that increases the risk of total mortality and cardiovascular mortality (CVM). The URRAH study (Uric Acid Right for Heart Health) is a multicentre retrospective, observational study, which collected data from several large population-based longitudinal studies in Italy and subjects recruited in the hypertension clinics of the Italian Society of Hypertension. Total mortality was defined as mortality for any cause, CVM as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure. A total of 22 714 subjects were included in the analysis. Multivariate Cox regression analyses identified an independent association between SUA and total mortality (hazard ratio, 1.53 [95% CI, 1.21-1.93]) or CVM (hazard ratio, 2.08 [95% CI, 1.146-2.97]; P <0.001). Cutoff values of SUA able to discriminate total mortality (4.7 mg/dL [95% CI, 4.3-5.1 mg/dL]) and CVM status (5.6 mg/dL [95% CI, 4.99-6.21 mg/dL]) were identified. The information on SUA levels provided a significant net reclassification improvement of 0.26 and of 0.27 over the Heart Score risk chart for total mortality and CVM, respectively ( P <0.001). Sex-specific cutoff values for total mortality and CVM were also identified and validated. In conclusion, SUA levels increasing the risk of total mortality and CVM are significantly lower than those used for the definition of hyperuricemia in clinical practice. Our data provide evidence of a cardiovascular SUA threshold that might contribute in clinical practice to improve identification of patients at higher risk of CVM.

The role of uric acid (UA) on the arterial stiffness progression has been evaluated only in three studies. Our aim was to evaluate its role as a possible determinant of the pulse wave velocity (PWV) progression over a 3.7 ± 0.5 years follow-up period in hypertensive patients. Specific sex analysis was done due to the well-known sex interaction with UA levels. We enrolled 422 consecutive hypertensive outpatients. At baseline anamnestic, blood pressure (BP) and laboratory data as well as PWV were assessed. PWV was performed again at follow-up examination. Hyperuricemia was defined as a UA > 6 mg/dL for women and > 7 mg/dL for men. Baseline age was 53.2 ± 13 years, 58% were males, systolic and diastolic BP (SBP/DBP) 141.7 ± 17.7/86.8 ± 10.8 mm Hg, UA 5.2 ± 1.4 mg/dL, and PWV 8.5 ± 1.9 m/s. At follow-up, despite better BP values (-8.5 ± 24.6 for SBP and -7.5 ± 15.4 for DBP), PWV increases to 9.1 ± 2.3 m/s (P < 0.001) with mean ΔPWV of+ 0.5 ± 2.2 m/s. A total of 61 patients were hyperuricemic (14.4%), and they present higher PWV baseline (9.0 ± 2.5 vs 8.5 ± 1.8 m/s, P = 0.03) without significant differences in ΔPWV. Hyperuricemic female (6.2%, 11 patients) presents higher baseline PWV without significant differences in ΔPWV. No differences were found in arterial stiffness in hyperuricemic males (20.4%, 50 patients). UA showed association with baseline and ΔPWV in the whole population but it loses statistical significance at the linear regression model. Same figures were also for sex analysis. Our findings provide evidence that baseline UA levels are not determinants of PWV progression over a median follow-up of 3.8 years' in hypertensive patients., (©2019 Wiley Periodicals, Inc.)

Cross-sectional and longitudinal data analysis of the PAMELA (Pressioni Monitorate E Loro Associazioni) population was performed to assess the association between prehypertension and left ventricular hypertrophy (LVH) at entry and the risk of new-onset LVH associated to this condition in the subset of participants with normal LV mass index (LVMI). A total of untreated 1397 participants with measurable echocardiographic parameters at baseline were considered in the cross-sectional analysis. The longitudinal analysis included 880 participants without LVH at baseline and with measurable LVMI at follow-up examination performed 10 years later. At entry, after adjustment for major confounders LVH prevalence rates (LVM/body surface area) showed a significant, progressive increase from the normotensive (2.1%), to prehypertension (6.7%), and hypertension group (18.3%). The incidence of LVH increased progressively from the normotensive to prehypertension and hypertension group (9.0%, 23.2%, and 36.5%, respectively). The risk of new LVH was significantly greater in prehypertension who progressed to sustained hypertension (odds ratio, 4.21; CI, 1.64-10.83; P=0.003) than in those with persistent prehypertension (odds ratio, 1.89; CI, 0.77-5.11; P=0.21) compared with persistent normotensive participants after adjustment for age, sex, baseline LVMI, obesity, glucose, creatinine, total cholesterol and the use of antihypertensive drugs at follow-up. Further adjustments for changes in body mass index, metabolic variables, and creatinine during the follow-up did not modify the strength of association between prehypertension and new-onset LVH. Our findings offer a new piece of evidence on the association of prehypertension with LVH and support the view that preventive actions for this condition affecting a large fraction of the general population should be intensified.

The present study was aimed at assessing the relationships between absolute and individual residual blood pressure (BP) variability and cognitive function in a general population. This cross-sectional study evaluated cognitive function using minimental state evaluation (MMSE) in 471 subjects enrolled in the PAMELA study. MMSE was calculated 10 years after initial enrollment of the subjects in the PAMELA study. Measurements included office, home, and 24-hour ambulatory BP monitoring. BP variability was obtained by calculating: (a) 24-hour standard deviation (SD) for systolic and diastolic BP and (b) individual residual BP variability. Mean age (±SD) of the subjects enrolled was 63 ± 5.7 years at the initial evaluation, with a 10-year increase when MMSE was performed. There was no significant difference in BP or heart rate values measured at office, home, or during 24-h BP monitoring between subjects with MMSE < 24 and those with ≥24. BP variability measured by SBP and DBP SD was also similar between these two groups. However, individual residual BP variability was significantly greater in subjects with lower MMSE and this difference became more pronounced when the study population was divided in three groups according to MMSE score (10-20, 21-23, 24-30). Individual residual SBP and DBP variability gradually decreased with the increase in MMSE score. Our data show that a sensitive parameter for the development of cognitive impairment is not BP or absolute BP variability but rather its short-term erratic component, which has been previously shown to be an important prognostic marker for organ damage, cardiovascular, and all-cause mortality., (©2018 Wiley Periodicals, Inc.)

Aim: In the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study, clinical and metabolic variables as well as office, home and ambulatory blood pressure (BP) values were simultaneously measured at baseline and after a 10-year follow-up. The study design allowed us to assess the value of selective and combined elevation of different BP phenotypes in predicting new-onset metabolic syndrome (MetS)., Methods: The present analysis included 1182 participants without MetS at baseline, as defined by the APT III criteria. On the basis of office, 24-h ambulatory BP and home values, participants were divided into four groups: normal, white-coat hypertension (WCH), masked hypertension and sustained hypertension., Results: Compared with participants with in-office and out-of-office normal BP, a greater incidence of new-onset age-adjusted and sex-adjusted MetS was observed in WCH (OR = 1.75, CI 1.01-3.04, P = 0.0046), masked hypertension (OR = 2.58, CI 1.26-5.30; P = 0.009) and sustained hypertension (OR = 2.14, CI 1.20-3.79, P = 0.009)) when out-of-office BP was defined by ambulatory criteria. This was not the case when out-of-office BP was defined by home criteria, as only the WCH group showed a greater risk (OR 2.16, CI 1.28-3.63, P = 0.003). Similar findings were obtained for single components of the MetS such as abdominal obesity and hyperglycemia., Conclusion: Our study provides evidence that either isolated or combined BP elevations identified by office/ambulatory measurements, carry an increased risk of new-onset MetS, whereas, only WCH is associated with a greater risk of incident MetS whenever BP phenotypes are identified by office/home measurements. In a clinical perspective, a comprehensive evaluation of BP status based on office/ambulatory measurements may improve diagnosis of new-onset MetS and activate measures for its prevention.

Background: Although several data suggest that serum uric acid (SUA) predicts future development of metabolic abnormalities, the evidence is not conclusive in Mediterranean populations., Methods: A total of 3200 individuals were randomly selected from the residents of Monza (North Italy) to be representative of its general population for sex and age (25-74 years). The participation rate was 64%. At baseline and 10 years later, we measured waist circumference, office blood pressure, fasting blood glucose, serum triglycerides, serum HDL cholesterol and SUA., Results: The analysis was carried out in individuals without metabolic syndrome at baseline (N = 1192) when looking for incidence of metabolic syndrome, without impaired fasting glucose (IFG) at baseline (N = 1320) when looking for incidence of IFG and without diabetes mellitus at baseline (N = 1352) when looking for incidence of diabetes mellitus. Adjusting for confounders, a 1-SD increase of baseline SUA was not associated with and increased risk of new-onset metabolic syndrome, but with new-onset IFG [relative risk (RR) = 1.26, confidence interval (CI) 1.06-1.5, P = 0.01]. It was associated with a 29% increased risk of new-onset diabetes mellitus, that was more than twice in the highest as compared with the lowest quartile of baseline SUA (RR = 1.29, CI 0.98-1.7, P = 0.07, and RR = 2.16, CI 0.95-4.88, P = 0.07). Focusing the analysis on the individuals with age above the median value, SUA increase was significantly associated with an increased risk of new-onset metabolic syndrome, IFG and diabetes mellitus., Conclusion: SUA increase is associated with an increased risk of developing IFG and, in the population fraction with age above the median value, also metabolic syndrome and diabetes mellitus.

The aim of the present study is to investigate the predictive value of pulse pressure (PP) on cardiovascular events in the general population and in both sexes, separately. The study involved 2045 participants from the PAMELA study who underwent 24-hour ambulatory blood pressure (BP) monitoring. The participants were followed from the initial medical visit for a time interval of 137 ± 23 months. It was found that office, home, and 24-hour blood pressures were significantly higher in the individuals who experienced cardiovascular (CV) events. Office, 24-hour, and daytime PP were independent predictors of CV events after adjustment for main demographic and clinical parameters in the whole study population. Nighttime PP was an additional independent predictor in men. In conclusion, PP represents an important predictor of cardiovascular events in the general population, particularly among men. Daytime and 24-hour PP have greater predictive importance than nighttime PP in the general population., (©2018 Wiley Periodicals, Inc.)

Stratification of cardiovascular risk is of fundamental importance in white coat hypertension (WCH) to identify individuals in need of closer follow-up and perhaps antihypertensive drug treatment. In subjects representative of the general population of Monza (Italy), the risk of cardiovascular and all-cause mortality was assessed >16 years in stable and unstable WCH individuals, that is, those in whom ambulatory blood pressure (BP) normality was associated with a persistent or nonpersistent office BP elevation at 2 consecutive visits, respectively. Data were compared with those from an entirely normotensive group, that is, ambulatory and persistent office BP normality. Compared with the normotensive group, the risk of cardiovascular and all-cause death was not significantly different in unstable WCH, whereas in stable WCH the risk was increased also when data were adjusted for baseline confounders, including ambulatory BP (hazard ratio, 16; P=0.001 for cardiovascular death and 1.92; P=0.02 for all-cause death). At a multivariable analysis, office BP was among the factors independently predicting death, and results were superimposable with use of Monza population-derived and guidelines-derived cutoff values for ambulatory BP normality (125/79 and 130/80 mm Hg, respectively). Thus, only when office BP is persistently elevated does WCH reflect the existence of an abnormal long-term mortality risk. This means that in WCH office BP is prognostically relevant and that repeated collection of its values is clinically important to better define patient risk., (© 2015 American Heart Association, Inc.)

Aim: We estimated the risk of cardiovascular and all-cause mortality associated with left ventricular hypertrophy (LVH) as assessed by left ventricular mass (LVM), normalized by various indexation methods in 1716 representatives of the general population of Monza, enrolled in the Pressioni Arteriose Monitorate E Loro Associazioni study., Methods: LVH was defined according to four sex-specific criteria derived from the upper limits of normality for LVM index in the healthy normotensive fraction of the Pressioni Arteriose Monitorate E Loro Associazioni population. Death certificates were collected over an average 211 months of follow-up., Results: During follow-up, 89 fatal cardiovascular events and 264 all-cause deaths were observed. LVH prevalence rates in the whole population ranged from 14.2% [LVM/body surface area (BSA)] to 18.0% (LVM/height). Adjusted risk (for baseline covariates, including ambulatory blood pressure) of cardiovascular mortality was increased in patients with LVH, regardless of the indexation type: LVH/BSA [hazard ratio 3.19, 95% confidence interval (CI) 2.02-5.06, P < 0.0001], LVH/height (hazard ratio 2.39, 95% CI 1.51-3.78, P = 0.0002), LVH/height (hazard ratio 2.38, 95% CI 1.50-3.76, P = 0.0002), LVH/height (hazard ratio 2.28, 95% CI 1.44-3.60 P = 0.0004). Similar findings were observed for all-cause mortality and when LVM was assessed as a continuous variable. The fraction of patients (5%) classified into the LVH group by height, but not by BSA, had a mild increased LVM index and showed no increased risk., Conclusions: LVH, irrespective of indexation methods for LVM, confers an increased risk of cardiovascular and all-cause mortality in the general population. LVH, detected by height-based indexes, but not by BSA-based criteria, was not associated with increased mortality; this finding, however, was based on a small group of patients and will deserve further investigations.

Cardiovascular events have their greatest prevalence in the early morning period. Whether this is attributable to an arousal-dependent blood pressure (BP) increase is far from being clear. It is also not clear to what extent this phenomenon reflects overall 24-hour BP variability. In 2051 subjects (aged 25-74 years) representative of the population of Monza (Italy), we measured 24-hour ambulatory systolic BP (SBP) and calculated the difference between the 2-hour average values after morning arousal and the lowest 3 or average 2-hour values before arousal (morning BP surge 1 and 2, respectively). For either measure, we sought the relationship with a variety of indices of 24-hour SBP variability and collected information on (1) the occurrence of cardiovascular and all cause deaths during a follow-up of ≈16 years and (2) the appearance of echocardiographic left ventricular hypertrophy after 10 years from the baseline visit. Morning SBP surge 1 was directly related to indices of 24-hour SBP variability, including those made independent on the magnitude of the day-night SBP difference. There was a weak positive relationship between morning SBP surge 1 and the risk of cardiovascular and all-cause death, which disappeared after adjustment for confounders. This was the case also for development of left ventricular hypertrophy. Morning SBP surge 2 was smaller, inconsistently related to 24-hour SBP variability and not at all related to fatal events or new-onset left ventricular hypertrophy. In a white population, morning BP surge was not found to be an independent predictor of cardiovascular death, all-cause death, or development of high cardiovascular risk (as documented by new-onset cardiac damage) even when appropriately assessed by measures that reflect its association with 24-hour BP variability., (© 2014 American Heart Association, Inc.)

Objective: Serum uric acid (SUA) has been associated with an increased cardiovascular risk, but no conclusive evidence exists on whether it is an independent risk factor or a reflection of other risk factors to which it is related. We examined the relationship of SUA with a number of cardiovascular variables [including risk factors never evaluated before, such as organ damage and out-of-office blood pressure (BP)], as well as its prognostic relevance in the population., Methods: In 2045 participants of the Pressioni Arteriose Monitorate E Loro Associazioni study, we measured, along with SUA, metabolic, renal, and anthropometric variables, left-ventricular mass index, and office, home and ambulatory BP. Cardiovascular and all-cause mortality was assessed over a 16-year follow-up period, and measurements were repeated 10 years after the initial data collection., Results: Baseline SUA had a near-normal distribution, with a mean value of 4.9 ± 1.3 (SD) mg/dl and a significant direct relationship with BP and metabolic variables, serum creatinine and left-ventricular mass index. It was among the factors independently predicting new-onset home and ambulatory hypertension, the increased risk of developing these conditions for 1  mg/dl increase of SUA after adjustment for all available potential confounders being 34 and 29%, respectively (P = 0.015 and P = 0.014). An increase in SUA of 1  mg/dl also independently predicted cardiovascular and all-cause mortality, the fully adjusted increase in risk being 22% (P = 0.03) and 12% (P = 0.04), respectively., Conclusion: In the general population of the Pressioni Arteriose Monitorate E Loro Associazioni study, SUA correlated with a number of cardiovascular risk factors. Nevertheless, it independently predicts new-onset out-of-office hypertension, and long-term cardiovascular and all-cause mortality.

Aim: We assessed the value of three electrocardiographic (ECG) voltage criteria in detecting left ventricular hypertrophy (LVH) and in predicting cardiovascular events and all-cause mortality in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) population., Methods: At entry, 1549 individuals (age 50 ± 13 years, 50.5% men) underwent diagnostic tests including laboratory investigations, 24-h ambulatory blood pressure monitoring, and standard ECG and echocardiography., Results: The sensitivity of ECG criteria for LVH was lowest for Sokolow-Lyon voltage (1.5 and 0.78%), intermediate for Cornell voltage (20.5 and 19.0%), and highest for RaVL wave amplitude (26.0 and 36.2%), independently of whether left ventricular mass was indexed to body surface area or height, respectively. After adjustment for age, sex, night-time SBP, low-density lipoprotein and high-density lipoprotein cholesterol, serum glucose, BMI, smoking, and previous cardiovascular events, only Cornell voltage index [hazard ratio for a 0.1  mV increase: 1.050, 95% confidence interval (CI): 1.017-1.083, P < 0.003] predicted an increased risk of cardiovascular events as well as all-cause mortality. Furthermore, when the categorical relationship between ECG-graphic LVH and cardiovascular outcomes was investigated in multiple models, only LVH identified by the Cornell voltage index remained an independent predictor of cardiovascular events (hazard ratio = 2.466, CI 1.459-4.168, P = 0.0008) and all-cause deaths (hazard ratio = 2.984, CI 1.380-6.449, P = 0.005)., Conclusion: Despite the limited sensitivity of ECG voltage criteria in detecting LVH, our results show that Cornell voltage index may improve cardiovascular risk stratification in a general population independently of several confounding factors.

Background and Aims: Elevated values of body mass index (BMI) and waist circumference (WC) are associated with an augmented cardiovascular (CV) risk. It is debated, however, whether and to what extent this depends on the body fat increase 'per se' or on the related cardiometabolic alterations., Methods and Results: In 2005 subjects randomly selected from the general population of Monza (Italy), we assessed BMI, WC, office, home and 24 h blood pressure (BP), heart rate and metabolic variables. The impact of BMI and WC on the incidence of CV events, CV and all-cause mortality was estimated during a 148-month follow-up. Progressively higher values of BMI and WC were associated with a progressive increase in office, home and 24 h BP and in erratic BP variability (P < 0.0001 for trend). Metabolic variables were directly and significantly (P < 0.0001) related to BMI and WC, while an inverse significant relationship was detected with high-density lipoprotein (HDL)-cholesterol. The incidence of CV events, CV and all-cause deaths increased progressively from the lowest to the highest quintile of BMI and WC (P for trend always <0.005). Baseline BMI and WC higher by respectively 1 kg m⁻² and 1 cm were associated with an increased risk of CV events, CV and all-cause death by 8%, 12% and 7% (for baseline BMI) and 4%, 5% and 4% (for baseline WC), respectively. After adjustment for confounders, only the increased risk of CV death related to higher baseline BMI remained significant (hazard ratio (HR) 1.062, confidence interval (CI) 95% 1.003-1.126, P < 0.05)., Conclusion: The adverse prognostic impact of the accumulation of body fat is mediated by the associated haemodynamic and metabolic alterations. Baseline values of BMI, however, are an independent predictor of CV mortality., (Copyright © 2012 Elsevier B.V. All rights reserved.)

PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) is an epidemiological study, originally designed to determine the normality of home and ambulatory blood pressure values. The study was performed on 3,200 subjects, aged 25 to 74 years, randomly selected from the general population of Monza (Milan, Italy). In the study context we performed clinical, home and ambulatory blood pressure measurements, echocardiographic assessment of cardiac structure and function as well as laboratory examinations (glucose and lipids). Personal and family histories were collected. The same procedures were repeated 10 years later. During a 12-year follow-up, the incident cardiovascular events were validated. Cardiovascular and all-cause fatal events were collected for a 16-year follow-up. This article will review the main results of the PAMELA study, with particular emphasis on (1) the prognostic value of the different blood pressure measurements, (2) the relationships between metabolic variables and blood pressure and (3) the clinical relevance and prognostic importance of left ventricular mass values and alterations.

Background and Aim: Upper reference values of echocardiographic left-ventricular mass in the European population are based on scanty data mostly derived from northern European population-based samples. Furthermore, data in apparently healthy populations have included individuals with conditions affecting left-ventricular mass such as obesity, diabetes and masked hypertension. Thus, from 1051 individuals with normal office blood pressure (BP) belonging to the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study population, we selected a group of 675 sustained normotensive individuals in order to provide reliable echocardiographic reference values for defining the criteria of left-ventricular hypertrophy (LVH)., Methods: The study group (women 58%, mean age 42 ± 11 years) was identified after excluding individuals with isolated home or ambulatory hypertension, obesity, diabetes, cardiovascular diseases and echocardiographic examinations of insufficient quality to evaluate left-ventricular mass., Results: Sex-specific upper limits of normality [mean + 1.96 standard deviation (SD)] for left-ventricular mass, left-ventricular mass indexed to body surface area, heightand height were the following: 213 g, 114 g/m, 51 g/h, 123 g/h in men and 161 g, 99  g/m, 47 g/h, 101 g/h in women. In multivariate analyses, body size measures and ambulatory BP levels were the most important correlates of left-ventricular mass., Conclusions: Our investigation by providing upper reference limits of left-ventricular mass in a southern European population sample, carefully selected after exclusion of a large number of conditions affecting left-ventricular mass, may offer a contribution for revising diagnostic criteria of echocardiographic LVH currently recommended by European hypertension guidelines.

Obesity is associated with a higher risk of developing diabetes mellitus (DM), hypertension (HT), and left ventricular hypertrophy (LVH). The present study assessed in the general population the impact of body weight and visceral obesity on the development of alterations in glucose metabolism and cardiac structure, as well as of elevation in blood pressure. In 1412 subjects randomly selected and representative of the general population of Monza, we assessed twice (in 1990/1991 and 2000/2001) body mass index (BMI); waist circumference; office, home, and 24-hour ambulatory (24-hour) blood pressure, fasting glycemia, and left ventricular mass (echocardiography). New-onset high-risk conditions were DM; impaired fasting glucose; office, home, and 24-hour HT; and LVH. The incidence of new-onset DM; impaired fasting glucose; office, home, and 24-hour HT; and LVH increased progressively from the quintile with the lowest to the quintile with the highest BMI values. Adjusting for confounders, the risk of developing new-onset DM; impaired fasting glucose; office, home, and 24-hour HT; and LVH increased significantly for an increase of 1 kg/m(2) of BMI and 1 cm of waist circumference (respectively, 8.4% [P<0.01], 9.5% [P<0.0001], 4.2% [P<0.0001], 3.9% [P<0.001], 2.5% [P<0.05], and 5.1% [P<0.001] for BMI and 3.2% [P<0.001], 3.5% [P<0.0001], 1.8% [P<0.0001], 1.5% [P<0.0001], 1.4% [P<0.001], and 2.6% [P<0.0001]). These data provide evidence that an increase in BMI and waist circumference is associated with a linearly increased adjusted risk of developing conditions with high cardiovascular risk, such as DM, impaired fasting glucose, in- and out-of-office HT, and LVH.

Objectives: Previous studies have shown that left ventricular hypertrophy (LVH) represents a cardiovascular risk factor independently of clinic blood pressure (BP). The present study was aimed at determining the impact of LVH on the incidence of cardiovascular morbid and fatal events taking into account not only classical risk factors but also home and ambulatory BP values, which have been shown to have an important independent prognostic impact., Methods: In 1716 patients belonging to the 'Pressioni Arteriose Monitorate E Loro Associazioni' population of Monza, we quantified left ventricular mass index and identified LVH by standard cutoff values. We also measured clinic, home and 24-h ambulatory BPs together with serum glucose and lipids., Results: During a follow-up of 148 months, the rate of fatal and nonfatal (hospitalizations) cardiovascular events as well as of all-cause death was markedly greater (four-fold to five-fold) in patients as compared with those without LVH. In LVH individuals, the increased risk remained significant even when data were adjusted for a large number of other confounding factors including home BP, 24-h mean BP and ambulatory BP. Results were similar when left ventricular mass was indexed by height and body surface area. A 10% increase in left ventricular mass index was associated with a significant increase in cardiovascular risk or all-cause deaths. In multivariate analysis, left ventricular mass index was always an independent predictor of cardiovascular events and death for any cause., Conclusion: Our data provide evidence that LVH is an important risk factor even when the contribution of different BPs to risk is fully taken into account.

The hypothesis has been advanced that cardiovascular prognosis is related not only to 24-hour mean blood pressure but also to blood pressure variability. Data, however, are inconsistent, and no long-term prognostic study is available. In 2012 individuals randomly selected from the population of Monza (Milan), 24-hour ambulatory blood pressure (Spacelabs 90207) was measured via readings spaced by 20 minutes. Systolic and diastolic blood pressure variability was obtained by calculating the following: (1) the SD of 24-hour, day, and night mean values; (2) the day-night blood pressure difference; and (3) the residual or erratic blood pressure variability (Fourier spectral analysis). Fatal cardiovascular and noncardiovascular events were registered for 148 months. When adjusted for age, sex, 24-hour mean blood pressure, and other risk factors, there was no relationship between the risk of death and 24-hour, day, and night blood pressure SDs. In contrast, the adjusted risk of cardiovascular death was inversely related to day-night diastolic BP difference (beta coefficient=-0.040; P<0.02) and showed a significant positive relationship with residual diastolic blood pressure variability (beta coefficient=0.175; P<0.002). Twenty-four-hour mean blood pressure attenuation of nocturnal hypotension and erratic diastolic blood pressure variability all independently predicted the mortality risk, with the erratic variability being the most important factor. Our data show that the relationship of blood pressure to prognosis is complex and that phenomena other than 24-hour mean values are involved. They also provide the first evidence that short-term erratic components of blood pressure variability play a prognostic role, with their increase being accompanied by an increased cardiovascular risk.

Background: Studies in hypertensive patients suggest that ambulatory blood pressure (BP) is prognostically superior to office BP. Much less information is available in the general population, however. Obtaining this information was the purpose of the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study., Methods and Results: Office, home, and 24-hour ambulatory BP values were obtained in 2051 subjects between 25 and 74 years of age who were representative of the general population of Monza (Milan, Italy). Subjects were followed up for an average of 131 months, during which time cardiovascular and noncardiovascular fatal events were recorded (n=186). Office, home, and ambulatory BP values showed a significant exponential direct relationship with risk of cardiovascular or all-cause death. The goodness of fit of the relationship was greater for systolic than for diastolic BP and for night than for day BP, but its overall value was not better for home or ambulatory than for office BP. The slope of the relationship, however, was progressively greater from office to home and ambulatory BP. Home and night BP modestly improved the goodness of fit of the risk model when added to office BP., Conclusions: In the PAMELA population, risk of death increased more with a given increase in home or ambulatory than in office BP. The overall ability to predict death, however, was not greater for home and ambulatory than for office BP, although it was somewhat increased by the combination of office and outside-of-office values. Systolic BP was almost invariably superior to diastolic BP, and night BP was superior to day BP.

Background: The prevalence and clinical significance of isolated office (or white coat) hypertension is controversial, and population data are limited. We studied the prevalence of this condition and its association with echocardiographic left ventricular mass in the general population of the PAMELA (Pressione Arteriose Monitorate E Loro Associazioni) Study., Methods and Results: The study involved a large, randomized sample (n=3200) representative of the Monza (Milan) population, 25 to 74 years of age. Participants in the study (64% of the sample) underwent measurements of office, home, 24-hour ambulatory blood pressure, and echocardiography. Isolated office hypertension was defined as systolic or diastolic values >/=140 mm Hg or >/=90 mm Hg, respectively. Home and ambulatory normotension were defined according to criteria previously established from the PAMELA Study, for example, <132/83 mm Hg (systolic/diastolic) for home and 125/79 mm Hg for 24-hour average blood pressure. Treated hypertensive subjects were excluded from analysis that was made on a total of 1637 subjects. Depending on normotension being established on systolic or diastolic blood pressure measured at home or over 24 hours, the prevalence of isolated office hypertension ranged from 9% to 12%. In these subjects, left ventricular mass index was greater (P<0.01) than in subjects with normotension both in and outside the office. This was the case also for prevalence of left ventricular hypertrophy. Left ventricular mass index and hypertrophy were similarly greater in subjects found to have normal office but elevated home or ambulatory blood pressure ( approximately 10% of the population)., Conclusions: Isolated office hypertension has a noticeable prevalence in the population and is accompanied by structural cardiac alterations, suggesting that it is not an entirely harmless phenomenon. This is the case also for the opposite condition, that is, normal office but elevated home or ambulatory blood pressure, which implies that limiting blood pressure measurements to office values may not suffice in identification of subjects at risk.

Objective: Clinic blood pressure values are known to change according to seasonal influences. We therefore examined home and 24 h ambulatory blood pressure values to determine whether these measurements are also affected by the seasons., Design and Methods: In 2051 subjects of the Pressione Arteriose Monitorate E Loro Associazioni (PAMELA) study, we measured clinic (sphygmomanometric measurements), home (semi-automatic device) and ambulatory (Spacelabs 90207) systolic blood pressure, diastolic blood pressure and heart rate. Because the overall sample was evenly distributed over each month (except August), we were able to make a cross-sectional determination of whether the values differed between seasons. The corresponding heart rates were also evaluated., Results: As expected, summer was associated with the lowest clinic blood pressure and winter with the highest, and this was the case also for home and 24 h average blood pressure, although seasonal differences in the latter were less pronounced. Seasonal clinic, home and ambulatory blood pressure patterns were similar for normotensive subjects (n = 1152), untreated hypertensives (n = 540) and treated hypertensives (n = 359). Heart rate values did not differ by season., Conclusions: Seasonal influences on blood pressure are not limited to conventional measurements but characterize daily values as well. These effects are visible in both normal and elevated blood pressure values, regardless of the effect of antihypertensive drugs. This has implications both for the clinician and for studies aimed at evaluating the effects of antihypertensive treatment.